Conformationally tuned antibacterial oligomers target the peptidoglycan of Gram-positive bacteria

Andrew J. Christofferson, Aaron Elbourne, Samuel Cheeseman, Yue Shi, Manon Rolland, Daniel Cozzolino, James Chapman, Christopher F. McConville, Russell J. Crawford, Peng Yuan Wang, Nghia P. Truong, Athina Anastasaki, Vi Khanh Truong

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6 Citations (Scopus)

Abstract

The recent rise of antibiotic resistance amongst Staphylococcus aureus (S. aureus) populations has made treating Staph-based infections a global medical challenge. Therapies that specifically target the peptidoglycan layer of S. aureus have emerged as new treatment avenues, towards which bacteria are less likely to develop resistance. While the majority of antibacterial polymers/oligomers have the ability to disrupt bacterial membranes, the design parameters for the enhanced disruption of peptidoglycan outer layer of Gram-positive bacteria remain unclear. Here, the design of oligomeric structures with favorable conformational characteristics for improved disruption of the peptidoglycan outer layer of Gram-positive bacteria is reported. Molecular dynamics simulations were employed to inform the structure design and composition of cationic oligomers displaying collapsed and expanded conformations. The most promising diblock and triblock cationic oligomers were synthesized by photo-induced atom transfer radical polymerization (photo ATRP). Following synthesis, the diblock and triblock oligomers displayed average antibacterial activity of ~99% and ~98% for S. aureus and methicillin-resistant S. aureus (MRSA), respectively, at the highest concentrations tested. Importantly, triblock oligomers with extended conformations showed significantly higher disruption of the peptidoglycan outer layer of S. aureus compared to diblock oligomers with more collapsed conformation, as evidenced by a number of characterization techniques including scanning electron, confocal and atomic force microscopy. This work provides new insight into the structure/property relationship of antibacterial materials and advances the design of functional materials for combating the rise of drug-resistant bacteria.

Original languageEnglish
Pages (from-to)850-862
Number of pages13
JournalJournal of Colloid and Interface Science
Volume580
DOIs
Publication statusPublished - 15 Nov 2020

Keywords

  • Antibacterial
  • Gram-positive
  • Oligomer
  • Peptidoglycan
  • Photo-induced ATRP

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