title: Lipid transport in Mycobacterium tuberculosis and its implications in virulence and drug development.
abstract: Tuberculosis is still a major health problem worldwide and one of the main causes of death by a single infectious agent. Only few drugs are really effective to treat tuberculosis, hence, the emergence of multiple, extensively, and totally drug resistant bacilli compromises the already difficult antituberculosis treatments. Given the persistent global burden of tuberculosis, it is crucial to understand the underlying mechanisms required for the pathogenicity of Mycobacterium tuberculosis (Mtb), the causal agent of tuberculosis, in order to pave the way for developing better drugs and strategies to treat and prevent tuberculosis. The exclusive mycobacterial cell wall lipids such as trehalose monomycolate and dimycolate (TMM, TDM), phthiocerol dimycocerosate (PDIM), sulpholipid-1 (SL-1), diacyl trehalose (DAT), and pentacyl trehalose (PAT), among others, are known to play an important role in pathogenesis; thus, proteins responsible for their transport are potential virulence factors. MmpL and MmpS proteins mediate transport of important cell wall lipids across the mycobacterial membrane. In Mtb, MmpL3, MmpL7 and MmpL8 transport TMM, PDIM and SL-1 respectively. The translocation of DAT and biosynthesis of PAT is likely due to MmpL10. MmpL and MmpS proteins are involved in other processes such as drug efflux (MmpL5 and MmpL7), siderophore export (MmpL4/MmpS4 and MmpL5/MmpS5), and heme uptake (MmpL3 and MmpL11). Altogether, these proteins can be regarded as new potential targets for antituberculosis drug development. We will review recent advances in developing inhibitors of MmpL proteins, in the challenging context of targeting membrane proteins and the future prospects for potential antituberculosis drug candidates.
authors.affiliation: Departamento de Microbiología, Facultad de Medicina, Universidad de Zaragoza and Instituto de Investigación Sanitaria Aragón (IIS Aragón), c/Domingo Miral s/n, 50009-Zaragoza, and Ciber de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Bailo
authors.affiliation: School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors.forename: Apoorva
authors.initials: A
authors.lastname: Bhatt
authors.affiliation: Departamento de Microbiología, Facultad de Medicina, Universidad de Zaragoza and Instituto de Investigación Sanitaria Aragón (IIS Aragón), c/Domingo Miral s/n, 50009-Zaragoza, and Ciber de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Spain. Electronic address: ainsa@unizar.es.
authors.forename: José A
authors.initials: JA
authors.lastname: Aínsa
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002473:Cell Wall / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D003311:Cord Factors / Q000378:metabolism; D015195:Drug Design; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D015870:Gene Expression; D006017:Glycolipids / Q000378:metabolism; D006418:Heme / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D003311:Cord Factors; D006017:Glycolipids; D026901:Membrane Transport Proteins; C000599913:MmpL3 protein, Mycobacterium tuberculosis; C514650:MmpL7 protein, Mycobacterium tuberculosis; D037521:Virulence Factors; C021099:trehalose monomycolate; D006418:Heme; C009355:sulfolipid I
keywords: AU1235 (PubChem CID: 3754047); BM212 (PubChem CID: 456926); Drug resistance; Lipid transport; MmpL/S proteins; SQ109 (PubChem CID: 5274428); Transport proteins; Tuberculosis