A naturally inspired antibiotic to target multi-drug-resistant pathogens
| Autor: | Zongqiang Wang, Bimal Koirala, Yozen Hernandez, Matthew Zimmerman, Steven Park, David S. Perlin, Sean F. Brady |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Acinetobacter baumannii
Multidisciplinary Neutropenia Colistin Drug Resistance Transferases (Other Substituted Phosphate Groups) Microbial Sensitivity Tests Article Biosynthetic Pathways Anti-Bacterial Agents Mice Ethanolamines Genes Bacterial Multigene Family Drug Resistance Bacterial Gram-Negative Bacteria Animals Humans Gram-Negative Bacterial Infections Genome Bacterial Plasmids |
| Zdroj: | Nature |
| Popis: | Gram-negative bacteria are responsible for an increasing number of deaths from antibiotic resistant infections.(1,2) The bacterial natural product, colistin, is considered the last line of defense against a number of Gram-negative pathogens. The recent global spread of the plasmid-borne mobilized colistin resistance gene mcr-1 (phosphoethanolamine (PEtN) transferase) threatens colistin’s utility.(3) Bacterial-derived antibiotics often appear in nature as collections of similar structures that are encoded by evolutionarily related biosynthetic gene clusters (BGCs). This structural diversity is, at least in part, likely a response to the development of natural resistance, which often mechanistically mimics clinical resistance. Here, we proposed that a solution to mcr-1 mediated resistance might have evolved among naturally occurring colistin congeners. Our search of sequenced bacterial genomes identified a BGC that was predicted to encode the most structurally divergent colistin congener described to-date. Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens containing mcr-1 as well as intrinsically resistant pathogens with chromosomally encoded PEtN transferase genes. These include extremely drug resistant (XDR) Acinetobacter baumannii and intrinsically colistin resistant Neisseria gonorrhoeae which, due to a lack of effective treatment options, are considered among the highest level Gram-negative threats.(4) In a mouse neutropenic infection model, a biphenyl analog of macolacin proved to be effective against colistin resistant XDR A. baumannii, thus providing a new naturally inspired and easily produced therapeutic lead for combating colistin resistant pathogens. |
| Databáze: | OpenAIRE |
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