The combined use of para-aminosalicylic acid (PAS) and streptomycin in pulmonary tuberculosis

Nagley, M.M.

doi:10.1016/s0041-3879(50)80136-8

Cited by 3 publications

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“…Emergence of resistance during streptomycin monotherapy ( 34 ) and its noted reduction by the addition of p -aminosalicylic acid ( 35 , 36 ) lead to the paradigm of combination TB drug therapy. The current core TB regimen calls for a four-drug combination of isoniazid, rifampin, ethambutol, and pyrazinamide.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase

Palencia

Li²,

Bu³

et al. 2016

Antimicrob Agents Chemother

120

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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.

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Section: Resultsmentioning

confidence: 99%