Structure-Uptake Relationship Studies of Oxazolidinones in Gram-Negative ESKAPE Pathogens

Ziwei Hu, Inga V. Leus, Brinda Chandar, Bradley S. Sherborne, Quentin P. Avila, Valentin V. Rybenkov, Helen I. Zgurskaya, Adam S. Duerfeldt

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

The clinical success of linezolid for treating Gram-positive infections paired with the high conservation of bacterial ribosomes predicts that if oxazolidinones were engineered to accumulate in Gram-negative bacteria, then this pharmacological class would find broad utility in eradicating infections. Here, we report an investigative study of a strategically designed library of oxazolidinones to determine the effects of molecular structure on accumulation and biological activity. Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa strains with varying degrees of compromise (in efflux and outer membrane) were used to identify motifs that hinder permeation across the outer membrane and/or enhance efflux susceptibility broadly and specifically between species. The results illustrate that small changes in molecular structure are enough to overcome the efflux and/or permeation issues of this scaffold. Three oxazolidinone analogues (3e, 8d, and 8o) were identified that exhibit activity against all three pathogens assessed, a biological profile not observed for linezolid.

Original languageEnglish (US)
Pages (from-to)14144-14179
Number of pages36
JournalJournal of medicinal chemistry
Volume65
Issue number20
DOIs
StatePublished - Oct 27 2022

Bibliographical note

Funding Information:
This work was supported by the National Institute of Allergy and Infectious Disease of the National Institutes of Health (R01AI136795, H.I.Z., V.V.R., and A.S.D.) The content included in this manuscript does not necessarily reflect the position or the policy of the federal government, and no official endorsement should be inferred. The authors thank Dr. Alexander S. Mankin for sharing E. coli strains. The authors gratefully acknowledge the collegiality, collaboration, and scientific discussion provided by the other SPEAR-GN team members.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

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