Computational identification of a systemic antibiotic for gram-negative bacteria.

Autor: Miller RD; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Iinishi A; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Modaresi SM; Biozentrum, University of Basel, Basel, Switzerland., Yoo BK; Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA., Curtis TD; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Lariviere PJ; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Liang L; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Son S; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Nicolau S; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Bargabos R; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Morrissette M; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Gates MF; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Pitt N; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Jakob RP; Biozentrum, University of Basel, Basel, Switzerland., Rath P; Biozentrum, University of Basel, Basel, Switzerland., Maier T; Biozentrum, University of Basel, Basel, Switzerland., Malyutin AG; Beckman Institute, California Institute of Technology, Pasadena, CA, USA., Kaiser JT; Beckman Institute, California Institute of Technology, Pasadena, CA, USA., Niles S; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Karavas B; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Ghiglieri M; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA., Bowman SEJ; National Crystallization Center, Hauptman-Woodward Medical Research Institute, Buffalo, NY, USA., Rees DC; Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA.; Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA, USA., Hiller S; Biozentrum, University of Basel, Basel, Switzerland. sebastian.hiller@unibas.ch., Lewis K; Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA. k.lewis@northeastern.edu.
Jazyk: angličtina
Zdroj: Nature microbiology [Nat Microbiol] 2022 Oct; Vol. 7 (10), pp. 1661-1672. Date of Electronic Publication: 2022 Sep 26.
DOI: 10.1038/s41564-022-01227-4
Abstrakt: Discovery of antibiotics acting against Gram-negative species is uniquely challenging due to their restrictive penetration barrier. BamA, which inserts proteins into the outer membrane, is an attractive target due to its surface location. Darobactins produced by Photorhabdus, a nematode gut microbiome symbiont, target BamA. We reasoned that a computational search for genes only distantly related to the darobactin operon may lead to novel compounds. Following this clue, we identified dynobactin A, a novel peptide antibiotic from Photorhabdus australis containing two unlinked rings. Dynobactin is structurally unrelated to darobactins, but also targets BamA. Based on a BamA-dynobactin co-crystal structure and a BAM-complex-dynobactin cryo-EM structure, we show that dynobactin binds to the BamA lateral gate, uniquely protruding into its β-barrel lumen. Dynobactin showed efficacy in a mouse systemic Escherichia coli infection. This study demonstrates the utility of computational approaches to antibiotic discovery and suggests that dynobactin is a promising lead for drug development.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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