Abstract
The rapid emergence of drug-resistant bacteria is a major global health concern. Antimicrobial peptides (AMPs) and peptidomimetics have arisen as a new class of antibacterial agents in recent years in an attempt to overcome antibiotic resistance. A library of phenylglyoxamide-based small molecular peptidomimetics was synthesised by incorporating an N-alkylsulfonyl hydrophobic group with varying alkyl chain lengths and a hydrophilic cationic group into a glyoxamide core appended to phenyl ring systems. The quaternary ammonium iodide salts 16d and 17c showed excellent minimum inhibitory concentration (MIC) of 4 and 8 μM (2.9 and 5.6 μg/mL) against Staphylococcus aureus, respectively, while the guanidinium hydrochloride salt 34a showed an MIC of 16 μM (8.5 μg/mL) against Escherichia coli. Additionally, the quaternary ammonium iodide salt 17c inhibited 70% S. aureus biofilm formation at 16 μM. It also disrupted 44% of pre-established S. aureus biofilms at 32 μM and 28% of pre-established E. coli biofilms 64 μM, respectively. A cytoplasmic membrane permeability study indicated that the synthesised peptidomimetics acted via disruption and depolarisation of membranes. Moreover, the quaternary ammonium iodide salts 16d and 17c were non-toxic against human cells at their therapeutic dosages against S. aureus.
Highlights
Infections caused by multidrug-resistant bacteria pose a serious threat to humans and are a major health concern [1]
Biofilms are communities of bacteria encased in an extracellular polymeric matrix adhering to a surface [6,7,8]
In our ourprevious previous studies, reported phenylglyoxamideand biphenylglyoxaIn studies, we we reported phenylglyoxamideand biphenylglyoxamidemide-based small molecular antimicrobial peptidomimetics and 2 1)
Summary
Infections caused by multidrug-resistant bacteria pose a serious threat to humans and are a major health concern [1] This multi-drug resistance arises from the selective survival pressure exerted by the mechanism of action of conventional antibiotics [2]. Bacteria resist antibiotics through various mechanisms, such as enzymatic degradation of antibiotics, reducing the permeability of the bacterial cell membrane, removal of antibiotics via efflux, and mutation or enzymatic alteration of drug binding sites [3,4,5]. Another survival strategy displayed by bacteria is the formation of biofilms. As biofilms further complicate the treatment of bacterial infections, the ideal novel antibiotic should target planktonic bacteria, and have the ability to disrupt bacterial biofilms
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