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

doi:10.1371/journal.pone.0249841

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

Institute for Therapeutics Discovery and Development

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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 language	English (US)
Article number	e0249841
Journal	PloS one
Volume	16
Issue number	5 May
DOIs	https://doi.org/10.1371/journal.pone.0249841
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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.",

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Assessment of carbapenems in a mouse model of Mycobacterium tuberculosis infection

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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