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Resistant no more: new antibiotics on the horizon: present-day antibiotics may be superseded by a new class of bacteria-killing drugs.

For more than 70 years, antibiotics have been the path of most resistance against infectious disease: The drugs have transformed medical care since penicillin was discovered in 1928, reducing illness and saving lives.

But not anymore--in fact, according to a 2013 report from the Centers for Disease Control and Prevention, at least two million Americans annually become infected with antibiotic-resistant bacteria, and at least 23,000 die as a direct result of those infections, or from comorbidities that are complicated by those infections.

As concern about bacterial resistance grows, there has been a resurgence in research and development in the field of antibiotics, with scientists studying new kinds of drugs to replace those that are no longer effective. A recent study (Journal of the American Chemical Society, Jan. 14,2014) focuses on a promising new class of molecules called acyldepsipeptides (ADEPs), which kill bacteria in a way that no currently marketed antibacterial drug does. "The molecules that we have synthesized are among the most potent antibacterial agents ever reported in the literature," says lead study author Jason Sello, PhD, professor of chemistry at Brown University.

CELLULAR GARBAGE DISPOSAL.

ADEPS are naturally occurring compounds that kill bacteria by binding to a protein in cells that act as a "cellular garbage disposal," according to Professor Sello. Called ClpP, the protein breaks down other proteins that are no longer needed, or are damaged and could be harmful to the cell--a vital natural process. But when ClpP is bound by ADEPs, it's no longer so selective about the proteins it degrades. In essence, binding by ADEP causes the garbage disposal to run amok and devour all kinds of proteins throughout the cell.

RUNAWAY CLP. For bacteria, a runaway ClpP is deadly; however, while natural ADEPs showed promise, killing bacteria that cause staph infections, some kinds of pneumonia, tuberculosis, and other types of infection in the lab, they were not good drug candidates. "While they killed bacteria on a petri dish, if you tried to actually cure an infection in a mouse, the natural products didn't work," observes study co-author Daniel Carney, a graduate student in Sello's group.

LOCK AND KEY CONCEPT. Not to be deterred, the team turned to formulating synthetic ADEPS in the hope of identifying compounds with potential as new drugs. One approach involved making the ADEP molecule more rigid. Compared to the ClpP molecule to which it binds, the ADEP molecule is a bit "floppy," Professor Sello explains. "We often use the expression 'lock and key' to describe how a small molecule binds to a protein. One can imagine that it is easier to fit a rigid key into a lock rather than a floppy key. In the same sense, rigid molecules often bind to their protein targets more tightly."

The result was a modified ADEP molecule that was about seven times better than the standard ones at binding to ClpP. The final step was testing whether the rigid ADEPs were better at killing bacteria in a test tube. In those tests, the modified compounds were much more potent than standard ADEPs against three different dangerous bacteria (see chart).

"We believe that some of the increase in potency may stem from the fact that the rigidified ADEPs bind ClpP more tightly and have an enhanced capacity to cross the cell membrane," says Professor Sello. Encouraged by their results, Sello and his team are working to develop the ADEPs into next-generation antibacterial drugs. The next step--a study to test how well the compounds work in mice--is already underway.

IMPACT OF ADEPs ON COMMON INFECTIOUS BACTERIA

Bacteria         What it causes                      Modified ADEPs
Staphylococcus   Skin infections, pneumonia, food    32 x more potent
aureus           poisoning, toxic shock syndrome,
                 bacteremia (blood poisoning)

Enterococcus     Endocarditis (inflammation of       600 x more potent
faecalis         the heart), bacteremia, urinary
                 tract infections, meningitis

Streptococcus    Pneumonia, sepsis (blood             1,200 x more
pneumoniae       infection),                          potent


THE VIEW FROM DUKE

VIVIAN H. CHU, MD, MHS, Assistant Professor of Medicine, Department of Medicine, Division of Endocrinology & Metabolism, Duke

ADEPs Essentially Cause Bacteria to Self-Destruct

"Despite the rising prevalence of resistant bacteria, the development of new systemic antibacterial drugs has declined steadily over the past three decades. Of the 14 systemic antibacterial drugs that have been approved by the Food and Drug Administration (FDA) since 1998, only four had a novel mechanism of action. This is a problem. The present study of ADEPs is compelling for several reasons. It shows that ADEP compounds can have high levels of in vitro (test tube) activity against bacteria that have worrisome levels of resistance and are common in both community and hospital settings: Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumonia. The ADEP compounds represent a novel mechanism of action; that is, instead of inhibiting activities of the bacteria like most antibiotics, they activate bacterial targets, essentially causing self-destruction. Finally, this mechanism of action is useful fora broad spectrum of bacterial species ('gram-positive bacteria'). It will be interesting to see how well these compounds perform in animal models."
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Publication:Duke Medicine Health News
Date:Apr 1, 2014
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