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<p>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 (<i>N</i> = 18) and a 2-log-fold decrease in chronically infected animals (<i>N</i> = 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 (<i>N</i> = 30) and Beagle dogs (<i>N</i> = 6). Four-month safety studies in both rats (<i>N</i> = 20) and dogs (<i>N</i> = 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月13日

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  • Brendan M. Crowley,
  • Helena I. Boshoff,
  • Aidan Boving,
  • Vee Y. Tan,
  • Jianghai Zhu,
  • Forrest Hoyt,
  • Randy R. Miller,
  • Julie Ehrhart,
  • Christopher W. Boyce,
  • Katherine Young,
  • Philippe G. Nantermet,
  • Jing Su,
  • Lihu Yang,
  • Ronald E. Painter,
  • Emily B. Corcoran,
  • Jason L. Hoar,
  • Sangmi Oh,
  • David L. Holtzman,
  • Micha Levi,
  • Aparna Anderson,
  • Monicah A. Otieno,
  • Matthew Zimmerman,
  • Firat Kaya,
  • Lisa M. Massoudi,
  • Michelle E. Ramey,
  • Allison A. Bauman,
  • Anne J. Lenaerts,
  • Gregory T. Roberston,
  • Véronique Dartois,
  • Charles D. Wells,
  • Clifton E. Barry III,
  • David B. Olsen

摘要

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.