Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase. Academic Article uri icon

abstract

  • 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.

published proceedings

  • Antimicrob Agents Chemother

altmetric score

  • 9.5

author list (cited authors)

  • Palencia, A., Li, X., Bu, W., Choi, W., Ding, C. Z., Easom, E. E., ... Alley, M.

citation count

  • 65

complete list of authors

  • Palencia, Andrés||Li, Xianfeng||Bu, Wei||Choi, Wai||Ding, Charles Z||Easom, Eric E||Feng, Lisa||Hernandez, Vincent||Houston, Paul||Liu, Liang||Meewan, Maliwan||Mohan, Manisha||Rock, Fernando L||Sexton, Holly||Zhang, Suoming||Zhou, Yasheen||Wan, Baojie||Wang, Yuehong||Franzblau, Scott G||Woolhiser, Lisa||Gruppo, Veronica||Lenaerts, Anne J||O'Malley, Theresa||Parish, Tanya||Cooper, Christopher B||Waters, M Gerard||Ma, Zhenkun||Ioerger, Thomas R||Sacchettini, James C||Rullas, Joaquín||Angulo-Barturen, Iñigo||Pérez-Herrán, Esther||Mendoza, Alfonso||Barros, David||Cusack, Stephen||Plattner, Jacob J||Alley, MRK

publication date

  • October 2016