Adapting antibacterial display to identify serum active macrocyclic peptide antibiotics.

Autor:	Randall JR; Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712., Groover KE; Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712., O'Donnell AC; Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712., Garza JM; Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712., Cole TJ; Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712., Davies BW; Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Jul 29. Date of Electronic Publication: 2023 Jul 29.
DOI:	10.1101/2023.07.28.550711
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 towards 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. Significance: Traditional methods of natural antibiotic discovery are low throughput and cannot keep pace with the development of antimicrobial resistance. Synthetic peptide display technologies offer a high-throughput means of screening drug candidates, but rarely consider functionality beyond simple target binding and do not consider retention of function in vivo . Here, we adapt a function-based, antibacterial display technology to screen a large library of peptide macrocycles directly for bacterial growth inhibition in human serum. This screen identifies an optimized non-toxic macrocyclic peptide antibiotic retaining in vivo function, suggesting this advancement could increase clinical antibiotic discovery efficiency.
Databáze:	MEDLINE
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