Adapting antibacterial display to identify serum-active macrocyclic peptide antibiotics.

Autor:	Randall JR; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA., Groover KE; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA., O'Donnell AC; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA., Garza JM; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA., Cole TJ; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA., Davies BW; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
Jazyk:	angličtina
Zdroj:	PNAS nexus [PNAS Nexus] 2023 Aug 17; Vol. 2 (8), pp. pgad270. Date of Electronic Publication: 2023 Aug 17 (Print Publication: 2023).
DOI:	10.1093/pnasnexus/pgad270
Abstrakt:	The lack of available treatments for many antimicrobial-resistant infections highlights the critical need for antibiotic discovery innovation. Peptides are an underappreciated antibiotic scaffold because they often suffer from proteolytic instability and toxicity toward human cells, making in vivo use challenging. To investigate sequence factors related to serum activity, we adapt an antibacterial display technology to screen a library of peptide macrocycles for antibacterial potential directly in human serum. We identify dozens of new macrocyclic peptide antibiotic sequences and find that serum activity within our library is influenced by peptide length, cationic charge, and the number of disulfide bonds present. Interestingly, an optimized version of our most active lead peptide permeates the outer membrane of Gram-negative bacteria without strong inner-membrane disruption and kills bacteria slowly while causing cell elongation. This contrasts with traditional cationic antimicrobial peptides, which kill rapidly via lysis of both bacterial membranes. Notably, this optimized variant is not toxic to mammalian cells and retains its function in vivo, suggesting therapeutic promise. Our results support the use of more physiologically relevant conditions when screening peptides for antimicrobial activity which retain in vivo functionality. (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)
Databáze:	MEDLINE
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