Brendan M. Crowley, Helena I. Boshoff, Aidan T 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 Holtzman, Micha Levi, Aparna Anderson, Monicah A. Otieno, Matthew Zimmerman, Firat Kaya, Lisa M. Massoudi, Michelle E. Ramey, Allison Bauman, Anne J. Lenaerts, Gregory T. Roberston, Véronique Dartois, Charles D. Wells, Clifton E. Barry, David B. Olsen
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.