The diverse family of MmpL transporters in mycobacteria: from regulation to antimicrobial developments.
Mycobacterial genomes contain large sets of loci encoding membrane proteins that belong to a family of multidrug resistance pumps designated Resistance-Nodulation-Cell Division (RND) permeases. Mycobacterial membrane protein Large (MmpL) transporters represent a subclass of RND transporters known to participate in the export of lipid components across the cell envelope. These surface-exposed lipids with unusual structures play key roles in the physiology of mycobacteria and/or can act as virulence factors and immunomodulators. Defining the substrate specificity of MmpLs and their mechanisms of regulation helps understanding how mycobacteria elaborate their complex cell wall. This review describes the diversity of MmpL proteins in mycobacteria, emphasising their high abundance in a few opportunistic rapid-growing mycobacteria. It reports the conservation of mmpL loci between Mycobacterium tuberculosis and non-tuberculous mycobacteria, useful in predicting the role of MmpLs with unknown functions. Paradoxically, whereas MmpLs participate in drug resistance mechanisms, they represent also attractive pharmacological targets, opening the way for exciting translational applications. The most recent advances regarding structural/functional information are also provided to explain the molecular basis underlying the proton-motive force driven lipid transport. Overall, this review emphasises the Janus-face nature of MmpLs at the crossroads between antibiotic resistance mechanisms and exquisite vulnerability to drugs.
Institut de Recherche en Infectiologie de Montpellier (IRIM), CNRS, UMR 9004, Université de Montpellier, France.
Albertus
A
Viljoen
INSERM, UMR1173, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, 78180, France.
Violaine
V
Dubois
INSERM, UMR1173, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, 78180, France.
Fabienne
F
Girard-Misguich
Institut de Recherche en Infectiologie de Montpellier (IRIM), CNRS, UMR 9004, Université de Montpellier, France.
Mickaël
M
Blaise
INSERM, UMR1173, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, 78180, France.
Jean-Louis
JL
Herrmann
Institut de Recherche en Infectiologie de Montpellier (IRIM), CNRS, UMR 9004, Université de Montpellier, France.|IRIM, INSERM, 34293, Montpellier, France.
Laurent
http://orcid.org/0000-0002-6604-4458
L
Kremer
D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D002473:Cell Wall / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D026901:Membrane Transport Proteins / Q000378:metabolism* / Q000502:physiology*; D009169:Mycobacterium tuberculosis / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018892:Proton-Motive Force; D037521:Virulence Factors / Q000378:metabolism
D000890:Anti-Infective Agents; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D037521:Virulence Factors