2. Academic Validation
  3. Discovery and development of a new oxazolidinone with reduced toxicity for the treatment of tuberculosis

Discovery and development of a new oxazolidinone with reduced toxicity for the treatment of tuberculosis

  • Nat Med. 2026 Feb;32(2):553-560. doi: 10.1038/s41591-025-04164-x.
Brendan M Crowley 1,  Helena I Boshoff 2,  Aidan Boving 2,  Vee Y Tan 2,  Jianghai Zhu 3,  Forrest Hoyt 3,  Randy R Miller 4,  Julie Ehrhart 5,  Christopher W Boyce 6,  Katherine Young 7,  Philippe G Nantermet 8,  Jing Su 8,  Lihu Yang 8,  Ronald E Painter 9,  Emily B Corcoran 10,  Jason L Hoar 4,  Sangmi Oh 2,  David L Holtzman 11,  Micha Levi 11,  Aparna Anderson 11,  Monicah A Otieno 11,  Matthew Zimmerman 12,  Firat Kaya 12,  Lisa M Massoudi 13,  Michelle E Ramey 13,  Allison A Bauman 13,  Anne J Lenaerts 13,  Gregory T Roberston 13,  Véronique Dartois 12,  Charles D Wells 11,  Clifton E Barry 3rd 14,  David B Olsen 7
Affiliations

Affiliations

  • 1 Discovery Chemistry, Merck & Co., West Point, PA, USA. [email protected].
  • 2 Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
  • 3 Research Technologies Branch, Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
  • 4 Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck & Co., Rahway, NJ, USA.
  • 5 Department of Nonclinical Drug Safety, Merck & Co., West Point, PA, USA.
  • 6 Discovery Pharmaceutical Sciences, Merck & Co., West Point, PA, USA.
  • 7 Infectious Disease and Vaccines, Merck & Co., Rahway, NJ, USA.
  • 8 Discovery Chemistry, Merck & Co., West Point, PA, USA.
  • 9 Quantitative Biosciences, Merck & Co., West Point, PA, USA.
  • 10 Discovery Process Chemistry, Merck & Co., Rahway, NJ, USA.
  • 11 Gates Medical Research Institute, Cambridge, MA, USA.
  • 12 Hackensack Meridian Health, Nutley, NJ, USA.
  • 13 Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO, USA.
  • 14 Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA. [email protected].
PMID: 41530381 DOI: 10.1038/s41591-025-04164-x
Abstract

Linezolid, an Oxazolidinone, is a cornerstone of treatment regimens for highly drug-resistant tuberculosis but cannot be used in drug-susceptible disease because of toxicity. This toxicity results from inhibition of mammalian mitochondrial protein synthesis. Here we show the development of a new Oxazolidinone, MK-7762, with antitubercular activity that is better than linezolid and limited mitochondrial protein synthesis inhibition. The cryogenic electron microscopy structure of the stalled mycobacterial ribosome with MK-7762 revealed the basis for this selectivity. BALB/c mouse models of disease showed MK-7762 reduced lung Bacterial burden by a 3-log-fold decrease in an acute model (N = 18) and a 2-log-fold decrease in chronically infected Animals (N = 18). MK-7762 showed lesion penetration similar to linezolid in C3HeB/FeJ mice. MK-7762 had pharmacokinetic properties predicting low once-daily doses in humans and a favorable 14-day preclinical safety profile in Wistar Han rats (N = 30) and Beagle dogs (N = 6). Four-month safety studies in both rats (N = 20) and dogs (N = 24) showed no changes in hematology parameters at exposures well above the 100-mg predicted human dose. These data will enable MK-7762 to be explored as a component of new tuberculosis treatment combinations for all forms of the disease.

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