RT Journal Article
T1 Discovery of novel oral protein synthesis inhibitors of mycobacterium tuberculosis that target leucyl-tRNA synthetase
A1 Palencia, Andrés
A1 Mendoza Losana, Alfonso
AB The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against M. tuberculosis. Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.
PB American Society for Microbiology
SN 0066-4804
YR 2016
FD 2016-09-23
LK https://hdl.handle.net/10016/38873
UL https://hdl.handle.net/10016/38873
LA eng
NO A.J.L. acknowledges NIH/NIAID contract NO1 AI-95385 (TuberculosisAntimicrobial Acquisition and Coordinating Facility) for the efficacy testingin mouse models of acute and chronic of infections.
DS e-Archivo
RD 17 jul. 2024