Novel approaches to controlling Mycobacterium tuberculosis latency and infection by inhibiting the electron transport chain

The emergence of drug resistant strains of Mycobacterium tuberculosis (Mtb) has prompted a search for novel antimycobacterial agents. Mtb is an obligate aerobe capable of long term persistence under conditions of low oxygen tension. Analysis of the Mtb genome predicts the existence of a branched aerobic respiratory chain terminating in a cytochrome bd system and a cytochrome aa3 system. We demonstrate that cytochrome bd oxidase is important for mycobacterial growth under low oxygen conditions, as is found in granulomas. Both chains can be initiated with type II NADH:menaquinone oxidoreductase (Ndh, NdhA). We present the first detailed biochemical characterization of the aerobic respiratory chains from Mtb through the study of cytochrome bd oxidase and Ndh enzymes. We introduce a new class of antitubercular compounds, phenothiazines, which specifically inhibit Ndh and NdhA activity. Several phenothiazines analogs are highly tuberculocidal in vitro, suppress Mtb growth in a mouse model of acute infection, and represent lead compounds that may give rise to a new class of selective antibiotics. As detailed understanding of the molecular mechanisms controlling dormancy emerges, drugs affecting the electron transport chain may prove to be important agents in activating bacilli from dormancy thereby shortening the course of tuberculosis treatment.