click to enlarge Learning from nature's defenses against bacteria. (Source: PolyMedix, Inc. )

Seventy percent of infections in the US are now drug resistant¹, making the rapid rise of drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus a serious medical problem. A unique solution involves the development of synthetic antibiotic compounds that have a mechanism to directly target and disrupt bacterial membranes.  

PMX-30063, an antibiotic compound currently being developed by PolyMedix, Inc. (Radnor, PA) for the broad treatment of Staphylococcus/MRSA infections, is a small, non-peptidic molecule that mimics human host defense proteins (i.e., defensins). A proprietary computational de novo drug design platform, created by National Academy of Science members Drs. William DeGrado and Michael Klein and licensed from the University of Pennsylvania, was used in its design. PolyMedix’s approach has been to create synthetic small molecules that are able to mimic the unique mechanism of action of defensins but with a stability that allows their use as a systemic drug.

The properties of PMX-30063, as well as those of other PolyMedix defensin-mimetic compounds, work via the direct biophysical disruption of bacterial cell membranes. Consequently, the compound is bactericidal, rather than bacteriostatic as the majority of existing antibiotics are. The direct lysis of the membranes minimizes the chances that bacterial resistance will arise. In this sense the compound is able to imitate the mechanisms of natural human immunity.

Phase 1 single- and multi-dose clinical studies with PMX-30063 have been completed. Both of these were dose-escalation studies in healthy volunteers receiving PMX-30063 at various dose levels. The primary endpoints of these studies were safety assessments. In the single-dose study, a maximally tolerated single dose of 2.5 mg/kg was achieved. In the multi-dose study, the maximum dose given was 0.6 mg/kg/day for 5 days (total amount administered 3.0 mg/kg). Additional ex vivo antimicrobial assays were also performed as part of the multi-dose Phase 1B study. These results showed PMX-30063 to be bactericidal against MRSA and MSSA in human serum in blood samples starting at single doses as low as 0.1 to 0.3 mg/kg.

PolyMedix is planning to initiate a Phase 2 clinical trial in patients with Staph infections (including MRSA and MSSA) in the second quarter of 2010; the clinical target is expected to be acute bacterial skin and skin structure infections (ABSSSI). It is anticipated that Phase 2 studies should be completed by the end of the first quarter of 2011.

The continuing development of PMX-30063 suggests a novel potential solution to the serious problem of Staph resistance.

Reference
1. Todar K. Todar’s Online Textbook of Bacteriology, p1. Available at: http://www.textbookofbacteriology.net/resantimicrobial.html. Accessed April 6, 2010.