Despite the recent downward trend in drug use, the prevalence of injection drug abuse is still higher than in the early 1990s. The health and social consequences of drug abuse - HIV/AIDS, tuberculosis, violence, and crime - have a devastating impact on society and cost billions of dollars each year. Injection drug abuse is particularly remarkable in that abusers face unique secondary consequences of their addictions, such as HIV/AIDS and tuberculosis, which are both potential complicating factors in their overall treatment. Among injection drug users with HIV/AIDS, the grampositive bacterium Mycobacterium tuberculosis is the principle causative agent of TB infections seen. Treatment for TB infections against Mycobacterium tuberculosis in these populations involves the administration of the antibiotics rifampicin and isoniazid but emerging multidrug-resistant (MDR) TB strains have seriously compromised and complicated treatment. To explore alternative methodologies for the treatment and control of TB infections we propose to study the antimicrobial peptide nisin. Over the last 50 years, nisin has demonstrated an undiminished selective cytotoxicity towards gram-positive bacteria. Recent in vitro studies have shown that nisin exhibits antimycobacterial activities by depleting ATP and the proton motive force in mycobacteria and also by causing the loss of the permeability barrier of the cytoplasmic membrane. The goal of the studies described herein is to understand the biosynthesis of nisin by investigating the enzymes responsible for its synthesis and to explore the hypothesis that modifications to these enzymes can generate novel enzymes capable of generating new antibiotics based on the nisin framework that display greater antimycobactericidal activity.
