A zinc (II) gentamicin metalloantibiotic with outstanding antimicrobial activity and reduced susceptibility to bacterial resistance mechanisms: Experimental and theoretical explorations

Abstract

This paper reports the development of a complex between the antibiotic gentamicin sulfate (GEN), consisting of four major congeners, and zinc ions (Zn(II)GEN complex). The composition of the complex aligns well with the proposed molecular formula [Zn₂+(L)(3H₂O)(2SO₄2􀀀 ]. The Zn(II)GEN complex significantly enhanced inhibitory and bactericidal activity against S. aureus, E faecalis, P. aeruginosa, and E. coli. Unlike gentamicin sulfate alone, the Zn(II)-GEN complex did not induce drug-resistant mutants. Molecular modeling predicted predominantly hexacoordinated complexes involving three contact points with gentamicin and three with water, which agreed with the spectroscopic studies. The complexes adopted a restricted conformation of gentamicin, resulting in its hydrophilic groups being excluded from the solvent, which is consistent with the higher permeability. Molecular Modeling studies of the Zn(II)GEN complex with 16S RNA revealed a restricted bioactive conformation with stable interactions with residues A1493, G1494, and U1495, a structural requirement for antimicrobial activity. Free energy of binding analyses show that the Zn(II)GEN complex had better pharmacodynamic properties than the pure compound. A favored bioactive conformation formed upon the complexation of gentamicin sulfate with Zn(II) increased the complex’s potency against bacteria and allowed it to penetrate bacterial cells. The complex also reduces the likelihood of antimicrobial resistance. The strategy is a good starting point for research into combating bacteria.