Adjuvant therapies against tuberculosis: discovery of a 2-aminothiazole targeting Mycobacterium tuberculosis energetics

Abstract

Aim: To evaluate the activity of the 2-aminothiazole UPAR-174 following an unexplored approach: targeting Mycobacterium tuberculosis with lipophilic compounds that present antituberculosis and efflux inhibitory activity.

Methods: Antituberculosis activity was assessed against replicating, nonreplicating and intracellular bacilli. Its capacity to inhibit active efflux was determined. ATP quantification and membrane potential analysis were performed. Intracellular activity was studied on human-monocyte-derived macrophages.

Results: UPAR-174 is an efflux inhibitor active against replicating, nonreplicating and intracellular M. tuberculosis. It dissipates the membrane potential and causes ATP depletion.

Conclusion: Targeting M. tuberculosis with lipophilic efflux inhibitors, exploring their dual activity - dissipation of the proton motive force and efflux inhibition - represents an attractive strategy to fight against drug-resistant tuberculosis.

Keywords: ATP depletion; PMF; UPAR-174; efflux inhibitors; lipophilicity; mycobacterial metabolism; tuberculosis.