Indolylalkyltriphenylphosphonium Analogues Are Membrane-Depolarizing Mycobactericidal Agents

ACS Med Chem Lett. 2017 Oct 9;8(11):1165-1170. doi: 10.1021/acsmedchemlett.7b00287. eCollection 2017 Nov 9.


Agents that selectively target the mycobacterial membrane could potentially shorten treatment time for tuberculosis, reduce relapse, and curtail emergence of resistant strains. The lipophilicity and extensive charge-delocalized state of the triphenylphosphonium cation strongly favor accumulation within bacterial membranes. Here, we explored the antimycobacterial activities and membrane-targeting properties of indolylalkyltriphenylphosphonium analogues. The most active analogues preferentially inhibited growth of Mycobacterium tuberculosis H37Rv (MIC50 2-4 μM) and were bactericidal against Mycobacterium bovis BCG (MBC99 3 μM). In spite of their propensity to accumulate within membranes, we found no evidence that these compounds permeabilized mycobacterial membranes or induced cell-envelope stress. Our investigations indicated that their bacterical effects stem from sustained depolarization of mycobacterial membranes and ensuing disruptive effects on electron transfer and cell division.