2. Academic Validation
  3. Computational Design of Cyclic Peptide Inhibitors of a Bacterial Membrane Lipoprotein Peptidase

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

  • ACS Chem Biol. 2024 May 17;19(5):1125-1130. doi: 10.1021/acschembio.4c00076.
Timothy W Craven 1 2,  Mark D Nolan 3,  Jonathan Bailey 4 5,  Samir Olatunji 4,  Samantha J Bann 6,  Katherine Bowen 3,  Nikita Ostrovitsa 3,  Thaina M Da Costa 7,  Ross D Ballantine 6,  Dietmar Weichert 4,  Paul M Levine 1 2,  Lance J Stewart 1 2,  Gaurav Bhardwaj 1 2,  Joan A Geoghegan 7 8,  Stephen A Cochrane 6,  Eoin M Scanlan 3,  Martin Caffrey 4,  David Baker 1 2 9
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Washington, Seattle, Washington 98195, United States.
  • 2 Institute for Protein Design, University of Washington, Seattle, Washington 98195, United States.
  • 3 School of Chemistry, Trinity College Dublin, Dublin D02 R590, Ireland.
  • 4 School of Medicine and School of Biochemistry and Immunology, Trinity College Dublin, Dublin D02 R590, Ireland.
  • 5 Biological Inorganic Chemistry Laboratory, The Francis Crick Institute, London NW1 1AT, U.K.
  • 6 School of Chemistry and Chemical Engineering, Queen's University Belfast, David Keir Building, Stranmillis Road, Belfast BT9 5AG, U.K.
  • 7 Department of Microbiology, Moyne Institute of Preventive Medicine, School of Genetics and Microbiology, Trinity College Dublin, Dublin D02 VF25, Ireland.
  • 8 Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, U.K.
  • 9 Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, United States.
PMID: 38712757 DOI: 10.1021/acschembio.4c00076
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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