Direct Inhibition of MmpL3 by Novel Antitubercular Compounds

Wei Li, Casey M. Stevens, Amitkumar N. Pandya, Zbigniew Darzynkiewicz, Pankaj Bhattarai, Weiwei Tong, Mercedes Gonzalez-Juarrero, E. Jeffrey North, Helen I. Zgurskaya, Mary Jackson

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

MmpL3, an essential transporter involved in the export of mycolic acids, is the proposed target of a number of antimycobacterial inhibitors under development. Whether MmpL3 serves as the direct target of these compounds, however, has been called into question after the discovery that some of them dissipated the proton motive force from which MmpL transporters derive their energy. Using a combination of in vitro and whole-cell-based approaches, we here provide evidence that five structurally distinct MmpL3 inhibitor series, three of which impact proton motive force in Mycobacterium tuberculosis, directly interact with MmpL3. Medium- to high-throughput assays based on these approaches were developed to facilitate the future screening and optimization of MmpL3 inhibitors. The promiscuity of MmpL3 as a drug target and the mechanisms through which missense mutations located in a transmembrane region of this transporter may confer cross-resistance to a variety of chemical scaffolds are discussed in light of the exquisite vulnerability of MmpL3, its apparent mechanisms of interaction with inhibitors, and evidence of conformational changes induced both by the inhibitors and one of the most commonly identified resistance mutations in MmpL3.

Original languageEnglish (US)
Pages (from-to)1001-1012
Number of pages12
JournalACS Infectious Diseases
Volume5
Issue number6
DOIs
StatePublished - Jun 14 2019

All Science Journal Classification (ASJC) codes

  • Infectious Diseases

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    Li, W., Stevens, C. M., Pandya, A. N., Darzynkiewicz, Z., Bhattarai, P., Tong, W., Gonzalez-Juarrero, M., North, E. J., Zgurskaya, H. I., & Jackson, M. (2019). Direct Inhibition of MmpL3 by Novel Antitubercular Compounds. ACS Infectious Diseases, 5(6), 1001-1012. https://doi.org/10.1021/acsinfecdis.9b00048