2. Academic Validation
  3. Mtb-Selective 5-Aminomethyl Oxazolidinone Prodrugs: Robust Potency and Potential Liabilities

Mtb-Selective 5-Aminomethyl Oxazolidinone Prodrugs: Robust Potency and Potential Liabilities

  • ACS Infect Dis. 2024 May 10;10(5):1679-1695. doi: 10.1021/acsinfecdis.4c00025.
Helena I M Boshoff 1,  Katherine Young 2,  Yong-Mo Ahn 1,  Veena D Yadav 1,  Brendan M Crowley 2,  Lihu Yang 2,  Jing Su 2,  Sangmi Oh 1,  Kriti Arora 1,  Jenna Andrews 1,  Michelle Manikkam 3,  Michelle Sutphin 3,  Anthony J Smith 4,  Danielle M Weiner 3,  Michaela K Piazza 3,  Joel D Fleegle 3,  Felipe Gomez 3,  Emmannual K Dayao 3,  Brendan Prideaux 2,  Matthew Zimmerman 5,  Firat Kaya 5,  Jansy Sarathy 5,  Vee Yang Tan 1,  Laura E Via 3,  Richard Tschirret-Guth 2,  Anne J Lenaerts 4,  Gregory T Robertson 4,  Véronique Dartois 4,  David B Olsen 2,  Clifton E Barry 3rd 1
Affiliations

Affiliations

  • 1 Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institutes of Health, Bethesda, Maryland 20892, United States.
  • 2 Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 3 Tuberculosis Imaging Program, Division of Intramural Research, National Insititute of Allergy and Infectious Disease, National Insititutes of Health, Bethesda, Maryland 20892, United States.
  • 4 Mycobacterial Research Laboratories, Department of Microbiology, Immunology, and Pathology, Colorado State University, Ft Collins, Colorado 80521, United States.
  • 5 Hackensack Meridian Health Center for Discovery & Innovation, Nutley, New Jersey 07110, United States.
PMID: 38581700 DOI: 10.1021/acsinfecdis.4c00025
Abstract

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.

Keywords

antibacterial; nonhuman primate; oxazolidinone; pro-drug; tuberculosis.

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