Exploitation of key enzymes of the mycothiol biosynthesis to improve treatment of mycobacterium avium complex infections.

Worldwide, pulmonary disease caused by members of the Mycobacterium avium complex (MAC) is increasing. Treatment of MAC lung disease requires a multidrug chemotherapy that takes up to 12 months and often leads to adverse drug effects, treatment failure, MAC reinfection and the emergence of drug resistance. New strategies need to be explored that can lead to more successful treatment of MAC infection. Mycothiol cysteine ligase (MshC) and the mycothione reductase (Mtr) are two key enzymes of the bacillary redox homeostasis and are unexploited drug targets. We hypothesize that these genes play an essential role for both the virulence and the stress tolerance within MAC and that targeting these genes would synergize with existing and emerging antimycobacterial therapeutics. In this project proposal we aim to investigate these hypotheses by the generation of a panel of recombinant MAC strains in order to study the impact of the target genes on the physiological growth, stress tolerance, cellular and in vivo virulence and synergy with existing and emerging MAC therapeutics. The findings can support future target-based drug development programs of potential Mtr and MshC inhibitors. In the long run, the findings within this research could lead to a safer, shorter and more cost-effective treatment of MAC infection.

Keywords:TARGETED THERAPY, REDOX HOMEOSTASIS

Disciplines:Proteins, Infectious diseases, Bacteriology