Beating the Number-One Killer in AIDS: Tuberculosis

The success of treating HIV/AIDS with antiretroviral therapy has been a good news, bad news proposition. Individuals with HIV and AIDS are living longer due to the success of antiretroviral therapies. While these agents – of which more than twenty have been approved in the U.S. – do an adequate job of keeping the human immunodeficiency virus at bay for long periods, some experts suspect the benefit is not as great as it might be. While fewer people are dying from HIV infection, an alarming number today are succumbing to tuberculosis, particularly multiple drug-resistant tuberculosis (MDR TB) and extensively drug-resistant tuberculosis (XR TB).

Once quite treatable, TB has slowly evolved resistance to first- and second-line antibiotics, throwing the wisdom of employing antibiotics to treat TB into doubt. Now, Radnor-based PolyMedix reports that a series of small-molecule mimics of host defense peptides (HDPs), which in vitro stop the TB bacteria in its tracks. While structurally quite different from HDPs, PolyMedix’s HDP mimics share a critical similarity: They are amphiphilic, meaning they possess both hydrophilicity and hydrophobicity – affinity for oily and watery components of cells. This quality permits HDP mimics to disrupt the membranes of Mycobacterium organisms, which cause TB. Once this occurs the TB bacterium dies. This mechanism of action, the direct lysis of bacterial cell membranes, is fundamentally different from currently marketed antibiotics used for TB and other systemic infections. This mechanism of action of PolyMedix’s compounds also makes bacterial resistance unlikely to develop.

Researchers from PolyMedix and the University of Pennsylvania reported their findings in a poster, “Antimicrobial Molecules for Treatment of Multi-drug Resistant (MDR) and Extensively Drug Resistant (XDR) Strains of Mycobacterium Tuberculosis,” at the HIV DART conference on antiretroviral therapies, held in Puerto Rico December 9-12, 2008.

Investigators screened a library of PolyMedix’s HDP mimics in collaboration with the Tuberculosis Antimicrobial Acquisition Facility, a branch of the National Institute of Allergy and Infectious Diseases. Three of the antimicrobial compounds exhibited high antimicrobial activity (IC90 < 5 µg/ml) against H37Rv, a common laboratory strain of M. tuberculosis, with selectivity greater than 30-120 fold for TB versus mammalian cells.

Because they have a biophysical mechanism of action, and do not operate through known biological pathways or specific molecular targets, PolyMedix’s HDP mimics are unlikely to cause antimicrobial resistance – the mechanism by which antibiotic drugs lose their effectiveness over time. PolyMedix has confirmed the lack of experimental resistance to these and other of its HDP mimic antibiotic compounds against a wide range of infectious agents through “serial passaging” studies. These tests involve re-culturing the infective organism, grown in the presence of the drug, for many generations. No increase in minimum inhibitory concentration has been noted for any bacterium paired with a PolyMedix HDP mimic compound.