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.
“The next step is to improve on the three HDP mimics using classical medicinal chemistry,” notes Richard Scott, Ph.D., Polymedix VP of Research and presenter on the landmark poster.
“Drugs that act through typical antibiotic mechanisms are doomed eventually to fail,” Dr. Scott adds. “Host defense peptides have evolved in higher organisms over millions of years, specifically to avoid these mechanisms. That is what we have captured in our HDP mimics.”
PolyMedix has several HDPs in development for treating bacterial diseases. The most advanced lead compound, PMX-30063, is currently in Phase I clinical testing. PolyMedix plans to develop PMX-30063 as a systemic agent to broadly treat many kinds of Staph infections. The company is looking for partners to help bring its promising anti-TB compounds into the clinic.
MDR and XDR TB in the Context of HIV
TB has been on the rise since the 1980s, with new infections rising dramatically in Southeast Asia and Africa. Health officials believe that TB’s resurgence is a direct result of the epidemic of HIV/AIDS in these regions. By 1993 the World Health Organization declared TB to be a global emergency. Fifteen years later, and despite being treatable for decades, TB has become one of the world's major causes of illness and death. One-third of the world's population (two billion people) are TB carriers, and in 2006 14 million had active disease and 1.7 million died from TB. Approximately 700,000 cases (5% of all TB cases) were reported among individuals co-infected with HIV, but of the fatalities 14% were co-infected.
Most carriers never become sick from the TB bacterium, but those with HIV/AIDS and other conditions that compromise the immune system carry nearly three times the risk for developing TB. In addition to suffering the highest levels of sickness and death from TB, individuals co-infected with TB and HIV become potential reservoirs for the deadliest forms of MDR-TB and XDR-TB.
Individuals with “normal” TB are usually cured after a relatively brief regimen of antibiotics. MDR-TB may be transmitted between individuals, or arise when the standard antibiotics are prescribed improperly or when patients fail to follow dosing regimens. Similarly, XDR-TB arises when second-line drugs are prescribed improperly, or when patients fail to complete treatment for MDR-TB. MDR-TB and XDR-TB antibiotic regimens are much longer than for “regular” TB – sometimes as long as one to two years. “Compliance is often poor for long therapeutic regimens,” says Dr. Scott, “which in turn helps breed antibiotic resistance.” Even when patients comply with treatment regimens, HIV drugs and tuberculosis medicines appear to work at odds, each reducing the other’s effectiveness.
XDR-TB is still a relatively rare form of MDR-TB, but among those co-infected with HIV the mortality rate is about 90%. XDR-TB alarms public health officials because the disease is transmitted, like other forms of TB, through coughs or sneezes of infected individuals.
Individuals living with HIV are particularly prone to problems with dosing regimens as many live in undeveloped countries. HIV-positive individuals in developed countries experience antibiotic compliance problems as well.
The poster’s first author, David Miller, internationally known AIDS treatment activist, Board member of the AIDS Institute and a member of the Cornell Adult AIDS clinical trial group, is an outspoken advocate for devoting research dollars to the fight against tuberculosis. As Miller points out, federal funding for AIDS is poorly allocated as far as the life-and-death issues affecting HIV-infected individuals.
“We should continue to fund AIDS vaccines and research into more effective antiretroviral medicines, but these are long-term projects,” says Mr. Miller. “Today, more people with HIV are dying from tuberculosis, a disease with the potential to spread like wildfire in a crowded urban environment, including among people who are HIV-negative.”