Synergism between natural products and antibiotics against infectious diseases.Abstract
Antibiotics have been effective in treating infectious diseases, but resistance to these drugs has led to the emergence of new and the reemergence of old infectious diseases, One strategy employed to overcome these resistance mechanisms is the use of combination of drugs, such as [beta]-lactams together with [beta]-lactamase inhibitors. Several plant extracts have exhibited synergistic activity against microorganisms. This review describes in detail, the observed synergy and mechanism of action between natural products including flavonoids flavonoids,
n.pl common plant pigment compounds that act as antioxidants, enhance the effects of vitamin C, and strengthen connective tissue around capillaries. and essential oils and synthetic drugs in effectively combating bacterial, fungal and mycobacterial infections. The mode of action of combination differs significantly than that of the same drugs acting individually; hence isolating a single component may lose its importance thereby simplifying the task of pharma industries.
[C] 2008 Elsevier GmbH. All rights reserved.
Keywords: Infectious diseases; Antibiotic resistance; Natural products; Resistance modifying agents; Synergy
Infectious diseases are caused by bacteria, viruses, parasites and fungi, and it is due to a complex interaction between the pathogen, host and the environment. The discovery of antibiotics had eradicated the infections that once ravaged the humankind. But their indiscriminate use has led to the development of multidrug-resistant pathogens. Around 90-95% of Staphylococcus aureus strains worldwide are resistant to penicillin (Casal et al., 2005) and in most of the Asian countries 70-80% of the same strains are methicillin resistant (Chambers, 2001). There are considerable reports on the progress of resistance to the last line of antibiotic defense, which has led to the search for reliable methods to control vancomycin-resistant Enter-ococci (VRE VRE
VRE Vancomycin-resistent enterococcus, see there ) and S. aureus (VRSA VRSA Vancomycin-resistant Staphylococcus aureus. Cf Vancomycin-resistant enterococcus. ), and methicillin-resistant S. aureus (MRSA MRSA Methicillin-resistant Staphylococcus aureus. See MARSA. ). In addition, the synergy between tuberculosis and the AIDS epidemic, along with the surge of multidrug-resistant isolates of Mycobacterium tuberculosis, has reaffirmed it as a primary health threat. Multidrug-resistant TB (MDRTB) is associated with high death rates (50-80%), spanning within a relatively short period of time (4-16 weeks) from diagnosis to death (WHO, 2004). In developing countries, MDRTB has increased in incidence and it interferes with TB control programs.
Plant-derived antibacterials are always a source of novel therapeutics. A quick look at the way nature, especially plants, are tackling the issue of infection will provide a deeper understanding of the methodology, which needs to be adopted for the design and development of novel highly effective antiinfectious agents in general, and antimycobacterials in particular. The scarcity of infective diseases in wild plants is in itself an indication of the successful defense mechanisms developed by them. Plants are known to produce an enormous variety of small-molecule (MW < 500) antibiotics--generally classified as 'phytoalexins'. Their structural space is diverse having terpenoids, glycosteroids, flavonoids and polyphenols. Be that as it may, it is interesting to note that most of these small molecules have weak antibiotic activity--several orders of magnitudes less than that of common antibiotics produced by bacteria and fungi. In spite of the fact that plant-derived antibacterials are less potent, plants fight infections successfully. Hence, it becomes apparent that plants adopt a different paradigm--"synergy"--to combat infections. A case in study to reiterate this view is the observation on the combined action of berberine berberine /ber·ber·ine/ (bur´bur-en) an alkaloid from species of Berberis and related plants, and from Hydrastis canadensis; and 5'-methoxyhydnocarpin, both of which are produced by berberry plants. Berberine, a hydrophobic alkaloid that intercalates into DNA DNA: see nucleic acid.
or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. , is ineffective as an antibacterial because it is readily extruded by pathogen--encoded multidrug resistance pumps (MDRs). Hence, the plant produces 5'-methoxyhydnocarpin that blocks the MDR MDR,
n See multidrug resistance.
n the abbreviation for minimum daily requirement, specifically the Minimum Daily Requirements for Specific Nutrients compiled by the United States Food and Drug Administration. pump (Stermitz et al., 2000). This combination is a potent antibacterial agent (Lewis and Ausubel, 2006). Using this cue, Ball et al. (2006) reported that covalently linking berberine to IN[F.sub.55], an inhibitor of MDR, results in a highly effective antibiotic that readily accumulates in bacteria.
This paper introduces and provides examples of synergistic interactions of the secondary metabolites of plants with antibiotics in the treatment of infectious diseases. The understanding of the molecular mechanisms of synergy would pave a new strategy for the treatment of infectious diseases, overcome drug-resistant pathogens, and decrease the use of antibiotics and hence the side effects created by them.
Synergy towards bacterial infection
The development of antibiotic resistance can be natural (intrinsic) or acquired and this can be transmitted within same or different species of bacteria. Natural resistance is achieved by spontaneous gene mutation and the acquired resistance is through the transfer of DNA fragments like transposons from one bacterium to another. Bacteria gains antibiotic resistance due to three reasons namely: (i) modification of active site of the target resulting in reduction in the efficiency of binding of the drug, (ii) direct destruction or modification of the antibiotic by enzymes produced by the organism or, (iii) efflux efflux Medtalk That which flows outward of antibiotic from the cell (Sheldon, 2005). One strategy employed to overcome these resistance mechanisms is the use of combination of drugs. Inhibitors of [beta]-lactamases have been long known and they are administered with antibiotics as co-drugs. The most successful strategy that has been adopted to overcome the resistance to penicillinase is by administering clavulinic acid, with the drugs sulbactam and tazobactam (Lee et al., 2003b). But the frequent use of clavulanate has led to the emergence of resistant bacterial strains (Blasquez et al., 1993; Enright et al., 2002). The appearance of extended spectrum [beta]-lactamase and resistance against IMP-1 (a new [beta]-lactam), cephalosporins and carbapenems have further necessitated the need for developing new [beta]-lactamase inhibitors (Chaibi et al., 1999).
[FIGURE 1 OMITTED]
The secondary metabolites from plant are good sources for combination therapy. As shown in Fig. 1, there are a wide range of phytochemicals which act as multidrug resistance modifiers depicted and their mechanism of action is discussed in the following sections.
Receptor or active site modification
For selective antimicrobial action the target site plays a vital role. Introduction of mutations in the target site alters it, leading to a reduction in the activity of the drug towards the microbe. Two examples of receptor (target) modification are (a) mutations in RNA polymerase and DNA gyrase, rendering rifamycins and quinolones inactive (Heep et al., 2000; Willmott and Maxwell, 1993), and (b) modification in the structural confirmation of penicillin-binding proteins (PBPs) resulting in the development of penicillin resistance. The most important example of a target change is the production of PBP2a, an altered transpeptidase.
[beta]-Lactam antibiotics (BLA) are highly specific inhibitors of the metabolism of peptidoglycan peptidoglycan /pep·ti·do·gly·can/ (pep?ti-do-gli´kan) a glycan (polysaccharide) attached to short cross-linked peptides; found in bacterial cell walls.
n. and they target the membrane bound D,D-peptidase domain of the PBPs (Ghysen, 1994). These peptidases cross link the bacterial peptidoglycan cell wall which maintain the integrity of the latter (Berger-Bachi and Rohrer, 2002). S. aureus acquires resistance to all penicillins and cephalosporins with the acquisition of the gene mecA (Enright et al., 2002), which is carried on a large genetic element called the staphylococcal cassette chromosome mec (SCC SCC - strongly connected component mec). This is acquired by a parasexual parasexual /para·sex·u·al/ (-sek´shoo-al) accomplished by other than sexual means, as by genetic study of in vitro somatic cell hybrids. horizontal transfer from a coagulase-negative Staphylococcus sp. (Ito et al., 2003). The house keeping PBPs are BLA sensitive whereas the MecA (PBP 2a) have reduced affinity to BLA (Lu et al., 1999). A number of BLAs, including modified cephalosporins (Vouillamoz et al., 2004), carbapenems (Kurazono et al., 2004) and trinem (Ferrari et al., 2003) have been designed with enhanced activity against PBP2a.
Another approach to overcome resistance is to include inhibitors of the PBP2a in the treatment strategy. A number of reports are available listing the synergistic interactions of BLA with natural compounds to overcome resistant microorganisms. The later includes catechins (Camellia camellia (kəmēl`yə) [for G. J. Kamel, a Moravian Jesuit missionary], any plant of the genus Camellia in the tea family, evergreen shrubs or small trees native to Asia but now cultivated extensively in warm climates and in sinesis) (Takahashi et al., 1995), EGCg (Epigallocatechin gallate) from green tea (Suresh et al., 1997), tellimagrandin I and rugosin B from rose red (Rosa canina) (Shiota et al., 2000), baicalin from Scutellaria amoena (Liu et al., 2000) and corilagin from Arctostaphylos uva-ursi (Shimizu et al., 2001). Corilagin, a polyphenol polyphenol
Any of various alcohols containing two or more benzene rings that each have at least one hydroxyl group (OH) attached. Many polyphenols occur naturally in plants and some kinds, such as the flavonoids and tannins, are believed to be beneficial from Arctostaphylos uva-ursi is found to markedly reduce the Minimum Inhibitory Concentration minimum inhibitory concentration Lab medicine The minimum antibiotic concentration needed to inhibit bacterial growth from a clinical isolate–eg, a bloodborne infection, which is a form of antimicrobial susceptibility testing. Cf Minimum bactericidal concentration. (MIC) of [beta]-lactams in MRSA. Shimizu et al. (2001) suggest that there are two possibilities regarding the mechanism of action of corilagin, namely inhibition of PBP2a activity or inhibition of its production. They later reported that the PBP2a of MRSA cells grown in the presence of corilagin or tellimagrandin I lost its ability to bind to to contract; as, to bind one's self to a wife s>.
See also: Bind BOCILLIN FL, a fluorescent-labeled benzylpenicillin benzylpenicillin /ben·zyl·pen·i·cil·lin/ (ben?zil-pen?i-sil´in) penicillin G.
See penicillin G.
see penicillin G. (Shiota et al., 2004).
Studies through reverse transcription-PCR and a semiquantitative PBP2a latex agglutination agglutination, in biochemistry
agglutination, in biochemistry: see immunity.
agglutination, in linguistics
agglutination, in linguistics: see inflection. assays indicted that, EGCg did not suppress either the mRNA expression of PBP2a or its production. But the synergy between EGCg and BLA was achieved since both directly or indirectly attacked the same target site namely, peptidoglycan present on the cell wall (Yam et al., 1998; Zhao et al., 2001). EGCg was found to synergistically syn·er·gis·tic
1. Of or relating to synergy: a synergistic effect.
2. Producing or capable of producing synergy: synergistic drugs.
3. enhance the activity of carbapenems against MRSA but the mechanism of action has not been studied (Hu et al., 2002). Nicolson et al. (1999) have shown that diterpene di·ter·pene
Any of a class of terpenes containing 20 carbon atoms and 4 branched methyl groups.
highly irritant plant diterpenoid esters, e.g. daphnane, tigliane, ingemane. derivative 416 potentiated the activity of methicillin by significantly reducing the expression of PBP2a.
There is a wide list of phytochemicals which act as inhibitors and a few of them are glycosylated flavones suppressing topoisomerase IV activity (Bernard et al., 1997), myricetin inhibiting DnaB helicase (Griep et al., 2007), allicin allicin /al·li·cin/ (al´i-sin) an oily substance, extracted from garlic, which has antibacterial activity.
allicin inhibiting RNA RNA: see nucleic acid.
in full ribonucleic acid
One of the two main types of nucleic acid (the other being DNA), which functions in cellular protein synthesis in all living cells and replaces DNA as the carrier of genetic synthesis (Feldberg et al., 1988) and compounds from the plant Polygonum Polygonum
genus of toxic plants in the family Polygonaceae, called collectively smartweeds. Some cause nitrate-nitrite poisoning, some cause photosensitization; includes P. aviculare (wireweed), P. convolvulus (Fallopia convolvulus), P. esculentum, P. cuspidatum inhibiting bacterial DNA primase (Hegde et al., 2004). These phytochemicals when used in combination with other classes of antibiotics have the potential to either inhibit the modified targets or exhibit a synergy by blocking one or more of the other targets in the metabolic pathway. Table 1 lists the synergy observed between natural products and commercial antibiotics against bacteria.
Table 1. Synergism between natural products and antibiotics against bacterial infection Natural product Antibiotics Microorganisms Carnosic acid Tetracycline Tet (K) possessing strains Carnosol Erythromycin Msr (A) MSSA [beta]- Epigallocatechin- Ampicillin/sulbactam lactamase producing gallate (EGCg) S. aureus EGCg Penicillin Penicillinase producing S. aureus Ampicillin EGCg Carbapenems MRSA EGCg [beta]-Lactam MSSA, MRSA EGCg Tetracycline S. aureus with Tet (K) MDR pump Tea catechin Oxacillin MRSA Totatrol Methicillin MSSA, MRSA Berberine 5'-Mehoxyhydnocarpin Nor (A) mutant (Berberis plant) Green tea extract Levofloxacin Escherichia coli 0157 in gnotobiotic mouse model Craneberry juice - Helicobacter pylori extact Blueberry, Grape seed and oregano extract Oregano and Lactic acid Vibrio cranberry extract parahemolyticus Isoflavone Mupirocin MRSA Bidwillon B from Erythrina variegata [alpha]-Mangostin Vancomycin MRSA and Vancomycin enterococci Gentamycin Aqueous crude Tetracycline Streptococcus sanguis, khat extracts Fusobacterium nucleatum Corilagin from [beta]-Lactams such as MRSA Arctostaphylos oxacillin. cefmetazole uva-ursi Baicalin [beta]-Lactam antibiotics MRSA Tellimagrandin I [beta]-Lactams MRSA from rose red tree, Rugosin B from [beta]-Lactams MRSA rose red tree Diterpenes from Tetracycline S. aureus possessing Lycopus europaeus Tet (K), Msr (A) MDR pumps Erythromycin A penta- Erythromycin S. aureus possessing Tet substituted (K), pyridine from Nor (A) MDR pumps Jatropha elliptica Ciprofloxacin Pomegranate chloramphenicol, MRSA extract gentamicin, ampicillin, tetrcycline, and oxacillin MSSA Myricetin Amoxicillin/clavulanate, Extended-spectrum amplicillin/sulbactam and -lactmases cefoxitin (ESBL) producing Isopimaric acid Reserpine MRSA from Pinus nigra Totarol, Isonicotinic acid hydrazide Mycobacterium ferulenol (INH) intracellulare, (from Ferula M. smegmatis, communis) and M. xenopei and plumbagin (from M. chelonei Plumbago zeylanica) Erybraedin A or Vancomycin Vacomycin-resistant eryzerin C enterococci (VRE) and isolated MRSA S. mutans, non- from the roots of susceptible E. coli Erythrina and C. albicans zeyheri, Butylated hydroxyanisole, (BHA) green tea Sopheoraflavanone Vancomycin MRSA G hydrochloride, fosfomycin, methicillin, cefozonam, gentamicin, minocycline and levofloxacin Essential oil-1, Antibiotics Bacterial species 8 cineol, linalool, alpha-terpineol and terpinen-4-o1 from Melaeuca leucodendron and oil from Ocimum gratissimum Novoimanin from Ampicillin, kanamycin, Staphlococcus Hypericum fusidic acie and rifocin aureus 209 perforatum L. Natural product Mechanism of action References Carnosic acid Inhibit the MDR pumps, Oluwatuyi et Tet (K) and Msr (A) al. (2004) Carnosol Epigallocatechin- Inhibits [beta]-lactamase Hu et al. (2001) gallate (EGCg) EGCg Inhibits penicillinase Zhao et al. (2001) EGCg - Hu et al. (2002) EGCg EGCg directly binds t o the Yoshida et al. (1990) peptidoglycan and inhibits cell wall EGCg Blocks MDR efflux pumps Roccaro et al. (2004) Tea catechin - Takahashi et al. (1995) Totatrol PBP 2a production Pao et al. (1998) Berberine (Berberis Inhibits Nor (A) MDR Smith et al. (2005) plant) pump Green tea extract - Isogai et al. (2001) Craneberry juice - Vattem et al. extract Blueberry, (2005) Grape seed and oregano extract Oregano and - Lin et al. (2005) cranberry extract Isoflavone Bidwillon B and mupirocin Sato et al. (2004) Bidwillon B from inhibited the Erythrina variegata incorporation of thymidine, uridine, glucose and isoleucine [alpha]-Mangostin - Sankagami et al. (2005) Aqueous crude - Al-hebshi et al. khat extracts (2006) Corilagin from Inhibits PBP2a production Shimizu et al. (2001) Arctostaphylos or activity uva-ursi Baicalin Inhibits [beta]-lactamase Liu et al. (2000) Tellimagrandin I - Shiota et al. (2000) from rose red tree, Rugosin B from - Shiota et al. (2000) rose red tree Diterpenes from Blocks MDR pumps Gibbons et al. (2003) Lycopus europaeus A penta- Blocks MDR pumps Marquez et al' (2005) substituted pyridine from Jatropha elliptica Pomegranate Blocks Nor (A) pump Braga et al. (2005) extract Myricetin - Lin et al. (2005) Isopimaric acid Blocks Nor (A) pump Simonetti et al. from Pinus nigra (2004) Totarol, ferulenol - Mossa et al. (2004) (from Ferula communis) and plumbagin (from Plumbago zeylanica) Erybraedin A or - Sato et al. (2004) eryzerin C isolated from the roots of Erythrina zeyheri, Butylated - Shiota et al. (2004) hydroxyanisole, (BHA) green tea Sopheoraflavanone - Sakagami et al. (1998) G Essential oil-1, 8 - Jedlickova et al. cineol, linalool, (1992) alpha-terpineol and terpinen-4-o1 from Melaeuca leucodendron and oil from Ocimum gratissimum Novoimanin from - Avenirova et al. Hypericum (1975) perforatum L.
Enzymatic degradation and modification of the drug
Bacterial cells spend a considerable amount of energy to resist antibiotics. One way the cells achieve active drug resistance is by the synthesis of enzymes that selectively target and destroy or modify the antibiotics. The various enzymatic strategies that lead to antibiotic inactivation are through hydrolysis, group transfer or redox redox (rē`dŏks): see oxidation and reduction. mechanisms (Wright, 2005). Hydrolytically susceptible chemical bonds (such as ester or amide bonds) are cleaved by enzymes that are expressed by the resistant organisms. The modification of the active group in the drug through acylation acylation
introduction of an acyl radical into the molecules of a compound. , phosphorylation phosphorylation, chemical process in which a phosphate group is added to an organic molecule. In living cells phosphorylation is associated with respiration, which takes place in the cell's mitochondria, and photosynthesis, which takes place in the chloroplasts. , glycosylation, nucleotidylation or ribosylation by the organism could make the former innocuous. Redox mechanism involves the oxidation-reduction of the antibiotics leading to the information of inactive compound (Wright, 2005).
[beta]-Lactamases are one such family of enzymes that cleave the [beta]-lactam ring of cephalosporins and penicillins. They act through the serine residue in the active site of the enzyme or through the activation of the Z[n.sup.2]+center (Bush, 1998, 2002). inhibitors of [beta]-lactamases have long been known. The combination of ampicillin ampicillin (ăm'pĭsĭl`ĭn), a penicillin-type antibiotic that is effective against both gram-negative microorganisms and gram-positive microorganisms such as Escherichia coli. and sulbactam inhibits [beta]-lactamase and increases the spectrum of activity of the former. Zhao et al. (2002) have confirmed that EGCg inhibits the penicillinase produced by S. aureus thereby restoring the activity of penicillin. It acts in a dose-dependent manner, with 50% inhibition at a concentration of 10[micro]g/ml. The combination of ampicillin and sulbactam is effective but is not powerful enough against MRSA and strains producing [beta]-lactamases. When they are further combined with EGCg, the MI[C.sub.90] of this combination is reduced to 4mg/ml from an initial value of 16mg/ml (Hu et al., 2001). The potent synergy between these concoctions could possibly have clinical use.
Reduced accumulation of the antibiotic within the bacterial cell
Reduced accumulation of the antibiotic inside the microorganism microorganism /mi·cro·or·gan·ism/ (-or´gah-nizm) a microscopic organism; those of medical interest include bacteria, fungi, and protozoa. could be because of two reasons namely decreased permeability of the drug through the outer membrane of the cell or, the efflux of the accumulated drug out of the cell.
Decreased outer membrane permeability
Cells of Gram-negative bacteria are surrounded by an additional membrane (outer membrane, OM), which provide them with a hydrophilic hydrophilic /hy·dro·phil·ic/ (-fil´ik) readily absorbing moisture; hygroscopic; having strongly polar groups that readily interact with water.
adj. surface and functions as a permeability barrier for many external hydrophobic agents including detergents, hydrophobic dyes and antibiotics (Helander et al., 1997a; Vaara, 1992, 1999; Nikaido and Vaara, 1985). This barrier is due to the presence of lipopolysaccharide lipopolysaccharide /lipo·poly·sac·cha·ride/ (-pol?e-sak´ah-rid)
1. a molecule in which lipids and polysaccharides are linked.
2. (LPS LPS - Sets with restricted universal quantifiers.
["Logic Programming with Sets", G. Kuper, J Computer Sys Sci 41:44-64 (1990)]. ) molecules in the outer leaflet (Nikaido, 2003; Nikaido and Vaara, 1985), which makes up to 75% of the total membrane surface and forms specific contacts with integral outer membrane proteins (Omp), such as porins (Alexander and Rietschel, 2001; Bos and Tommassen, 2004). Bacterial lipoproteins anchor the OM to the periplasmic periplasmic /peri·plas·mic/ (-plas´mik) around the plasma membrane; between the plasma membrane and the cell wall of a bacterium. peptidoglycan layer (Brade et al., 1999). Divalent divalent /di·va·lent/ (di-va´lent) bivalent; carrying a valence of two.
di·va cations are tightly associated with the anionic membrane-proximal regions of the LPS molecules, strengthening the structure (Vaara, 1992). Some Gram-negative bacteria are known to contain glycosphingolipids instead of LPS in their OM (Kawahara et al., 1991).
Bivalent bivalent /bi·va·lent/ (bi-va´lent)
2. the structure formed by a pair of homologous chromosomes by synapsis along their length during the zygotene and pachytene stages of the first meiotic prophase. cations contribute to the stability of the OM by creating electrostatic interactions between the proteins and LPS (Leive, 1965; Vaara, 1981, 1999). EDTA EDTA: see chelating agents. is a chelator chelator A chemical–eg, EDTA that binds metal ions from solutions. See Chelation therapy. which sequesters these ions. Treatment with EDTA releases a large proportion of LPS from the OM, exposing the phosholipids and creating a hydrophobic pathway (Leive, 1965). EDTA has been reported to potentiate po·ten·ti·ate
1. To make potent or powerful.
2. To enhance or increase the effect of a drug.
3. To promote or strengthen a biochemical or physiological action or effect. the activity of cell wall degrading agents including lysozyme lysozyme: see immunity.
An enyme that was first identified and named by Alexander Fleming, who recognized its bacteriolytic properties. , nisin nisin
an antibiotic substance isolated from cultures of lactic acid producing streptococci and reputed to have antibacterial activity against gram-positive bacteria. and biocides (Leive, 1965; Vaara, 1981; Walsh et al., 2003a, b). In addition, there are a wide range of permeabilizers such as polycationic polymyxin B nonapeptide, which interact with and disorganize dis·or·gan·ize
tr.v. dis·or·gan·ized, dis·or·gan·iz·ing, dis·or·gan·iz·es
To destroy the organization, systematic arrangement, or unity of. the anionic LPS thereby sensitizing the bacteria to hydrophobic antibiotics (Vaara and Vaara, 1983a, b). Essential oils such as thymol thy·mol
A white crystalline aromatic compound derived from thyme oil and other oils or made synthetically and used as an antiseptic, a fungicide, and a preservative. and carvacrol car·va·crol
An aromatic phenolic compound, C10H14O, found in plants such as oregano and savory and used in flavorings and fungicides. as membrane permeabilizers (Fig. 1) have been studied by Helander and co-workers (Helander et al., 1998). Magnesium chloride disrupts the activity of EDTA and polyethylenimine, but it has no effect on the activity of carvacrol or thymol. This indicates that essential oils neither chelate chelate
Any of a class of coordination or complex compounds consisting of a central atom of a metal (usually a transition element) attached to a large molecule (ligand). nor intercalate with LPS by replacing the divalent cations which stabilize the OM (Helander et al., 1997a; Vaara, 1992).
The development of multidrug resistance pumps (MDRs) is one of the defense mechanisms employed by bacteria against the accumulation of antimicrobial drugs inside the cell. These efflux pumps either use ATP hydrolysis or ion gradient to expel the antibiotics. They are grouped into five major classes namely, the adenosine triphosphate triphosphate /tri·phos·phate/ (tri-fos´fat) a salt containing three phosphate radicals.
A salt or ester containing three phosphate groups. (ATP ATP: see adenosine triphosphate.
in full adenosine triphosphate
Organic compound, substrate in many enzyme-catalyzed reactions (see catalysis) in the cells of animals, plants, and microorganisms. )-binding cassette (ABC) superfamily superfamily /su·per·fam·i·ly/ (soo´per-fam?i-le)
1. a taxonomic category between an order and a family.
2. (Veen and Konings, 1998; Veen et al., 1996), the major facilitator superfamily (MFS MFS Medicare fee schedule ) (Pao et al., 1998), the small multidrug resistance family (SMR (Specialized Mobile Radio) The communications services used by police, ambulances, taxicabs, trucks and other delivery vehicles. Throughout the U.S., approximately 3,000 independent operators are licensed by the FCC to offer this service, which provides always-on ) (Paulsen et al., 1996), the resistance-nodualtion-cell division RND superfamily (Saier et al., 1994) and the multidrug and toxic compound extrusion (MATE) family (Brown et al., 1999). Of these the RND, SMR and MATE classes are unique to prokaryotes (Lynch, 2006).
The efflux pumps of S. aureus Qac A (MFS family), Smr (SMR family) and Nor A (MFS family) have been well characterized. The Nor A efflux pump is responsible for fluoroquinolone resistance (Yoshida et al., 1990); Qac A is responsible for acriflavine ac·ri·fla·vine
A brown or orange powder derived from acridine and used as a topical antiseptic.
an antiseptic dye used for topical application; average strength is 1:1000 to 1:8000 solution. and ethidium bromide resistance (Littlejohn et al., 1992) and Tet (K) and Msr (A) transporters are specific to tetracycline tetracycline (tĕ'trəsī`klēn), any of a group of antibiotics produced by bacteria of the genus Streptomyces. They are effective against a wide range of Gram positive and Gram negative bacteria, interfering with protein and macrolide efflux (Renau et al., 1999). Renau et al. (1999) have developed the first broad-spectrum RND pump-inhibitor, M[C.sub.-207,110] (phenylalanyl-arginyl-[beta]-naphthy-lamide), which potentiates the activity of levofloxacin, particularly the RND pumps against wild-type P. aeruginosa. Although these compounds are not effective antimicrobial agents by themselves, they reverse the resistance by blocking the efflux pumps.
Secondary metabolites of plants have shown to possess considerable activity against Gram-positive bacteria but not against Gram-negative species or yeast. In Gram-negative species, the outer membrane is a fairly effective barrier for amphiphatic compounds (Lewis and Lomovskaya, 2001). A set of multidrug resistance pumps (MDRs) extrude amphiphatic toxins across the outer membrane (Lewis, 2001; Nikaido, 1999). Tegos et al. (2002) have shown that MDR inhibitors M[C.sub.207,110] and IN[F.sub.271] dramatically increase the effectiveness of a set of 11 plant antimicrobials (e.g. Rhein, resveratrol res·ver·a·trol
A natural compound found in grapes, mulberries, peanuts, and other plants or food products, especially red wine, that may protect against cancer and cardiovascular disease by acting as an antioxidant, antimutagen, and , gossypol gossypol /gos·sy·pol/ (gos´i-pol) a toxin found in cottonseed and detoxified by heating; it has male antifertility properties, apparently having its effects in the seminiferous tubules.
n. , berberine) against Gram-negative bacteria. By contrast, certain plant-derived natural products can modulate MDR. For example carnosic acid (from Rosmarinus officinalis) (Oluwatuyi et al., 2004), and a penta substituted pyridine pyridine (pĭr`ĭdēn) or azine (ăz`ēn), C5H5N, colorless, flammable, toxic liquid with a putrid odor. It melts at −42°C; and boils at 115.5°C;. (from Jatropha elliptica) (Marquez et al., 2005), act as inhibitor of the Nor A efflux pump and restore the level of intracellular drug concentration.
Two isopirmarane diterpenes from the Lycopus europaeus enhance the activities of tetracycline and erythromycin erythromycin (ĭrĭth'rōmī`sĭn), any of several related antibiotic drugs produced by bacteria of the genus Streptomyces (see antibiotic). against two strains of S. aureus. Otherwise these strains are highly resistant to these antibiotics due to the presence of multidrug efflux pumps, Tet (K) and Msr (A) (Gibbons et al., 2003). EGCg increases the accumulation of tetracycline in S. aureus strains by inhibiting the Tet (K) and Tet (B) efflux pumps (Roccaro et al., 2004). EGCg also enhances the activity of norfloxacin against a Nor A harboring S. aureus strain (Gibbons et al., 2004). Isoflavones isolated from Lupinus argenteus act in synergy with norfloxacin against a mutant of S. aureus by inhibiting the MDR pump. Reserpine reserpine (rĕsûr`pēn), alkaloid isolated from the root of the snakeroot plant (Rauwolfia serpentina), a small evergreen climbing shrub of the dogbane family native to the Indian subcontinent. , a plant alkaloid potentiates the activity of fluoroquinolones (Schmitz et al., 1998) and tetracycline against multidrug-resistant S. aureus strain (Gibbons and Udo, 2000). Reserpine has been shown to inhibit LmrA, the MDR ABC efflux system of L. lactis (Marquez et al., 2005), but unfortunately bacterial resistance to this natural product has been observed (Ahmed et al., 1993). The calcium channel antagonist verapamil verapamil /ve·rap·a·mil/ (ve-rap´ah-mil) a calcium channel blocker that dilates coronary arteries and decreases myocardial oxygen demand, used as the hydrochloride salt in the treatment of angina pectoris and of hypertension and the , another known inhibitor of P-gp, also inhibits several bacterial ABC efflux pumps, including LmrA (Lee et al., 2003a; Pasca et al., 2004; Choudhuri et al., 2002).The efflux pump inhibitors from natural sources discussed so far can be co-administered with the antibiotic to decrease the degree of resistance of the bacteria to the drugs, reverse the acquired resistance of the microorganism or reduce the emergence of resistant bacterial strains (Marquez et al. 2005).
Synergy and MDRTB therapy
Tuberculosis has established itself as a primary health threat. Few new agents are in development today for treating TB, and none has been designed specifically to shorten the treatment regimen and provide the break-through in therapy that is sorely needed if the epidemic is to be brought under control. Drug design targeting the latency stage and synergistic interaction between the various drug candidates might prove to be good alternatives.
Antimycobacterial treatment has always been a combination therapy. Today's TB treatment, which dates back to 1970s, is long and burdensome, requiring at least 6 months of multidrug chemotherapy. Novel targets are being identified alongside developing better drugs for known targets. Synergistic interaction between these drug like molecules is also gaining sufficient attention from the researchers (Chen et al., 2006; Vinogradova et al., 1999). Combination studies with natural products from plants and synthetic drugs are limited to few reports. Totarol ferulenol and plumbagin were observed to increase the potency of isonicotinic acid hydrazide hy·dra·zide
An acyl derivative of hydrazine.
A compound formed by combining hydrazine with an acyl compound. Hydrazides are important in the manufacture of certain medicines. by fourfold against Mycobacterium sp. (Mossa et al., 2004). A napthoquinone 7-methyljuglone, isolated from the roots of Euclea natalensis in combination with isoniazid isoniazid (ī'sōnī`əzĭd), drug used to treat tuberculosis. Also known as isonicotinic acid hydrazide, isoniazid is the most effective antituberculosis drug currently available. or rifampicin rifampicin /rif·am·pi·cin/ (rif´am-pi-sin) rifampin.
a derivative of rifamycin; an antibacterial and antifungal agent used in the treatment of mycobacterial infections, actinomycosis and histoplasmosis. resulted in a four-to sixfold reduction in the MIC of the synthetic drugs (Bapela et al., 2006). An aqueous extract from Cuminum cyminum seeds produced a 35% enhancement of rifampicin levels in rat plasma. This activity was due to a flavonoid glycoside, 3', 5-dihydroxyflavone-7-0-[beta]-D-galacturonide 4'-0-[beta]-D-glucopyranoside, found in the natural product. The altered bioavailability profile of rifampicin could be attributed to the permeation enhancing effect of this glycoside (Sachin et al., 2007).
Antifungal agents and synergism
Fungi have higher number of chromosomes and complex nuclear membrane, cell organelles and cell wall composition. Since the last three decades, the rate of death every year due to fungal infections has risen significantly. With the increased use of antifungal agents there is an increase in the number and variety of fungal strains resistant to these drugs. Also the present antifungal therapeutics is often toxic. Alternative therapy needs to be developed to suppress the emergence of antifungal resistance. This can be achieved by the use of combinations of existing agents or the development of new, safer and effective agents primarily from plant sources which can exhibit synergy with drugs. Table 2 lists the reported synergy observed between natural products and drugs towards fungal species.
Table 2. Combination of natural products and synthetic drugs to combat fungal infection Nautral products Synthetic Fungal species References drugs Allium sativum Ketaconazole T. rubrum, Pyun and T. Erinacei and Shin T. soudanense (2006) Essential oil fraction of Ketaconazole Aspergillus Shiota et P. graveolens and its niger and al. (2000) main components, A. flavus geraniol and citronellol Essential oil from Ketaconazole T. erinacei, Shin and Agastache T. mentagrophytes, Kang rugosa and its main T. rubrum, (2003) component, T. schoenleinii estragole and T. soudanense Euphorbia characias Ketoconazole Candida Giordani latex albicans et al. (2001) Scopoletin, vanillin, Fusarium Carpinella 4-hydroxy- verticillioides et al. 3-methoxycinnamaldehyde, (2005) and + Pinoresinol isolated from Melia azedarch L. fruits Santolina oil Clorimazole Candida Suresh et albicans al. (1997) Anethole Miconazole Candida Lee and albicans Kin (1999) Amphotericin B Essential oil from Amphotericin Candida Giordani Thymus B albicans et al. vulgaris thymol (2004) chemotype
Scopoletin, a hydroxycoumarin isolated from the fruits of Melia azedarach L. enhances the effect of two synthetic drugs namely, mancozeb and carboxin against Fusarium Fusarium
a genus of fungi; some species are plant pathogens and some are opportunistic infectious agents of humans and animals. Many also produce trichothecene toxins which cause poisoning of animals if the infected material, usually stored feed, is eaten. verticillioides (Carpinella et al., 2005). Synergistic interaction between EGCg and antimycotics such as amphotericin B and fluconazole fluconazole /flu·con·a·zole/ (floo-kon´ah-zol) a triazoleantifungal used in the systemic treatment of candidiasis and cryptococcal meningitis.
n. has been reported against C. albicans. EGCg possibly attacks the cell membrane and causes cell lysis (Toyoshima et al., 1993). Amphotericin B below the minimum fungicidal concentration (MFC) is known to enhance the permeability of catechin catechin /cat·e·chin/ (kat´e-kin) an astringent principle from the heartwood of Acacia catechu (catechu) and Uncaria gambier (gambir). through the fungal membrane, thereby increaseing its uptake into the cell (Hirasawa and Takada, 2004). A few herbal essential oils (Shin and Lim, 2004) particularly estragole, an oil from Agastache rugresa (Shin and Kang, 2003), Tea tree (Melaleuca alternifolia) oil (Hammer et al., 2000) and volatile oils from Allium allium
Any plant of a large genus (Allium) of bulbous, onion- or garlic-scented herbs of the lily family, including the onion, garlic, chive, leek, and shallot. Allium species are found in most regions of the world except the tropics and New Zealand and Australia. plants and Euphorbia euphorbia (yfôr`bēə): see spurge. characigs (Giordani et al., 2004) have demonstrated significant synergism with ketacona-zole against certain fungal species.
In a recent study by Han (2007), a synergistic effect of grape seed extract Grape seed extract contains chemicals known as polyphenols, (including the subclass of proanthocyanidins), which are recognized to be effective polyphenol antioxidants. (GSE GSE
general somatic efferent system. ) with amphotericin B was observed in both in vitro and in murine model of disseminated candidiasis candidiasis (kăn'dĭdī`əsĭs), infection of the mucous membranes caused by the fungus Candida albicans. Other terms for candidiasis are yeast infection, moniliasis (after a former name of the fungal genus), and thrush, the due to Candida albicans. Mice treated with combination of amphotericin B and GSE or amphotericin B alone survived 62.4 and 38.4 days, respectively. The combination therapy reduced more than 75% of amphotericin B required to achieve the same level of inhibition.
In vitro evaluation of synergy
The accurate prediction of synergy between commercial drugs or between a drug and a natural product based upon the results of in vitro testing is very crucial. A number of methods are used to detect synergy. However, the checkerboard and time-kill curve methods are the two most widely used techniques and the former is a relatively easy test to perform (White et al., 1996). The checkerboard is prepared in microtiter plate for multiple combinations of two antimicrobial agents in concentrations equal to, above, and below their minimal inhibitory concentrations for the microorganism that is being tested. Each row (x axis) in the plate will contain the same diluted concentration of the first antimicrobial compound; while the concentration in each subsequent row will be half this value. Similarly each column (y axis) in the plate will contain the same diluted concentration in each subsequent column will be half this value. The drugs combination in which the growth is completely inhibited is taken as effective MIC for the combination.
The time-kill method assesses the bactericidal bactericidal /bac·te·ri·ci·dal/ (bak-ter?i-si´d'l) destructive to bacteria.
An agent that destroys bacteria (e.g. activity of the individual as well as different concentration of the combination of drugs as a function of time. It is a labor intensive and time-consuming process (White et al., 1996). Tubes containing individual compounds and combination of compounds with concentrations ranging from one-quarter to twice the MIC for the bacterial strain of interest (NCCLS NCCLS National Committee for Clinical Laboratory Standards , 1987) are prepared. The tubes are inoculated with about 5 X [10 sup.5] colony forming units/ml of the strain, and they are incubated overnight. Aliquots of the samples from Oh of incubation (reflecting the initial inoculum inoculum /in·oc·u·lum/ (-ok´u-lum) pl. inoc´ula material used in inoculation.
n. pl. ) and 24 h of incubation (reflecting exposure of bacteria to the compound) are plated onto agar plates. Synergy is defined as a 100-fold or greater decrease in colony count at 24 h by the combination of agents with reference to the starting inoculum and also when compared to the most active single agent (Saiman, 2007).
E test is another method of recent origin. It consists of two plastic strips coated with a continuous gradient of each of the compound on one side. For evaluation of synergy, one compound strip is placed onto an agar plate for 1 h and then removed, and the second compound strip is placed on top of the gradient left behind by the first. The MIC of the combination is taken as the value at which the two inhibition zones intersect. If the use of the E strip could be standardized for testing the synergy of drugs and the results obtained could be demonstrated to be similar to those determined by established methods, this new test method would represent an attractive alternative to the labor-intensive procedures. Further, this method could be performed on a routine basis in a clinical microbiology laboratory (White et al., 1996). The standardization of these techniques for routine routine laboratory testing is the need because of the common use of combination therapies against the growing numbers of multiple drug-resistant strains.
Analysis of the synergy data
In all the above methods the interaction between the two antimicrobial agents is estimated by calculating the fractional inhibitory concentration of the combination (FIC) index. The FIC of each drug is calculated by dividing the concentration of the compound present in that well in combination where complete inhibition of growth of the microorganism is observed by the MIC of that compound alone to inhibit the microorganism. The FIC of the combination is then the sum of these two individual FIC values. When the FIC index of the combination is equal to or less than 0.5, the combination is termed as synergistic; when FIC index falls between 0.5 and 4.0, it indicates 'no interaction' between the agents, and a value above four indicates antagonism between the two compounds (Odds, 2003).
A convenient graphical way of representing the results of combination studies is by the use of an 'isobologram', introduced by Loewe and Muischnek (1926). It is independent of the mechanism of action, makes no assumption about the behavior of each compound. So it is applicable to multiple component mixtures. Combination of drugs X and Y that shows inhibition of the growth of the organism are represented in a graph using rectangular coordinates as (x,y) for the respective doses. In this format, the dose of drug X alone as (a) and drug Y alone as (b) are represented along the axes as (a,0) and (0,b). The straight line connecting these points is called the 'line of additivity'. This line provides a convenient means for visually discriminating additive from non-additive interactions on the basis of whether or not the coordinate of the combination falls on (additive), below (superadditive) or above (subadditive) this line. The determination requires statistical evaluation (Tallarida et al., 1989) because the technique obtains the individual or combination of doses as random variables from the dose response data and there is always an error involved in the estimation (Tallarida and Raffa, 1996). If synergy is occurring, the dose of the combination needed to produce the same effect will be less than the sum of the individual components and then the curve will be concave. In antagonism, the dose of combination will be greater than expected and the curve will be convex. The 'isobole' method has been well explained with several examples by Williamson (2001).
Synergistic interactions in other therapies
The successful use of combinations of plant extracts is not only observed in antiinfective therapy, but also seen in the treatment of several disorders including cancer, HIV HIV (Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. , inflammatory, stress-induced insomnia, osteoarthritis and hypertension (Williamson, 2001). Conventional medicine applies the "silver bullet" method, where single target therapy is employed. The recent trend has been the "herbal shotgun" method like Ayurveda, where multitargeted approach of the herbals and drugs is used. Today illness such as cancer, AIDS, hypertension, etc., are successfully treated with combination of 3-5 synthetic drugs. Cannabis extract is found to act in synergy as antispastic agent in mice than tetrahydrocannabinol tetrahydrocannabinol /tet·ra·hy·dro·can·nab·i·nol/ (THC) (-hi?dro-kah-nab´i-nol) the active principle of cannabis, occurring in two isomeric forms, both considered psychomimetically active. at an equivalent dose (Baker et al., 2000; cit. at Wagner, 2006). Ginkgolide A and B has been seen to act in synergy in the inhibition of PAF- induced thrombocyte thrombocyte: see blood clotting. aggregation (Wagner, 2001, 2006) In the case of cancer chemotherapy, the molecular targets for the phytochemicals is diverse hence it necessitates the need to understand the degree of its interaction with synthetic drugs. Multitargeted therapy approach involving the application of phytochemicals or phytoextracts and synthetic drugs as anticancer agents has been detailed in a review (Hemaiswarya and Doble, 2006).
Before prescribing an antibiotic treatment the guidelines usually suggest that a specimen containing the suspected organism is sent for culture and sensitivity. Microbiology departments, for their part, use in vitro sensitivity of isolates taken from patients with bacterial infections to recommend which antibiotic(s) to prescribe or to use as an empirical guide for treatment in other situations. There are a number of reports available on the different antibiotic combinations tested in vitro and applied to clinical scenario. But there are no reports on the use of natural products and synthetic drug combinations used in the clinical settings. As discussed in the review, there is plenty of hope for the purified natural products to be used in combination with antibiotics as antiinfective drugs. EGCg, demonstrates a synergistic behavior with antibiotics by destroying the [beta]-lactamase activity as well as by acting on the peptidoglycan of the cell wall. The safe consumption of tea for thousands of years indicates its low toxicity. EGCg, the principal constituent of tea, is absorbed through the digestive tract and distributed to many organs in animals and humans. This indicates the high bioavailability of EGCg which could enhance the activity of antibiotic under in vivo conditions. Thus the undesirable side effects of antibiotics on human and animal health could be possibly reduced by replacing at least in part the synthetic substances by negligibly toxic, highly specific antimicrobial compounds.
Several reports are available that describe the action of secondary metabolites from plants as antimicrobial agents. While the screening of natural compounds for antimicrobial activity is by itself a research area of major significance, the development of compounds with resistance modifying action is of interest since currently there are no known agents presently in use in clinics. In order to select a compound that could act in synergism with a drug it is necessary to understand the complete molecular mechanism of the drug action in the presence and absence of the natural compound. The problems that still need to be addressed are stability, selectivity and bioavailability of these natural products, and any adverse herb-drug interaction. To overcome multidrug resistance in the antimicrobial therapy a combination of drugs has to be used. The maximum benefit can be achieved when the pharmacokinetics of natural product and the antibiotic combination match. This does not mean that pharmacokinetic profiles for both agents should be identical. The optimal ratio and dosing regimens should be explored for higher efficacy and decreased toxicological profiles. Animal models with engineered strains lacking the particular resistant genotype can be used to very precisely define the pharmacokinetic and pharmacodynamic targets followed by regulated clinical trials. Even in vitro screening procedures for drug combination are time-consuming process which should be speeded up to achieve quick breakthroughs in combination therapy. Techniques such as isobologram can be used successfully to demonstrate regions of synergy between drug combinations from other regimes.
The recent developments in genomics, proteomics and metabolomics have created a new platform to distinguish the synergistic efficacy of phytoextracts and for the determination of their mode of action. By the application of the "-omic" technologies it should be possible to detect the mechanism of action as the gene/ protein expression profiles of the combination of drugs can be entirely different from the ones induced by the single drugs. This may lead to new phyto-based paradigms towards the use of complex plant mixtures in medicine (Ulrich-Merzenich et al., 2007).
As seen from this review, the number of natural compounds acting in synergy with synthetic drugs towards fungal and Mycobacterium species are minimal. This could be due to limited understanding of the mechanism of action of drugs against these organisms or insufficient screening of natural compounds. So research should be focused towards this direction to identify more natural compounds which exhibit synergistic behavior.
Ahmed, M., Borsch, C.M., Neyfakh, A.A., Schuldiner, S., 1993. Mutants of the Bacillus subtilis multidrug transporter Bmr with altered sensitivity to the antihypertensive alkaloid reserpine. J. Biol. Chem. 268, 11086-11089.
Alexander, C, Rietschel, E.T., 2001. Bacterial lipopolysaccharides and innate immunity. J. Endotoxin Res. 7, 167-202.
Al-hebshi, N., Al-haroni, M., Skaug, N., 2006. In vitro antimicrobial and resistance-modifying activities of aqueous crude khat khat: see staff tree.
Slender, straight, East African tree (Catha edulis; family Celastraceae). Reaching a height of 80 ft (25 m), the khat tree has large, oval, finely toothed, bitter-tasting leaves. extracts against oral microorganisms. Arch. Oral Biol. 51, 183-188.
Avenirova, E.L., Ashmarin, I.P., Movchan, N.A., Lapina, I.K., 1975. Combination of novoimanin with antibiotics with a different mechanism of action. Antibiotiki 20, 636-639.
Baker, D., Pryce, G., Coxford, J.L., Brown, P., Huffmann, I.W., Pertwee, R.G., Layward, L., 2000. Cannabinoids control spasticity and tremor in an animal model of multiple sklerosis. Nature 404, 84-87.
Ball, A.R., Casadei, G., Samosorn, S., Bremner, J.B., Ausubel, F.M., Moy, T.I., 2006. Conjugating berberine to a multidrug resistance pump inhibitor creates an effective antimicrobial. ACS (Asynchronous Communications Server) See network access server. Chem. Biol. 1, 594-600.
Bapela, N.B., Lall, N., Fourie, P.B., Franzblau, S.G., Van Rensburg, C.E., 2006. Activity of 7-methyljuglone in combination with antituberculous drugs against Mycobacterium tuberculosis. Phytomedicine 13, 630-635.
Berger-Bachi, B., Rohrer, S., 2002. Factors influencing methicillin resistant in staphylococci. Arch. Microbiol. 178, 165-171.
Bernard, F.X., Sable, S., Cameron, B., Provost, J., Desnottes, F., Crouzet, J., Blanche, F., 1997. Glycosylated flavones as selective inhibitors of topoisomerase IV. Antimicrob. Agents Chemother. 41, 992-998.
Blasquez, J., Baquero, M.R., Canton, I., Alos, I., Baquero, F., 1993. Characterization of a new TEM-type [beta]-lactamase resistant to clavulanate, sulbactam, and tazobactam. Antimicrob. Agents Chemother. 37, 2059-2063.
Bos, M.P., Tommassen, J., 2004. Biogenesis biogenesis /bio·gen·e·sis/ (-jen´e-sis)
1. origin of life, or of living organisms.
2. the theory that living organisms originate only from other living organisms. of the Gram-negative bacterial outer membrane. Curr. Opin. Microbiol. 7, 610-616.
Brade, H., Opal, S.M., Vogel, S.N., Membrane, D.C., 1999. In: Morrison (Ed.), Endotoxin in Health and Disease. Marcel Dekker, Inc., New York and Basel, pp. 31-38.
Braga, L.C., Leite, A.A.M., Xavier, K.G.S., Takahashi, J.A., Bemquerer, M.P., Chartone-Souza, E., Nascimento, A.M.A., 2005. Synergic synergic /syn·er·gic/ (sin-er´jik) acting together or in harmony.
Synergistic. interaction between pomegranate extract and antibiotics against Staphylococcus aureus. Can. J. Microbiol./Rev. Can. Microbial. 51, 541-547.
Brown, M.H., Paulsen, I.T., Skurray, R.A., 1999. The multidrug efflux protein Nor M is a prototype of a new family of transporters. Mol. Microbiol. 31, 393-395.
Bush, K., 1998. Metallo-[beta]-lactamases: a class apart. Clin. Infect. Dis. 27, S48-S53.
Bush, K., 2002. The impact of [beta]-lactamases on the development of novel antimicrobial agents. Curr. Opin. Investig. Drugs 3, 1284-1290.
Carpinella, M., Ferrayoli, C.G., Palacios, S.M., 2005. Antifungal synergistic effect of scopoletin, a hydroxycoumarin isolated from Melia azedarach L. fruits. J. Agric. Food Chem. 53, 2922-2927.
Casal, M., Vaquero, M., Rinder, H., Tortoli, E., Grosset, J., Rusch-Gerdes, S., Gutierrez, J., Jarlier, V., 2005. Microbial Drug Resist. 11, 62-67.
Chaibi, E.B., Sirot, D., Paul, G., Labia, R., 1999. Inhibitor-resistant TEM TEM
1. transmission electron microscope.
3. transmissible encephalopathy of mink. [beta]-lactamase: phenotypic, genetic and biochemical characteristics. J. Antimicrob. Chemother. 43, 447-458.
Chambers, H.F., 2001. The changing epidemiology of Staphylococcus aureus. Emerg. Infect. Dis. 7, 178-182.
Chen, P., Gearhart, J., Protopopova, M., Einck, L., Carol, A., 2006. Synergistic interactions of SQ109, a new ethylene diamine di·am·ine
Any of various chemical compounds containing two amino groups, especially hydrazine.
Noun 1. diamine - any organic compound containing two amino groups , with front-line antitubercular drugs in vitro. J. Antimicrob. Chemother. 58, 332-337.
Choudhuri, B.S., Bhakta, S., Barik, R., Basu, J., Kundu, M., Chakrabarti, P., 2002. Overexpression and functional characterization of an ABC (ATP-binding cassette) transporter encoded by the genes drrA and drrB of Mycobacterium tuberculosis. Biochem. J. 367, 279-285.
Enright, M.C., Robinson, D.A., Randle, G., Feil, E.J., Grundmann, H., Spratt, B.G., 2002. The evolutionary history of methicillin-resistant Staphylococcus aureus methicillin-resistant Staphylococcus aureus Methicillin-aminoglycoside resistant Staphylococcus aureus, MRSA An organism with multiple antibiotic resistances–eg, aminoglycosides, chloramphenicol, clindamycin, erythromycin, rifampin, tetracycline, (MRSA). Proc. Natl. Acad. Sci. USA 99, 7687-7692.
Feldberg, A.R.S., Chang, S.C., Kotik, T.N., Nadler, M., Neuwirth, Z., Sundstrom, D.C., Thompson, H.N., 1988. In vitro mechanism of inhibition of bacterial cell growth by allicin. Antimicrob. Agents Chemother. 32, 1763-1768.
Ferrari, L., Iavarone, L., Braggio, S., Di Modugno, E., 2003. In vitro and invivo pharmacokinetics-pharmacodynamics of GV143253A, a novel trinem. Antimicrob. Agents Chemother. 47, 2471-2480.
Ghysen, J.M., 1994. Molecular structures of penicillin-binding proteins and [beta]-lactamases. Trends Microbiol. 2, 372-380.
Gibbons, S., Oluwatuyi, M., Kaatz, G.W., 2004. A novel inhibitor of multidrug efflux pumps in Staphylococcus aureus. J. Antimicrob. Chemother. 48, 1968-1973.
Gibbons, S., Oluwatuyi, M., Veitch, N.C., Gray, A.I., 2003. Bacterial resistance modifying agents from Lycopus europaeus. Phytochemistry phytochemistry,
n the scientific study and classification of the chemical constituents of plants. 62, 83-87.
Gibbons, S., Udo, E.E., 2000. The effect of reserpine, a modulator of multidrug efflux pumps, on the in vitro activity of tetracycline against clinical isolates of methicillin resistant Staphylococcus aureus (MRSA) possessing the Tet(K) determinant. Phytother. Res. 14, 139-140.
Giordani, R., Regli, P., Kaloustian, J., Mikail, C., Abou, L., Portugal, H., 2004. Antifungal effect of various essential oils against Candida albicans. Potentiation potentiation /po·ten·ti·a·tion/ (po-ten?she-a´shun)
1. enhancement of one agent by another so that the combined effect is greater than the sum of the effects of each one alone.
2. posttetanic p. of antifungal action of amphotericin B by essential oil from Thymus vulgaris. Phytother. Res. 18, 990-995.
Giordani, R., Trebaux, J., Masi, M., Regli, P., 2001. Enhanced antifungal activity of ketaconaole by Euphorbia characias latex against Candida albicans. J. Ethnopharmacol. 78, 1-5.
Griep, M.A., Blood, S., Larson, M.A., Koepsell, S.A., Hinrichs, S.H., 2007. Myricetin inhibits Escherichia coli DnaB helicase but not primase. Bioorg. Med. Chem. 15, 7203-7208.
Hammer, K.A., Carson, C.F., Riley, T.V., 2000. In vitro activities of ketaconazole, econazole, miconazole miconazole /mi·con·a·zole/ (mi-kon´ah-zol) an imidazoleantifungal agent used as the base or the nitrate salt against tinea and cutaneous or vulvovaginal candidiasis. , and Melaleuca alternifolia (Tea tree) oil against Malassezia species. Antimicrob. Agents Chemother. 44, 467-469.
Han, Y., 2007. Synergic effect of grape seed extract with amphotericin B against disseminated candidiasis due to Candida albicans. Phytomedicine 14, 733-738.
Heep, M., Rieger, U., Beck, D., Lehn, N., 2000. Mutations in the beginning of the rpoB gene can induce resistance to rifamycins in both Helicobacter pylori and Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 44, 1075-1077.
Hegde, V.R., Pu, H., Patel, M., Black, T., Soriano, A., Zhao, W., Gullo, V.P., Chan, T.-M., 2004. Two new bacterial DNA primase inhibitors from the plant Polygonum cuspidatum. Bioorg. Med. Chem. Lett. 14, 2275-2277.
Helander, I.M., Alakomi, H.-L., Latva-Kala, K., Mattila-Sandholm, T., Pol, I., Smid, E.J., Gorris, L.G.M., Von Wright, A., 1998. Characterization of the action of selected essential oil components on Gram-negative bacteria. J. Agric. Food Chem. 46, 3590-3595.
Helander, I.M., Von Wright, A., Mattila-Sandholm, T., 1997a. Potential of lactic acid bacteria The Lactic Acid Bacteria (LAB) comprise a clade of Gram positive, low-GC, acid tolerant, non-sporulating, non-respiring rod or cocci that are associated by their common metabolic and physiological characteristics. and novel antimicrobials against Gram-negative bacteria. Trends Food Sci. Technol. 8, 146-150.
Hemaiswarya, S., Doble, M., 2006. Potential synergism of natural products in the treatment of cancer. Phytother. Res. 20, 239-249.
Hirasawa, M., Takada, K., 2004. Multiple effects of green tea catechin on the antifungal activity of antimycotics against Candida albicans. J. Antimicrob. Chemother. 53, 225-229.
Hu, Z.-Q., Zhao, W.-H., Asano, N., Yoda, Y., Hara, Y., Shimamura, T., 2002. Epigallocatechin gallate synergisti cally enhances the activity of carbapenems against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 46, 558-560.
Hu, Z.-Q., Zhao, W.-H., Hara, Y., Shimamura, T., 2001. Epigallocatechin gallate synergy with ampicillin/sulbactam against 28 clinical isolates of methicillin-resistant Staphylococcus aureus. J. Antimicrob. Chemother. 48, 361-364.
Isogai, E., Isogai, H., Hirose, K., Hayashi, S., Oguma, K., 2001. Invivo synergy between green tea extract and levofloxacin against enterohemorrhagic Escherichia coli enterohemorrhagic Escherichia coli EHEC Any of the E coli serotypes–eg O29, O39, O145 that produces shiga-like toxins, causing bloody inflammatory diarrhea, evoking a HUS. See Escherichia coli O157:H7, Hemolytic uremic syndrome. O157 infection. Curr. Microbiol. 42, 248-251.
Ito, T., Okuma, K., Ma, X.X., Yuzawa, H., Hiramatsu, K., 2003. Insights on antibiotics resistance of Staphylococcus aureus from its whole genome: genome island SCC. Drug Resist. Updat. 6, 41-52.
Jedlickova, Z., Mottl, O., Sery, V., 1992. Antibacterial properties of the Vietnamese cajeput oil and ocimum oil in combination with antibacterial agents. J. Hyg. Epidemiol. Microbiol. Immunol. 36, 303-309.
Kawahara, K., Seydel, U., Matsuura, M., Danbara, H., Rietschel, E.T., Zahringer, U., 1991. Chemical structure of glycosphingolipids isolated from Sphingomonas paucimobiles. FEBS Lett. 292, 107-110.
Kurazono, M., Ida, T., Yamada, K., Hirai, Y., Maruyama, T., Shitara, E., Yonezawa, M., 2004. In vitro activities of ME1036 (CP5609), a novel parenteral carbapenem, against methicillin-resistant staphylococci. Antimicrob. Agents Chemother. 48, 2831-2837.
Lee, E.-W., Huda, M.N., Kuroda, T., Mizushima, T., Tsuchiya, T., 2003a. EfrAB, an ABC multidrug efflux pump in Enterococcus faecalis. Antimicrob. Agents Chemother. 47, 3733-3738.
Lee, N., Yuen, K.Y., Kumana, C.R., 2003b. Clinical role of [beta]-lactam/[beta]-lactamase inhibitor combinations. Drugs 63, 1511-1524.
Lee, S.H., Kin, C.J., 1999. Selective combination effect of anethole to antifungal activities of miconazole and amphotericin B. Yakhak Hoeji 43, 228-232.
Leive, L., 1965. Release of lipopolysaccharide by EDTA treatment of E. coli. Biochem. Biophys. Res. Comm. 21, 290-296.
Lewis, K., 2001. In search of natural substrates and inhibitors of MDR pumps. J. Mol. Microbiol. Biotechnol. 3, 247-254.
Lewis, K., Ausubel, F.M., 2006. Prospects for plant derived antibacterials. Nat. Biotechnol. 24, 1504-1507.
Lewis, K., Lomovskaya, O., 2001. Drug efflux. In: Lewis, K., Salyers, A., Taber, H., Wax, R. (Eds.), Bacterial Resistance to Antimicrobials: Mechanisms, Genetics, Medical Practice and Public Health. Marcel Dekker, Inc., New York, NY, pp. 61-90.
Lin, R.-D., Chin, Y.P., Lee, M.H., 2005. Antimicrobial activity of antibiotics in combination with natural flavonoids against clinical extended-spectrum [beta]-lactamase (ESBL)-producing Klebsiella pneumoniae. Phytother. Res. 19, 612-617.
Littlejohn, T.G., Paulsen, I.T., Gillespie, M.T., Tennent, J.M., Midgley, M., Jones, I.G., Purewal, A.S., Skurray, R.A., 1992. Substrate specificity and energetics of antiseptic and disinfectant resistance in Staphylococcus aureus. FEMS Microbiol. Lett. 74, 259-265.
Liu, I.X., Durham, D.G., Richards, R.M., 2000. Baicalin synergy with [beta]-lactam antibiotics against methicillin-resistant Staphylococcus aureus and other [beta]-lactam-resistant strain of S. aureus. J. Pharm. Pharmacol. 52, 361-366.
Loewe, S., Muischnek, H., 1926. Nauyn-Schmiedeberg's Arch. Exp. Path. Pharmacol. 114, 313-326.
Lu, W.P., Sun, Y., Bauer, M.D., Paule, S., Koenigs, P.M., Kraft, W.G., 1999. Penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus: kinetic characterization of its interactions with [beta]-lactams using methicillin--resistant: kinetic characterization of its interactions with [beta]-lactams using electrospray mass spectrometry. Biochemistry 38, 6537-6546.
Lynch, S.A., 2006. Efflux systems in bacterial pathogens: an opportunity for therapeutic intervention? An industry view. Biochem. Pharmacol. 71, 946-956.
Marquez, B., Neuville, L., Moreau, N.J., Genet, J.P., Santos, A.F., de Andrade, M.C.C., Sant'Ana, A.E.G., 2005. Multidrug resistance reversal agent from Jatropha elliptica. Phytochemistry 66, 1804-1811.
Mossa, J.S., El-Feraly, F.S., Muhammad, I., 2004. Antimycobacterial constituents from Juniperus procera, Ferula Ferula
a plant genus in the family Apiaceae; contain coumarin and cause hemorrhagic diathesis; includes F. asafoetida, F. communis (giant fennel F. communis var. brevifolia). communis and Plumbago zeylanica and their in vitro synergistic activity with isonicotinic acid hydrazide. Phytother. Res. 2, 934-937.
NCCLS, National Committee for Clinical Laboratory Standards, 1987. Methods for Determining Bactericidal Agents. NCCLS Document M26-P, vol. 7. National Committee for Clinical Laboratory Standards, Villanova, PA.
Nicolson, K., Evans, G., O'Toole, P.W., 1999. Potentiation of methicillin activity against methicillin-resistant Staphylococcus aureus by diterpenes. FEMS Microbiol. Lett. 179, 233-239.
Nikaido, H., 1999. Microdermatology: cell surface in the interaction of microbes with the external world. J. Bacteriol. 181, 4-8.
Nikaido, H., 2003. Molecular basics of bacterial outer membrane permeability revisited. Microbiol. Mol. Biol. Rev. 4, 593-656.
Nikaido, H., Vaara, M., 1985. Molecular basis of bacterial outer membrane permeability. Microbiol. Rev. 49, 1-32.
Odds, F.C., 2003. Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob. Chemother. 52, 1.
Oluwatuyi, M., Kaatz, G.W., Gibbons, S., 2004. Antibacterial and resistance modifying activity of Resmarinus officinalis. Phytochemistry 65, 3249-3254.
Pao, S.S., Paulsen, I.T., Saier Jr., M.H., 1998. Major facilitator superfamily. Microbiol. Mol. Biol. Rev. 62, 1-34.
Pasca, M.R., Guglierame, P., Arcesi, F., Bellinzoni, M., De Rossi, E., Riccardi, G., 2004. Rv2686c-Rv2687c-Rv2688c, an ABC fluoroquinolone efflux pump in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 48, 3175-3178.
Paulsen, I.T., Skurray, R.A., Tam, R., Saier Jr., M.H., Turner, R.J., Weiner, J.H., Goldberg, E.B., Grinius, L.L., 1996. The SMR family: a novel family of multidrug efflux proteins involved with the efflux of lipophilic lipophilic,
adj/n the ability to dissolve or attach to lipids.
adj 1. showing a marked attraction to, or solubility in, lipids.
2. drugs. Mol. Microbiol. 19, 1167-1175.
Pyun, M.-S., Shin, S., 2006. Antifungal effects of the volatile oils from Allium plants against Trichophyton species and synergism of the oils with ketaconazole. Phytomedicine 13, 394-400.
Renau, T.E., Leger, R., Flamme, E.M., Sangalang, J., She, M.W., Yen, R., Gannon, C.L., Griffith, D., Chamberland, S., Lomovskaya, O., Hecker, S.J., Lee, V.J., Ohta, T., Nakayama, K., 1999. Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of fluoroquinolone antibacterial leuofloxacin. J. Med. Chem. 42, 4928-4931.
Roccaro, A.S., Blanco, A.R., Giuliani, F., Rusciano, D., Enea, V., 2004. Epigallocatechin gallate enhances the activity of tetracycline in Staphylococci by inhibitory its efflux from bacterial cells. Antimicrob. Agents Chemother. 48, 1968-1973.
Sachin, B.S., Sharma, S.C., Sethi, S., Tasduq, S.A., Tikoo, M.K., Tikoo, A.K., Satti, N.K., Gupta, B.D., Suri, K.A., Johri, R.K., Qazi, G.N., 2007. Herbal modulation of drug bioavailability: enhancement of rifampicin levels in plasma by herbal products and a flavonoid glycoside derived from Cuminum cyminum. Phytother. Res. 212, 157-163.
Saier Jr., M.H., Tam, R., Reizer, A., Reizer, J., 1994. Two novel families of bacterial membrane proteins concerned with nodulation nod·u·la·tion
The formation or presence of nodules.
the formation of or presence of nodules. , cell division and transport. Mol. Microbiol. 11, 841-847.
Saiman, L., 2007. Clinical utility of synergy testing for multidrug-resistant Pseudomonas aeruginosa isolated from patients with cystic fibrosis: 'the motion for'. Paediatr. Respir. Rev. 8, 249-255.
Sakagami, Y., Iinuma, M., Piyasena, K.G.N.P., Dharmarane, H.R.W., 2005. Antibacterial activity of [alpha]-mangostin against vancomycin resistant Enterococci (VRE) and synergism with antibiotics. Phytomedicine 12, 203-208.
Sakagami, Y., Mimura, M., Kajimura, K., Yokoyama, H., Linuma, M., Tanaka, T., Ohyama, M., 1998. Anti-MRSA activity of sophoraflavanone G and synergism with other antibacterial agents. Lett. Appl. Microbiol. 27, 98-100.
Sato, M., Tanaka, H., Oh-Uchi, T., Fukai, T., Etoh, H., Yamaguchi, R., 2004. Antibacterial activity of phytochemicals isolated from Erythrina zeyheri against vancomycin resistant enterococci and their combinations with vancomycin. Phytother. Res. 18, 906-910.
Schmitz, F., Fluit, A., Luckefahr, M., Engler, B., Hofmann, B., Verhoef, J., Heiz, ., Hadding, U., Jones, M., 1998. The effect of reserpine, an inhibitor of multidrug efflux pumps, on the in-vitro activities of ciprofloxacin, Sparfloxacin and moxifloxacin against clinical isolates of Staphyloccocus aureus. J. Antimicrob. Chemother. 42, 807-810.
Sheldon, A.T., 2005. Antibiotic resistance: a survival strategy. Clin. Lab. Sci. Summer. 18, 170-180.
Shimizu, M., Shiota, S., Mizushima, T., Ito, H., Hatano, T., Yoshida, T., Tsuchiya, T., 2001. Marked potentiation of activity of [beta]-lactams against methicillin-resistant Staphylococcus aureus by corilagin. Antimicrob. Agents Chemother. 45, 3198-3201.
Shin, S., Kang, C.-A., 2003. Antifungal activity of the essential oil of Agastache rugosa Kuntze and its synergism with ketaconazole. Lett. Appl. Microbiol. 36, 111-115.
Shin, S., Lim, S., 2004. Antifungal effects of herbal essential oils alone and in combination with ketoconazole ketoconazole /ke·to·co·na·zole/ (ke?to-kon´ah-zol) a derivative of imidazole used as an antifungal agent.
n. against Trichophyton sp. J. Appl. Microbiol. 97, 1289-1296.
Shiota, S., Shimizu, M., Mizushima, M. Ito, H., Hatano, T., Yoshida, T., Tsuchiya, T., 2000. Restoration of effectiveness of [beta]-lactams on methicillin resistant Staphylococcus aureus by tellimagrandin I from rose red. FEMS Microb. Lett. 185, 135-138.
Shiota, S., Shimizu, M., Sugiyama, J., Morita, Y., Mizushima, T., Tsuchiya, T., 2004. Mechanisms of action of corilagin and tellimagrandin I that remarkably potentiate the activity of [beta]-lactams against methicillin-resistant Staphylococcus aureus. Microbiol. Immunol. 48, 67-73.
Simonetti, G., Simonetti, N., Villa, A., 2004. Increased microbicidal activity of green tea (Camellia sinensis) in combination with butylated hydroxyanisole. J. Chemother. 16, 122-127.
Smith, E., Williamson, E., Zloh, M., Gibbons, S., 2005. Isopimaric acid from Pinus nigra shows activity against multidrug-resistant and EMRSA strains of Staphylococcus aureus. Phytother. Res. 19, 538-542.
Stermitz, F.R., Lorenz, P., Tawara, J.N., Zenewicz, L.A., Lewis, K., 2000. Synergy in a medicinal plant. Antimicrobial action of berberine potentiated by 5-methoxy hydnocarpin, a multidrug pump inhibitor. Proc. Natl. Acad. Sci. USA 97, 1433-1437.
Suresh, B.S., Dhanaraj, S.A., Elangosriram, K., Chinnaswamy, K., 1997. Anticandidal activity of Santolina chamaecyparissus volatile oil. J. Ethnopharmacol. 55, 151-159.
Takahashi, O., Cai, Z., Toda, M., Hara, Y., Shimamura, T., 1995. Appearance of antibacterial activity of oxacillin oxacillin /ox·a·cil·lin/ (ok?sah-sil´in) a semisynthetic penicillinase-resistant penicillin used as the sodium salt in infections due to penicillin-resistant, gram-positive organisms. against methicillin-resistant Staphylococcus aureus (MRSA) in the presence of catechin. Kansenshogaku Zasshi 69, 1126-1134.
Tallarida, R.J., Porreca, F., Cowan, A., 1989. Statistical analysis of drug-drug and site-site interactions with isobolograms. Life Sci. 45, 947-961.
Tallarida, R.J., Raffa, R.B., 1996. Testing for synergism over a range of fixed ratio drug combinations: replacing the isobologram. Pharmacol. Lett. 58, 23-28.
Tegos, G., Stermitz, F.R., Lomovskaya, O., Lewis, K., 2002. Multidrug pump inhibitors uncover remarkable activity of plant antimicrobials. Antimicrob. Agents Chemother. 46, 3133-3141.
Toyoshima, Y., Okuba, S., Toda, M., Hara, Y., Shimamura, T., 1993. Effect of catechin on the ultrastructure ultrastructure /ul·tra·struc·ture/ (-struk?chur) the structure beyond the resolution power of the light microscope, i.e., visible only under the ultramicroscope and electron microscope. of Trichophyton mentagrophytes. Kansenshogaku Zasshi 68, 295-303.
Ulrich-Merzenich, G., Zeitler, H., Jobst, D., Panek, D., Vetter, H., Wagner, H., 2007. Application of the '-Omic-' technologies in phytomedicine. Phytomedicine 14, 70-82.
Vaara, M., 1981. Increased outer membrane resistance to ethylenediaminetetraacetate and cations in novel lipid A mutants. J., Bacteriol. 148, 426-434.
Vaara, M., 1992. Agents that increase the permeability of the outer membrane. Microbiol. Rev. 56, 395-411.
Vaara, M., 1999. Lipopolysaccharide and the permeability of the bacterial outer lipopolysaccharide and the permeability of the bacterial outer membrane. In: Brade, H., Opal, S.M., Vogel, S.N., Morrison, D.C. (Eds.), Endotoxin in Health and Disease. Marcel Dekker, New York and Basel, pp. 31-38.
Vaara, M., Vaara, T., 1983a. Polycationic sensitize sen·si·tize
To make hypersensitive or reactive to an antigen, such as pollen, especially by repeated exposure. enteric bacteria to antibiotics. Antimicrob. Agents Chemother. 24, 107-113.
Vaara, M., Vaara, T., 1983b. Polycations as outer membrane destabilizing agents. Antimicrob. Agents Chemother. 24, 114-122.
Vattem, D.A., Lin, Y.-T., Ghaedian, R., Shetty, K., 2005. Cranberry synergies for dietary management of Helicobacter pylori infections. Process Biochem. 40, 1583-1592.
Veen, H.W.V., Konings, W.N., 1998. The ABC family of multidrug transporters in microorganism. Biochim. Biophys. Acta 1365, 31-36.
Veen, H.W.V., Venema, K., Bolhuis, H., Oussenko, I., Kok, J., Poolman, B., Driessen, A.J.M., Konings, W.N., 1996. Multidrug resistance mediated by a bacterial homolog hom·o·log
Variant of homologue. of the human multidrug transporter MDR1. Proc. Natl. Acad. Sci. USA 93, 10668-10672.
Vinogradova, T.I., Aleksandrova, A.E., Antonenkova, E.V., Elokhina, V.N., Nakhmanovich, A.S., 1999. Design and study of new agents having antitubercular activity: the original compound perchlosone as a potent agent of etiotropic therapy for tuberculosis. My p Probl. Tuberk. 3, 45-47.
Vouillamoz, J., Entenza, J.M., Hohl, P., Moreillon, P., 2004. LB11058, a new cephalosporin cephalosporin (sĕf'əlōspôr`ĭn), any of a group of more than 20 antibiotics derived from species of fungi of the genus Cephalosporium and closely related chemically to penicillin. Cephalosporins, e.g. with high penicillin-binding protein 2a affinity and activity in experimental endocarditis endocarditis (ĕn'dōkärdī`tĭs), bacterial or fungal infection of the endocardium (inner lining of the heart) that can be either acute or subacute. due to homogeneously methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 48, 4322-4327.
Wagner, H., 2001. Trends and challenges in phytomedicine. In: Yaniv, Z., Bachrach, U. (Eds.), Handbook of Medicinal Plants. Haworth Medical Press. Inc., Bindhamton, UK, pp. 3-28 (Chapter 1).
Wagner, H., 2006. Multitarget-therapy, the future of treatment for more than just functional dyspepsia. Phytomedicine 13 (SV), 122-129.
Walsh, S.E., Maillard, J.-Y., Russell, A.D., Catrenich, C.E., Charbonneau, D.L., Bartolo, R.G., 2003a. Development of bacterial resistance to several biocides and effects on antibiotic susceptibility. J. Hosp. Infect. 55, 98-107.
Walsh, S. E., Maillard, J.-Y., Russell, A.D., Catrenich, C.E., Charbonneau, D.L., Bartolo, R.G., 2003b. Activity and mechanisms of action of selected biocidal bi·o·cid·al
Of or relating to an agent that is destructive to living organisms.
biocidal (bī´ōsī´d agents on Gram-positive and Gram-negative bacteria. J. Appl. Microbiol. 94, 240-247.
White, R.L., Burgess, D.S., Manduru, M., Bosso, J.A., 1996. Comparison of three different in vitro methods of detecting synergy: time-kill, checkerboard and E-test. Antimicrob. Agents Chemother. 40, 1914-1918.
WHO, 2004. WHO project: ICP (1) (Internet Cache Protocol) A protocol used by one proxy server to query another for a cached Web page without having to go to the Internet to retrieve it. See CARP and proxy server. BCT 001. 2004 Monitoring of antimicrobial resistance. Report of an Intercountry Workshop, Vellore, Tamil Nadu, India, 14-17 October 2003. World Health Organization, New Delhi, March 2004.
Williamson, E.M., 2001. Synergy and other interactions in phytomedicines. Phytomedicine 8, 401-409.
Willmott, C.J., Maxwell, A., 1993. A single point mutation in the DNA gyrase A protein reduces binding of fluoroquinolones to the gyrase-DNA complex. Antimicrob. Agents Chemother. 37, 126-127.
Wright, G.D., 2005. Bacterial resistance to antibiotics: enzymatic degradation and modification. Adv. Drug Deliv. Rev. 57, 1451-1470.
Yam, Y.S., Hamilton-Miller, J.M.T., Shah, S., 1998. The effect of a component of tea (Camellia sinensis) on methicillin resistance, PBP2' synthesis, and [beta]-lactamase production in Staphylococcus aureus. J. Antimicrob. Chemother. 42, 211-216.
Yoshida, H., Bogaki, M., Nakamura, S., Ubukata, K., Konno, M., 1990. Nucleotide sequence and characterization of Staphylococcus aureus norA gene, which confers resistance to quinolones. J. Bacteriol. 172, 6942-6949.
Zhao, W.-H., Hu, Z.-Q., Hara, Y., Shimamura, T., 2002. Inhibition of penicillinase by epigallocatechin-gallate resulting in restoration of antibacterial activity of penicillin against penicillinase-producing Staphylococcus aureus. Antimicrob. Agents Chemother. 46, 2266-2268.
Zhao, W.-H., Hu, Z.-Q., Okuba, S., Hara, Y., Shimamura, T., 2001. Mechanism of synergy between epigallocatechin-gallate and [beta]-lactams against methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 45, 1737-1742.
Shanmugam Hemaiswarya (a), Anil Kumar Kruthiventi (b), Mukesh Doble (a).*
(a) Department of Biotechnology The Centre for Biotechnology at Acharya Nagarjuna University was established in year 1994 inaugurated by the then Secretary, Department of Biotechnology, Government of India, Dr.C.R.Bhatia. The centre was offering two academic programs, M.Sc. (Biotechnology) and M.Tech. , Indian Institute of Technology Madras, Chennai 600 036, India
(b) Division of Medicinal Chemistry, Institute of Life sciences, Hyderabad 500 046, India
* Corresponding author. Tel.: + 914422574107;
E-mail address: email@example.com (M. Doble).