Key to Antibiotic Resistance Is to Leave No Enemies Behind, Says Expert

Newswise — A new paper in the February 17th edition of the journal Molecular Cell describes how exposure to low levels of antibiotics increases mutations in E. coli and Staphylococcus bacteria hundreds of times more than normal, making the creation of drug-resistant strains more likely.

This finding adds to concerns about antibiotic resistance brought on by poor prescription practices among doctors, patients who don't take all their medicine and even low doses of antibiotics given to animals to help them grow faster.

The researchers found that while low levels of antibiotics may not be enough to kill off the bacteria, they still stress them. That stress causes the bacteria to produce free radicals, says James Collins, a biomedical engineer at Boston University and one of the paper's authors. Basically, if the antibiotic dose isn't high enough to kill every bacterium in sight, "you could be creating a zoo with a wide range of mutations," says Collins.

“Upping the antibiotic dosage may be a viable solution but not the ultimate one,” says Bozena Korczak, Vice President Drug Development at Radnor, PA-based PolyMedix Inc. Driven by science conducted at the University of Pennsylvania, PolyMedix is investigating a novel class of antibiotic drugs that imitate natural human immunity and mimic the activity of host defense proteins, creating a lower risk for developing bacterial resistance. Host defense proteins are the oldest and most effective antimicrobial defense system in virtually all living creatures. Even with hundreds of millions of years of evolution, the host defense proteins have not developed widespread bacterial resistance, validating PolyMedix’s approach for its new antibiotic drugs.

“Like anything in nature, bacteria have ways to fight its opponents, and do so either by pumping antibiotics out of themselves through a process called efflux, or by rapidly mutating and changing the shape of the target of attack of the antibiotic drug. They can do this, even with large doses of antibiotics, it’s their innate way to try to survive,” explains Korczak. “The best approach to preventing this phenomenon is by directly attacking the bacteria’s cell membrane, rendering them destroyed and dead in a way that there is little chance of resistance. They cannot live to fight another day.” PolyMedix’s investigational antibiotic agent, called PMX-30063, is the first of its kind with a novel mechanism of action intended to directly address the serious medical problem of bacterial drug resistance. The host defense proteins work fundamentally differently from all other known antibiotics. Rather than crossing the bacterial membrane to find a target like most antibiotics, PMX-30063 is a synthetic small molecule that is designed to work the same way as host defense proteins, by selectively targeting the cell membrane integrity. This unique mechanism of action makes resistance unlikely to develop. To study the ability of bacteria to resist an antibiotic drug, a laboratory experimental method known as “serial passage” is used by intentionally trying to create bacterial resistance. Using this experiment, PolyMedix has shown in multiple serial passages that resistance did not appear to its compounds in contrast to classical antibiotics.

“PMX-30063 is the first small molecule defensin-mimetic antibiotic drug for systemic use, whose mechanism of action is directly designed and intended to make bacterial resistance unlikely to develop. We believe this will be an important advancement in treating serious infections”, said Dr. Korczak.

So far, data from two Phase I clinical studies demonstrate that the compound is safe and well-tolerated in both single and multiple doses. In both studies, drug levels were achieved which suggest a beneficial therapeutic index. In addition, bactericidal concentrations against MSSA and MRSA have been achieved in healthy human subjects following administration of PMX30063. PolyMedix is on schedule to complete the third and final segment of the ongoing Phase 1B study with PMX-30063 by the end of the first quarter of 2010, and to start a Phase 2 clinical study for the treatment of pan-Staphylococcal infections, including MRSA, by the end of the second quarter of this year.

PolyMedix has received 9 grants and research contracts from the National Institutes of Health and branches of the military to help support the development of its defensin-mimetic antibiotic compounds.

About PMX-30063

PolyMedix's antibiotic compound, PMX-30063, is a small molecule mimetic of human host-defense proteins, one of the oldest and most effective antimicrobial defense systems found in virtually all living creatures. PMX-30063 has unique properties including a mechanism of action that is completely different than current antibiotic drugs, and intended to make bacterial resistance unlikely to develop. In addition, it is fast acting and kills bacteria directly rather than simply stopping reproduction. A Phase 1A single dose trial has been successfully completed as well as two segments of a Phase 1B multi-dose clinical trial. The combined results showed that it was possible to safely administer PMX-30063 without any serious side effects at doses which exceeded those associated with full efficacy in animal models of infection. The side effects seen at higher doses were all mild and fully reversible. The third segment of the Phase 1B trial is underway.

For more information, log on to www.polymedix.com