IntraBiotics' Protogrins Show Broad Spectrum Killing of Antibiotic Resistant Pathogens, Ulcer-Producing Bacteria and Pathogenic Fungi.

SUNNYVALE, Calif--(BUSINESS WIRE)--Sept. 17, 1996--Protegrin peptides, first discovered in pig white blood cells, may offer new broad-spectrum antimicrobial treatments for many infectious diseases, including those resistant to conventional antibiotics.

The peptides, under development by IntraBiotics Pharmaceuticals, Inc., rapidly kill a wide range of disease-causing organisms including Gram positive and Gram negative bacteria, bacteria associated with gastric ulcers, and pathogenic fungi. Moreover, attempts in the laboratory to induce bacterial resistance to protegrins failed under conditions where conventional antibiotics quickly produce resistance in bacteria.

At the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in New Orleans, IntraBiotics scientists and their collaborators today presented results of three studies demonstrating the potential of protegrins for fighting antibiotic resistant and other hard-to-treat infections. Separately, Dr. Robert Lehrer of the University of California, Los Angeles School of Medicine presented a study showing the potential for topically applied protegrins to treat important bacterial and viral sexually transmitted diseases.

In the first study, IntraBiotics and their collaborators at Panlabs of Taipei, Taiwan described the ability of protegrins to treat systemic infections by important pathogens including Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus faecium (VRE). All three of these organisms have become resistant to nearly all conventional antibiotics and thus represent serious health risks. For example, P. aeruginosa can cause life-threatening lung infections in patients with cystic fibrosis, and MRSA and VRE are frequent causes of serious hospital-acquired infections.

The researchers conducted two sets of experiments. In the first set, they infected mice by injecting into their abdominal cavity (intraperitoneally) either P. aeruginosa or S. aureus at levels which, if untreated, normally kill the animals within 24 hours. They then injected the mice intraperitoneally with protegrin (PG-1) immediately after infection at doses of 0.05 to 5.0 mg/kg. The researchers found that treatment with protegrin significantly reduced mortality in the animals over a seven day period in a dose-dependent manner. In the second series of experiments, the researchers infected mice intravenously with MRSA or VRE at levels that would normally kill 90% of the animals within seven days. They then administered PG-1 intravenously at doses of 2.5 to 5.0 mg/kg up to one hour after infection. The researchers reported significant, dose-related protection of the infected mice over the seven day period. The study, entitled "Protegrin Protects Mice from Systemic Infection by Antibiotic Resistant Pathogens," was presented by David J. Loury, Ph.D., director of preclinical development at IntraBiotics.

"Based on these results, Protegrins may offer an important new weapon for the treatment of serious infectious diseases, including those caused by bacteria that have become resistant to currently available antibiotics," commented John C. Fiddes, Ph.D., vice president of research and development at IntraBiotics and a co-author of the study.

In the second study, the IntraBiotics researchers demonstrated the ability of PG-1 to rapidly kill a variety of bacterial and fungal pathogens. At concentrations ranging from 0.5 to 4 ug/mL, PG-1 reduced the viability of both cultures MRSA or P. aeruginosa by more than 1000-fold in less than 15 minutes. Moreover this bacterial killing occurred much more rapidly with PG-1 treatment than was achievable using conventional antibiotics. The researchers also saw rapid fungicidal activity by PG-1 against Candida albicans. Additionally, they observed that MRSA did not become resistant to PG-1 when grown serially under conditions that increased the organism's resistance to the antibiotic norfloxacin by a factor of 85. Similarly P. aeruginosa did not develop resistance to PG-1 under growth conditions that increased the bacteria's resistance to norfloxacin and gentamicin by 10-fold and 190-fold respectively. The study, entitled "Broad Spectrum Antimicrobial Activity of Protegrin Peptides," was presented by Deborah A. Steinberg, Ph.D., director of microbiology at IntraBiotics.

"Unlike many antibiotics, which either halt the growth of microorganisms without actually killing them or kill them slowly, protegrins quickly kill both bacteria and fungi," said Dr. Steinberg. "In addition, protegrins appear to avoid the normal mechanisms by which bacteria quickly develop resistance to conventional antibiotics."

In the third study, the IntraBiotics researchers showed the potential of protegrins for treating gastric ulcers caused by Helicobacter pylori. In this study, PG-1 rapidly killed H. pylori in culture, with 8 ug/ml concentrations of the protegrin reducing bacterial populations by 100 and 10,000 fold after 15 and 60 minutes. Four day old H. pylori cultures remained susceptible to PG-1, suggesting the protegrin's killing activity did not depend on active bacterial growth. In addition, PG-1 was stable in acidic pH ranging from pH2 to pH7 and was resistant to pepsin, a digestive enzyme found in the stomach. In contrast, PG-1 was degraded by enzymes such as trypsin and chymotrypsin found in the lower gastrointestinal tract, thus avoiding the potential for lower G.I. tract side effects. The study, entitled "In Vitro Efficacy of Protegrins Against Helicobacter pylori," was also presented by Dr. Steinberg.

"Conventional antibiotics have demonstrated some success in eradicating H. pylori, but current antibiotic therapies for ulcers are complex and the rate of relapse high," commented Dr. Steinberg. "These findings suggest that protegrins could potentially eliminate H. pylori from the stomach effectively without disturbing the beneficial bacteria present in the lower G.I. tract, thus providing more effective treatments for gastric ulcers."

IntraBiotics Pharmaceuticals, Inc. is currently developing protegrins as potential treatments for multi-drug resistant infections, gastric ulcers, and oral infections that occur as a side-effect of chemotherapy. The company, founded in early 1994, is a privately held developer of novel antimicrobial drugs for the treatment and prevention of serious infectious disease. IntraBiotics bases its initial products on natural antimicrobial substances that are produced as part of the internal host defense systems of animals, including humans and other mammals.

CONTACT: IntraBiotics Pharmaceuticals, Inc.

Kenneth J. Kelley, 408/991-6400

or

J. Kureczka Associates

Joan E. Kureczka, 415/821-2413