Caught between two proteins: a mycobacterial inhibitor challenges the mold.
Elucidating the target or mechanism of action of potential drugs in the discovery pipeline is an integral component of most programs. For antibacterial compounds, generation of resistant mutants followed by whole genome sequencing has often been successful in uncovering the proteins involved in regulating compound activation, uptake, efflux and importantly, target processes. When this process succeeds, we are quick to declare a target. In a study reported by Sing and Dhar et al. (in press), the combination of resistant mutant generation, whole genome sequencing and recombineering to identify the target of a Mycobacterium tuberculosis growth inhibitor, pointed to a mechanism involving a scaffolding protein, Wag31, involved in polar elongation of mycobacterial cells. Time-lapse microscopy and electron microscopy confirmed the view that this inhibitor resulted in interruption of nascent cell wall biosynthesis. However, co-expression as well as regulated titration of the putative Wag31 target demonstrated that the wild-type allele was dominant and showed no synergy with the inhibitor. The most plausible explanation from their results was that this inhibitor interfered with the interaction of Wag31 with one of its interacting partners in the elongation complex.
Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, 20892-3206, USA.
Helena I
HI
Boshoff
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D009169:Mycobacterium tuberculosis / Q000235:genetics; D010457:Peptidoglycan / Q000378:metabolism; D011485:Protein Binding
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010457:Peptidoglycan; C000591547:Wag31 protein, Mycobacterium tuberculosis