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

Abstract

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.

The Use of Tethered Bilayer Lipid Membranes to Identify the Mechanisms of Antimicrobial Peptide Interactions with Lipid Bilayers

“…Typically, to some degree, these AMPs can be readily washed out of the membrane (Figure 6E,F). There have been numerous reports of AMPs or peptidomimetics that induce these responses [37,60,67,71,72]. The change in membrane conduction in these cases has been assigned to a modulation of intrinsic membrane pores via a rearrangement of the packing of the lipids according the CPP model (Figure 5).…”

Short Cationic Peptidomimetic Antimicrobials

“…To improve the antibacterial activity, the cationic groups were replaced with guanidine [94] or lysine to form dipeptide compounds with increased net charge (Figure 16). The guanidine cationic group compound 49 gave better antibacterial activity (MIC = 6 µg·mL −1 ) compared with the lysine dipeptide compound 50 (MIC = 23 µg·mL −1 ) against S. aureus .…”

Design, Synthesis and Biological Evaluation of Biphenylglyoxamide-Based Small Molecular Antimicrobial Peptide Mimics as Antibacterial Agents

“…Since ring-opened phenylglyoxamide derivatives possess an amide bond, they are potential candidates for the development of AMP mimics. Our group has previously reported the synthesis of phenylglyoxamides (e.g., 4 – 5 ) derived from N -acylisatins and N -sulfonylisatins [ 43 , 44 , 45 ]. Among these molecules, N -sulfonylphenylglyoxamide iodide salt 4b and N -naphthoylphenylglyoxamide guanidinium salt 5 had moderate to good minimum inhibitory concentrations (MIC) of 63 and 12 μM respectively, against Gram-positive S. aureus [ 43 , 44 ].…”