Indolylalkyltriphenylphosphonium Analogues Are Membrane-Depolarizing Mycobactericidal Agents.

ABSTRACT: 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 ?M) and were bactericidal against Mycobacterium bovis BCG (MBC₉₉ 3 ?M). 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.

SUBMITTER: Li M 

PROVIDER: S-EPMC5683698 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature