Abstract
There has been an increasing interest in the development of antimicrobial peptides (AMPs) and their synthetic mimics as a novel class of antibiotics to overcome the rapid emergence of antibiotic resistance. Recently, phenylglyoxamide-based small molecular AMP mimics have been identified as potential leads to treat bacterial infections. In this study, a new series of biphenylglyoxamide-based small molecular AMP mimics were synthesised from the ring-opening reaction of N-sulfonylisatin bearing a biphenyl backbone with a diamine, followed by the conversion into tertiary ammonium chloride, quaternary ammonium iodide and guanidinium hydrochloride salts. Structure–activity relationship studies of the analogues identified the octanesulfonyl group as being essential for both Gram-positive and Gram-negative antibacterial activity, while the biphenyl backbone was important for Gram-negative antibacterial activity. The most potent analogue was identified to be chloro-substituted quaternary ammonium iodide salt 15c, which possesses antibacterial activity against both Gram-positive (MIC against Staphylococcus aureus = 8 μM) and Gram-negative bacteria (MIC against Escherichia coli = 16 μM, Pseudomonas aeruginosa = 63 μM) and disrupted 35% of pre-established S. aureus biofilms at 32 μM. Cytoplasmic membrane permeability and tethered bilayer lipid membranes (tBLMs) studies suggested that 15c acts as a bacterial membrane disruptor. In addition, in vitro toxicity studies showed that the potent compounds are non-toxic against human cells at therapeutic dosages.
Highlights
Rapid emergence of antibiotic-resistant bacteria is a major global health concern
The N-octanesulfonyl group was appended to these antimicrobial peptides (AMPs) mimics as the hydrophobic group, and this hydrophobic group was modified to the N-butanesulfonyl group or N-naphthoyl group to study their effect on antibacterial activity
The ring-opening reaction of N-sulfonylisatins followed by the conversion of the resulting glyoxamide derivatives into tertiary ammonium chloride, quaternary ammonium iodide or guanidinium hydrochloride salts conferred the cationicity of the AMP mimics
Summary
Rapid emergence of antibiotic-resistant bacteria is a major global health concern. Since the late 1980s, there have been no new classes of antibiotics entering the market, with new clinical drugs merely being the structural derivatives of existing antibiotics with the same scaffolds [5,6,7]. These derivatives are prone to rapid resistance development and so can only retard but not overcome the bacterial resistance dilemma. There is an urgent need to develop novel classes of antibiotics to treat bacterial infection
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