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

Indolylalkyltriphenylphosphonium Analogues Are Membrane-Depolarizing Mycobactericidal Agents.

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Department of Medicine and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228.
Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543.
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey 07103, United States.


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.

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