Transport mechanism of Mycobacterium tuberculosis MmpL/S family proteins and implications in pharmaceutical targeting

Abstract

Tuberculosis caused by Mycobacterium tuberculosis remains a serious threat to public health. The M. tuberculosis cell envelope is closely related to its virulence and drug resistance. Mycobacterial membrane large proteins (MmpL) are lipid-transporting proteins of the efflux pump resistance nodulation cell division (RND) superfamily with lipid substrate specificity and non-transport lipid function. Mycobacterial membrane small proteins (MmpS) are small regulatory proteins, and they are also responsible for some virulence-related effects as accessory proteins of MmpL. The MmpL transporters are the candidate targets for the development of anti-tuberculosis drugs. This article summarizes the structure, function, phylogenetics of M. tuberculosis MmpL/S proteins and their roles in host immune response, inhibitors and regulatory system.

Corynebacterium glutamicum CrtR and Its Orthologs in Actinobacteria: Conserved Function and Application as Genetically Encoded Biosensor for Detection of Geranylgeranyl Pyrophosphate

“…Besides carotenogenesis genes, mmpL genes are also transcribed divergently to crtR , and are presumably controlled by CrtR. MmpL transporters are considered candidate targets for the development of anti-tuberculosis drugs [ 57 ], as they couple lipid synthesis and the export of bulky, hydrophobic substrates [ 58 ]. Thus, MmpL proteins are essential for the cell envelope, and support the infectivity and persistence of M. tuberculosis in its host [ 59 ].…”

Efflux pump inhibitors as a promising adjunct therapy against drug resistant tuberculosis: a new strategy to revisit mycobacterial targets and repurpose old drugs

“…For example, Rv1410c (P55) is involved in the maintenance of normal growth characteristics and in the oxidative stress response and Rv1258c is important for normal growth kinetics and cell morphology and it appears to play a relevant role in the stationary phase of growth [17][18][19]. Other transporters like the mycobacterial membrane proteins large (MmpL) are involved in the transport of lipids and promote cell wall biosynthesis [20,21]. In particular, MmpL3 is involved in the export of mycolates, one of the key components of the cell wall and MmpL7 exports phthiocerol dimycocerosate, a lipid component of the outer membrane [22][23][24][25][26].…”

Molecular Modelling and Atomistic Insights into the Binding Mechanism of MmpL3 Mtb

“…[6,7] The Mycobacterium tuberculosis encodes 14 MmpL proteins, all of which have transmembrane domains (TMD) and periplasmic loop domains (D). [8] However, MmpL3 is the only one considered essential for the replication and viability of mycobacterial cells. [6,9] The integrity of the mycobacterial cell is dependent on the MmpL3 as it contributes to the innate resistance of mycobacteria to antimicrobials.…”

“…[6,10] The cell envelope consists of five layers; capsule layer, mycomembrane, arabinogalactan, peptidoglycan, and plasma membrane. [8] This results in the thick, waxy, and impermeable make-up of the bacterial cell envelop, making it resistant to drugs. This suggests that the inactivation of the MmpL3 transporter will lead to rapid cell death.…”