Small molecule adjuvants that suppress both chromosomal and mcr-1 encoded colistin-resistance and amplify colistin efficacy in polymyxin-susceptible bacteria
| Autor: | William T. Barker, Tyler L. Harris, Courtney E. Chandler, Christian Melander, Sara E. Martin, T. Vu Nguyen, Robert K. Ernst, Yohei Doi, Roberta J. Melander, Christopher Goodell |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Acinetobacter baumannii medicine.drug_class Klebsiella pneumoniae Polymyxin 030106 microbiology Clinical Biochemistry Antibiotics Pharmaceutical Science Drug resistance Microbial Sensitivity Tests Biology Biochemistry Article Microbiology Small Molecule Libraries 03 medical and health sciences Antibiotic resistance Drug Discovery Drug Resistance Bacterial Gram-Negative Bacteria medicine polycyclic compounds Escherichia coli Polymyxins Molecular Biology Adjuvants Pharmaceutic Colistin Escherichia coli Proteins Organic Chemistry biochemical phenomena metabolism and nutrition biology.organism_classification bacterial infections and mycoses 030104 developmental biology Molecular Medicine bacteria MCR-1 lipids (amino acids peptides and proteins) medicine.drug |
| Zdroj: | Bioorganicmedicinal chemistry. 25(20) |
| ISSN: | 1464-3391 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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