Journal Article

A naturally inspired antibiotic to target multidrug-resistant pathogens

Park, Steven, Perlin, David S., Zimmerman, Matthew, Wang, Zongqiang, Hernandez, Yozen, Koirala, Bimal, Brady, Sean F.

2022

Overview

Gram-negative bacteria are responsible for an increasing number of deaths caused by antibiotic-resistant infections 1 , 2 . The bacterial natural product colistin is considered the last line of defence against a number of Gram-negative pathogens. The recent global spread of the plasmid-borne mobilized colistin-resistance gene mcr-1 (phosphoethanolamine transferase) threatens the usefulness of colistin 3 . Bacteria-derived antibiotics often appear in nature as collections of similar structures that are encoded by evolutionarily related biosynthetic gene clusters. This structural diversity is, at least in part, expected to be a response to the development of natural resistance, which often mechanistically mimics clinical resistance. Here we propose that a solution to mcr-1 -mediated resistance might have evolved among naturally occurring colistin congeners. Bioinformatic analysis of sequenced bacterial genomes identified a biosynthetic gene cluster that was predicted to encode a structurally divergent colistin congener. Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens expressing mcr-1 and intrinsically resistant pathogens with chromosomally encoded phosphoethanolamine transferase genes. These Gram-negative bacteria include extensively drug-resistant Acinetobacter baumannii and intrinsically colistin-resistant Neisseria gonorrhoeae , which, owing to a lack of effective treatment options, are considered among the highest level threat pathogens 4 . In a mouse neutropenic infection model, a biphenyl analogue of macolacin proved to be effective against extensively drug-resistant A. baumannii with colistin-resistance, thus providing a naturally inspired and easily produced therapeutic lead for overcoming colistin-resistant pathogens. The discovery and synthesis of a colistin congener provide a promising clinical lead against mcr-1 -encoding colistin-resistant pathogens, which are responsible for an increasing number of deaths from antibiotic-resistant infections.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/58 / 140/131 / 38/43 / 631/326/22/1290 / 631/92/349 / 639/638/92/60 / 64/60 / Acinetobacter baumannii - drug effects / Acinetobacter baumannii - enzymology / Acinetobacter baumannii - genetics / Amino acids / Animals / Anti-Bacterial Agents - pharmacology / Antibiotic resistance / Antibiotics / Bacteria / Biosynthetic Pathways - genetics / Chemical synthesis / Colistin / Colistin - pharmacology / Congeners / Divergence / Drug resistance / Drug Resistance, Bacterial - drug effects / Drug Resistance, Bacterial - genetics / Ethanolamines / Fermentation / Gene clusters / Genes / Genes, Bacterial / Genome, Bacterial / Genomes / Gonorrhea / Gram-negative bacteria / Gram-Negative Bacteria - drug effects / Gram-Negative Bacteria - enzymology / Gram-Negative Bacteria - genetics / Humanities and Social Sciences / Laboratories / Lipids / Metabolites / Mice / Microbial Sensitivity Tests / multidisciplinary / Multidrug resistance / Multidrug resistant organisms / Multigene Family / Natural products / Neutropenia / Neutropenia - drug therapy / Neutropenia - microbiology / Nosocomial infections / Pathogens / Peptides / Plasmids / Science / Science (multidisciplinary) / Transferases (Other Substituted Phosphate Groups)