Assessment of carbapenems in a mouse model of Mycobacterium tuberculosis infection.

We present further study of a subset of carbapenems, arising from a previously reported machine learning approach, with regard to their mouse pharmacokinetic profiling and subsequent study in a mouse model of sub-acute Mycobacterium tuberculosis infection. Pharmacokinetic metrics for such small molecules were compared to those for meropenem and biapenem, resulting in the selection of two carbapenems to be assessed for their ability to reduce M. tuberculosis bacterial loads in the lungs of infected mice. The original syntheses of these two carbapenems were optimized to provide multigram quantities of each compound. One of the two experimental carbapenems, JSF-2204, exhibited efficacy equivalent to that of meropenem, while both were inferior to rifampin. The lessons learned in this study point toward the need to further enhance the pharmacokinetic profiles of experimental carbapenems to positively impact in vivo efficacy performance.
Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: the authors declare that a United States patent (US10,695,322) has been granted, including J.S.F., G.L., and A.K. as inventors, relevant to the carbapenems disclosed herein. Novel Inhibitors of Bacterial Growth, U.S. Patent 10,695,322, issued June 30, 2020, Assignees: The Johns Hopkins University (Baltimore, MD), Rutgers, The State University of New Jersey (New Brunswick, NJ), Inventors: Gyanu Lamichhane (Towson, MD), Craig A. Townsend (Baltimore, MD), Evan Lloyd (Bunker Hill, WV), Amit Kaushik (Baltimore, MD), Pankaj Kumar (Baltimore, MD), Joel Freundlich (Princeton, NJ), Shaogang Li (Newark, NJ), Sean Ekins (Fuquay Varina, NC), Nicole Parrish (Bunker Hilol, WV. This does not alter our adherence to PLOS ONE policies on sharing data and materials.