Annihilation of bacterial biofilms is challenging owing to their formidable resistance to therapeutic antibiotics and thus there is a constant demand for development of potent antibiofilm agents that can abolish established biofilms. In the present study, the activity of a dipyridinium-based cationic amphiphile (compound 1) against established bacterial biofilms and the subsequent development of a compound 1-loaded nanocarrier for potential antibiofilm therapy are highlighted. Solution-based assays and microscopic analysis revealed the antagonistic effect of compound 1 on biofilms formed by Staphylococcus aureus MTCC 96 and Pseudomonas aeruginosa MTCC 2488. In combination studies, compound 1 could efficiently potentiate the action of tobramycin and gentamicin on P. aeruginosa and S. aureus biofilm, respectively. A human serum albumin (HSA)-based nanocarrier loaded with compound 1 was generated, which exhibited sustained release of compound 1 at physiological pH. The compound 1-loaded HSA nanocarrier (C1-HNC) displayed the signature membrane-directed activity of the amphiphile on target bacteria, efficiently eliminated established bacterial biofilms, and was observed to be nontoxic to a model human cell line. Interestingly, compound 1 as well as the amphiphile-loaded HSA nanocarrier could eradicate established S. aureus biofilm from the surface of a Foley's urinary catheter. On the basis of its biocompatibility and high antibiofilm activity, it is conceived that the amphiphile-loaded nanocarrier may hold potential in antibiofilm therapy.
In this paper, we present a critical assessment of the therapeutic potential of low molecular weight pyridine-based synthetic amphiphiles based on structure-guided bactericidal activity and a rational evaluation of their cytotoxic potential. Fluorescence-based structure-function studies revealed that the amphiphiles were membrane-acting and displayed a hierarchical pattern of bactericidal activity, which could be correlated with their charge density and hydrophobicity. The membrane-targeting activity of the most potent cationic amphiphile (compound 6) was vindicated as it induced extensive membranedisruption and dissipation of the transmembrane potential (DJ) in pathogenic bacteria. At concentrations equivalent to the minimum inhibitory concentration (MIC) against the Gram-positive pathogen S. aureus MTCC 96, none of the amphiphiles exerted any cytotoxic effect on model human cell lines (HeLa, MCF-7 and HT-29). However, at elevated concentrations, a distinct gradation in the cytotoxic effect was manifested, which is probably accounted by the charge density and conformational flexibility of the amphiphiles. A viable therapeutic application of compound 6 is demonstrated in combinatorial assays, wherein the proclivity of the amphiphile to disrupt bacterial membranes at very low concentration is exploited to enhance the uptake and bactericidal efficacy of erythromycin against Gram-negative pathogenic bacteria.
A rationally designed bactericidal amphiphile acts on compelling targets and has the potential to disarm resistance development in pathogenic bacteria.
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