A zinc complex of a neutral pyridine-based amphiphile: a highly efficient and potentially therapeutic bactericidal material

Abstract

The alarming rise in antibiotic-resistant pathogenic bacteria demands a prudent approach in the generation of therapeutic antibacterials. The present study illustrates the development of a potent amphiphilic bactericidal material tailored to leverage interactions with metal-reactive groups (MRGs) present in the bacterial cell surface envelope. Complexation of Zn(II) with a neutral pyridine-based synthetic amphiphile (C1) generated the cationic C1-Zn, which exhibited manyfold higher membrane-directed bactericidal activity compared to the neutral C1, or the cationic amphiphile bearing two pyridinium head groups (C2). The relevance of MRGs in C1-Zn–bacteria interactions was validated by amphiphile–bacteria binding studies and metal protection assays performed with Mg(II). C1-Zn retained its bactericidal activity even in simulated gastric fluid (SGF) and the enhanced membrane-directed bactericidal activity of C1-Zn could be garnered in adjuvant applications to increase the efficacy of the therapeutic antibiotic erythromycin. Given the relevance of Zn(II) in S. aureus biofilm formation, the antibiofilm potential of the amphiphile C1 realized through Zn(II) complexation could be demonstrated. The lack of resistance in target bacteria coupled with a favorable therapeutic index (IC₅₀/MIC) and non-toxic nature hold significant implications for C1-Zn as a potential antibacterial therapeutic material.