Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis

Aaron M. Teitelbaum, Anja Meissner, Ryan A. Harding, Christopher A. Wong, Courtney C. Aldrich, Rory P. Remmel

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Meropenem, a broad-spectrum parenteral β-lactam antibiotic, in combination with clavulanate has recently shown efficacy in patients with extensively drug-resistant tuberculosis. As a result of meropenem's short half-life and lack of oral bioavailability, the development of an oral therapy is warranted for TB treatment in underserved countries where chronic parenteral therapy is impractical. To improve the oral absorption of meropenem, several alkyloxycarbonyloxyalkyl ester prodrugs with increased lipophilicity were synthesized and their stability in physiological aqueous solutions and guinea pig as well as human plasma was evaluated. The stability of prodrugs in aqueous solution at pH 6.0 and 7.4 was significantly dependent on the ester promoiety with the major degradation product identified as the parent compound meropenem. However, in simulated gastrointestinal fluid (pH 1.2) the major degradation product identified was ring-opened meropenem with the promoiety still intact, suggesting the gastrointestinal environment may reduce the absorption of meropenem prodrugs in vivo unless administered as an enteric-coated formulation. Additionally, the stability of the most aqueous stable prodrugs in guinea pig or human plasma was short, implying a rapid release of parent meropenem.

Original languageEnglish (US)
Pages (from-to)5605-5617
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number17
DOIs
StatePublished - Sep 1 2013

Bibliographical note

Funding Information:
The research was supported by the National Institute of Health grant R21AI090147 to R.P.R. We thank Kathryn Nelson for carefully proofreading this manuscript.

Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.

Keywords

  • Aqueous stability
  • Meropenem
  • XDR-TB
  • β-Lactam prodrugs

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