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A naturally inspired antibiotic to target multidrug-resistant pathogens

Author

Listed:
  • Zongqiang Wang

    (The Rockefeller University)

  • Bimal Koirala

    (The Rockefeller University)

  • Yozen Hernandez

    (The Rockefeller University)

  • Matthew Zimmerman

    (Hackensack Meridian Health)

  • Steven Park

    (Hackensack Meridian Health)

  • David S. Perlin

    (Hackensack Meridian Health)

  • Sean F. Brady

    (The Rockefeller University)

Abstract

Gram-negative bacteria are responsible for an increasing number of deaths caused by antibiotic-resistant infections1,2. 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 colistin3. 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 pathogens4. 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.

Suggested Citation

  • Zongqiang Wang & Bimal Koirala & Yozen Hernandez & Matthew Zimmerman & Steven Park & David S. Perlin & Sean F. Brady, 2022. "A naturally inspired antibiotic to target multidrug-resistant pathogens," Nature, Nature, vol. 601(7894), pages 606-611, January.
  • Handle: RePEc:nat:nature:v:601:y:2022:i:7894:d:10.1038_s41586-021-04264-x
    DOI: 10.1038/s41586-021-04264-x
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    Cited by:

    1. Bin Ma & Caiyu Lu & Yiling Wang & Jingwen Yu & Kankan Zhao & Ran Xue & Hao Ren & Xiaofei Lv & Ronghui Pan & Jiabao Zhang & Yongguan Zhu & Jianming Xu, 2023. "A genomic catalogue of soil microbiomes boosts mining of biodiversity and genetic resources," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Christopher J. Barden & Fan Wu & J. Pedro Fernandez-Murray & Erhu Lu & Shengguo Sun & Marcia M. Taylor & Annette L. Rushton & Jason Williams & Mahtab Tavasoli & Autumn Meek & Alla Siva Reddy & Lisa M., 2024. "Computer-aided drug design to generate a unique antibiotic family," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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