Amphipathic guanidine-embedded glyoxamide-based peptidomimetics as novel antibacterial agents and biofilm disruptors

• Published in: Organic & biomolecular chemistry 2017-03, Vol.15 (9), p.2033-2051
• Main Authors: Nizalapur, Shashidhar, Kimyon, Onder, Yee, Eugene, Ho, Kitty, Berry, Thomas, Manefield, Mike, Cranfield, Charles G, Willcox, Mark, Black, David StC, Kumar, Naresh
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Biofilms - drug effects; Cell Line; Dose-Response Relationship, Drug; Escherichia coli; Escherichia coli - drug effects; Fibroblasts - drug effects; Guanidine - chemistry; Guanidine - pharmacology; Humans; Microbial Sensitivity Tests; Molecular Structure; Peptidomimetics - chemical synthesis; Peptidomimetics - chemistry; Peptidomimetics - pharmacology; Pseudomonas aeruginosa; Staphylococcus aureus; Staphylococcus aureus - drug effects; Structure-Activity Relationship; Sulfonylurea Compounds - chemistry; Sulfonylurea Compounds - pharmacology
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/C7OB00053G

Antimicrobial resistance in bacteria is becoming increasingly prevalent, posing a critical challenge to global health. Bacterial biofilm formation is a common resistance mechanism that reduces the effectiveness of antibiotics. Thus, the development of compounds that can disrupt bacterial biofilms is a potential strategy to combat antimicrobial resistance. We report herein the synthesis of amphipathic guanidine-embedded glyoxamide-based peptidomimetics via ring-opening reactions of N-naphthoylisatins with amines and amino acids. These compounds were investigated for their antibacterial activity by the determination of minimum inhibitory concentration (MIC) against S. aureus and E. coli. Compounds 35, 36, and 66 exhibited MIC values of 6, 8 and 10 μg mL against S. aureus, respectively, while compounds 55 and 56 showed MIC values of 17 and 19 μg mL against E. coli, respectively. Biofilm disruption and inhibition activities were also evaluated against various Gram-positive and Gram-negative bacteria. The most active compound 65 exhibited the greatest disruption of established biofilms by 65% in S. aureus, 61% in P. aeruginosa, and 60% in S. marcescens respectively, at 250 μM concentration, while compound 52 inhibited the formation of biofilms by 72% in S. marcescens at 250 μM. We also report here the in vitro toxicity against MRC-5 human lung fibroblast cells. Finally, the pore forming capability of the three most potent compounds were tested using tethered bilayer lipid membrane (tBLM) technology.