Cryo-EM structure and resistance landscape of M. tuberculosis MmpL3: An emergent therapeutic target

Author:

Adams, Oliver

Deme,Justin

Parker, Joanne L

Fowler, Philip W

Lea,Susan

Newstead, Simon
Author Address

Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK., The Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK; Central Oxford Structural Molecular Imaging Centre (COSMIC), University of Oxford, Oxford OX1 3RE, UK; Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA., Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK; National Institute of Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe, Oxford OX3 9DU, UK., The Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK; Central Oxford Structural Molecular Imaging Centre (COSMIC), University of Oxford, Oxford OX1 3RE, UK; Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA. Electronic address: susan.lea@nih.gov., Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK. Electronic address: simon.newstead@bioch.ox.ac.uk.,

Abstract:

Tuberculosis (TB) is the leading cause of death from a single infectious agent and in 2019 an estimated 10 million people worldwide contracted the disease. Although treatments for TB exist, continual emergence of drug-resistant variants necessitates urgent development of novel antituberculars. An important new target is the lipid transporter MmpL3, which is required for construction of the unique cell envelope that shields Mycobacterium tuberculosis (Mtb) from the immune system. However, a structural understanding of the mutations in Mtb MmpL3 that confer resistance to the many preclinical leads is lacking, hampering efforts to circumvent resistance mechanisms. Here, we present the cryoelectron microscopy structure of Mtb MmpL3 and use it to comprehensively analyze the mutational landscape of drug resistance. Our data provide a rational explanation for resistance variants local to the central drug binding site, and also highlight a potential alternative route to resistance operating within the periplasmic domain. Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

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