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

• Published in: Organic & biomolecular chemistry Vol. 15; no. 9; pp. 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: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 01.03.2017
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Biofilms - drug effects; Cell Line; Chemistry; Chemistry, Organic; 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; Physical Sciences; Pseudomonas aeruginosa; Science & Technology; Staphylococcus aureus; Staphylococcus aureus - drug effects; Structure-Activity Relationship; Sulfonylurea Compounds - chemistry; Sulfonylurea Compounds - pharmacology; BILAYER; DESIGN; SYNTHETIC MIMICS; INHIBITION; MECHANISM; ANTIMICROBIAL PEPTIDE; RESISTANCE; MODEL; BACTERIAL BIOFILMS
• 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 mu g mL(-1) against S. aureus, respectively, while compounds 55 and 56 showed MIC values of 17 and 19 mu g mL-1 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 mu M concentration, while compound 52 inhibited the formation of biofilms by 72% in S. marcescens at 250 mu M. 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.