TY - JOUR
T1 - Direct Inhibition of MmpL3 by Novel Antitubercular Compounds
AU - Li, Wei
AU - Stevens, Casey M.
AU - Pandya, Amitkumar N.
AU - Darzynkiewicz, Zbigniew
AU - Bhattarai, Pankaj
AU - Tong, Weiwei
AU - Gonzalez-Juarrero, Mercedes
AU - North, E. Jeffrey
AU - Zgurskaya, Helen I.
AU - Jackson, Mary
N1 - Funding Information:
This work was supported by a grant from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (AI116525) (to M.J., H.I.Z. and E.J.N.), a grant from the Bill and Melinda Gates Foundation (OPP1181207) (to M.J. and H.I.Z.), and a sponsored research contract with the Global Alliance for TB Drug Development (to M.J.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We are grateful to the Global Alliance for TB Drug Development for the provision of NITD-304 and NITD-349, to Dr. Remuinan-Blanco (GSK Tres Cantos Open Lab Foundation) for the provision of THPP1, and to Dr. Borlee (Colorado State University) for his help with confocal imaging.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/6/14
Y1 - 2019/6/14
N2 - 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.
AB - 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.
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U2 - 10.1021/acsinfecdis.9b00048
DO - 10.1021/acsinfecdis.9b00048
M3 - Article
C2 - 30882198
AN - SCOPUS:85064181355
VL - 5
SP - 1001
EP - 1012
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
SN - 2373-8227
IS - 6
ER -