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
  • 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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