Small molecule adjuvants that suppress both chromosomal and mcr-1 encoded colistin-resistance and amplify colistin efficacy in polymyxin-susceptible bacteria

William T. Barker, Sara E. Martin, Courtney E. Chandler, T. Vu Nguyen, Tyler L. Harris, Christopher Goodell, Roberta J. Melander, Yohei Doi, Robert K. Ernst, Christian Melander

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Abstract

Bacterial resistance to polymyxin antibiotics has taken on a new and more menacing form. Common are genomically-encoded resistance mechanisms to polymyxins, specifically colistin (polymyxin E), however, the plasmid-borne mobile colistin resistance-1 (mcr-1) gene has recently been identified and poses a new threat to global public health. Within six months of initial identification in Chinese swine in November 2015, the first human clinical isolation in the US was reported (Apr. 2016). Herein we report successful reversion of mcr-1-driven colistin resistance in Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli with adjuvants we previously reported as modulators of chromosomally-encoded colistin resistance. Further screening of our in-house library of nitrogen-dense heterocycles has identified additional chemical scaffolds that actively attenuate colistin resistance. Ultimately, we present a diverse cohort of adjuvants that both sensitize colistin-resistant and colistin-susceptible bacteria to this antibiotic, thus providing a potential avenue to both reduce colistin dosage and toxicity, and overcome colistin resistance.

Original languageEnglish
Pages (from-to)5749-5753
Number of pages5
JournalBioorganic and Medicinal Chemistry
Volume25
Issue number20
DOIs
Publication statusPublished - 01-01-2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Barker, W. T., Martin, S. E., Chandler, C. E., Nguyen, T. V., Harris, T. L., Goodell, C., Melander, R. J., Doi, Y., Ernst, R. K., & Melander, C. (2017). Small molecule adjuvants that suppress both chromosomal and mcr-1 encoded colistin-resistance and amplify colistin efficacy in polymyxin-susceptible bacteria. Bioorganic and Medicinal Chemistry, 25(20), 5749-5753. https://doi.org/10.1016/j.bmc.2017.08.055