Computational Design of Cyclic Peptide Inhibitors of a Bacterial Membrane Lipoprotein Peptidase.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 101282906 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8937 (Electronic) Linking ISSN: 15548929 NLM ISO Abbreviation: ACS Chem Biol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, D.C. : American Chemical Society, c2006-
    • Subject Terms:
      Peptides, Cyclic*/pharmacology ; Peptides, Cyclic*/chemistry ; Peptides, Cyclic*/chemical synthesis ; Anti-Bacterial Agents*/pharmacology ; Anti-Bacterial Agents*/chemistry ; Anti-Bacterial Agents*/chemical synthesis ; Drug Design*; Microbial Sensitivity Tests ; Depsipeptides/pharmacology ; Depsipeptides/chemistry ; Lipoproteins/chemistry ; Lipoproteins/metabolism ; Lipoproteins/pharmacology ; Lipoproteins/antagonists & inhibitors ; Bacterial Proteins ; Peptides ; Aspartic Acid Endopeptidases
    • Abstract:
      There remains a critical need for new antibiotics against multi-drug-resistant Gram-negative bacteria, a major global threat that continues to impact mortality rates. Lipoprotein signal peptidase II is an essential enzyme in the lipoprotein biosynthetic pathway of Gram-negative bacteria, making it an attractive target for antibacterial drug discovery. Although natural inhibitors of LspA have been identified, such as the cyclic depsipeptide globomycin, poor stability and production difficulties limit their use in a clinical setting. We harness computational design to generate stable de novo cyclic peptide analogues of globomycin. Only 12 peptides needed to be synthesized and tested to yield potent inhibitors, avoiding costly preparation of large libraries and screening campaigns. The most potent analogues showed comparable or better antimicrobial activity than globomycin in microdilution assays against ESKAPE-E pathogens. This work highlights computational design as a general strategy to combat antibiotic resistance.
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    • Accession Number:
      0 (signal peptidase II)
      0 (globomycin)
    • Publication Date:
      Date Created: 20240507 Date Completed: 20240517 Latest Revision: 20241207
    • Publication Date:
      20241209
    • Accession Number:
      PMC11106742
    • Accession Number:
      10.1021/acschembio.4c00076
    • Accession Number:
      38712757