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ACS Infect Dis ; 10(5): 1679-1695, 2024 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-38581700

RESUMO

Linezolid is a drug with proven human antitubercular activity whose use is limited to highly drug-resistant patients because of its toxicity. This toxicity is related to its mechanism of action─linezolid inhibits protein synthesis in both bacteria and eukaryotic mitochondria. A highly selective and potent series of oxazolidinones, bearing a 5-aminomethyl moiety (in place of the typical 5-acetamidomethyl moiety of linezolid), was identified. Linezolid-resistant mutants were cross-resistant to these molecules but not vice versa. Resistance to the 5-aminomethyl molecules mapped to an N-acetyl transferase (Rv0133) and these mutants remained fully linezolid susceptible. Purified Rv0133 was shown to catalyze the transformation of the 5-aminomethyl oxazolidinones to their corresponding N-acetylated metabolites, and this transformation was also observed in live cells of Mycobacterium tuberculosis. Mammalian mitochondria, which lack an appropriate N-acetyltransferase to activate these prodrugs, were not susceptible to inhibition with the 5-aminomethyl analogues. Several compounds that were more potent than linezolid were taken into C3HeB/FeJ mice and were shown to be highly efficacious, and one of these (9) was additionally taken into marmosets and found to be highly active. Penetration of these 5-aminomethyl oxazolidinone prodrugs into caseum was excellent. Unfortunately, these compounds were rapidly converted into the corresponding 5-alcohols by mammalian metabolism which retained antimycobacterial activity but resulted in substantial mitotoxicity.


Assuntos
Antituberculosos , Mycobacterium tuberculosis , Oxazolidinonas , Pró-Fármacos , Pró-Fármacos/farmacologia , Pró-Fármacos/química , Antituberculosos/farmacologia , Antituberculosos/química , Mycobacterium tuberculosis/efeitos dos fármacos , Oxazolidinonas/farmacologia , Oxazolidinonas/química , Animais , Testes de Sensibilidade Microbiana , Camundongos , Humanos , Linezolida/farmacologia , Linezolida/química , Farmacorresistência Bacteriana , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo
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