Grzegorzewicz AE, Pham H, Gundi VA, Scherman MS, North EJ, Hess T, Jones V, Gruppo V, Born SE, Korduláková J, Chavadi SS, Morisseau C, Lenaerts AJ, Lee RE, McNeil MR, Jackson M. Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nat Chem Biol. 2012 Feb 19. doi: 10.1038/nchembio.794. [Epub ahead of print]
This week’s article highlights research out of Colorado State University that identifies a potential anti-TB compound against a unique target– the inner membrane transporter MmpL3 of Mycobacterium tuberculosis–that inhibits an essential cell function of the mycobacteria.
New chemotherapeutics active against multidrug-resistant Mycobacterium tuberculosis are urgently needed. We report on the identification of an adamantyl urea compound that shows potent bactericidal activity against M. tuberculosis and a unique mode of action, namely the abolition of the translocation of mycolic acids from the cytoplasm, where they are synthesized to the periplasmic side of the plasma membrane and are in turn transferred onto cell wall arabinogalactan or used in the formation of virulence-associated, outer membrane, trehalose-containing glycolipids. Whole-genome sequencing of spontaneous-resistant mutants of M. tuberculosis selected in vitro followed by genetic validation experiments revealed that our prototype inhibitor targets the inner membrane transporter MmpL3. Conditional gene expression of mmpL3 in mycobacteria and analysis of inhibitor-treated cells validate MmpL3 as essential for mycobacterial growth and support the involvement of this transporter in the translocation of trehalose monomycolate across the plasma membrane.
Research by Helena Boshoff’s Lab at the NIH/NIAID also showing MmpL3 as a target of SQ109:
Tahlan K, Wilson R, Kastrinsky DB, Arora K, Nair V, Fischer E, Barnes SW, Walker JR, Alland D, Barry CE 3rd, Boshoff HI. SQ109 Targets MmpL3, a Membrane Transporter of Trehalose Monomycolate Involved in Mycolic Acid Donation to the Cell Wall Core of Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2012 Jan 17. [Epub ahead of print]
Additional TB R&D News: