Assessment of carbapenems in a mouse model of Mycobacterium tuberculosis infection

Ravindra Jadhav, Ricardo Gallardo-Macias, Gaurav Kumar, Samer S. Daher, Amit Kaushik, Kristina M. Bigelow, Eric L. Nuermberger, Gyanu Lamichhane, Joel S. Freundlich

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere0249841
JournalPloS one
Volume16
Issue number5 May
DOIs
StatePublished - May 2021

Bibliographical note

Funding Information:
G.L., J.S.F., and E.L.N. acknowledge support from award number R33AI111739 ?Development of oral carbapenem drugs for treatment of drug resistant TB? from the National Institutes of Health and National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2021 Jadhav et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Keywords

  • Animals
  • Antitubercular Agents/chemical synthesis
  • Carbapenems/chemical synthesis
  • Female
  • Lung/drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mycobacterium tuberculosis/drug effects
  • Tuberculosis/drug therapy

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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