The antibacterial activity of novel 1,10-phenanthroline complexes of Cu(II), Mn(II) and Ag(I) against multidrug-resistant clinical isolates derived from Irish patients. Metal drugs as antibacterial agents

Antimicrobial resistance (AMR) is one of the serious global health challenges of our time. There is now an urgent need to develop novel therapeutic agents that can overcome AMR, preferably through alternative mechanistic pathways from conventional treatments. The antibacterial activity of novel metal complexes (metal = Cu(II), Mn(II), and Ag(I)) incorporating 1,10-phenanthroline (phen) and various dicarboxylate ligands along with their simple metal salt and dicarboxylate precursors were investigated against common AMR pathogens. Overall, superior toxicity was evident in compounds that incorporate the phen ligand compared to the activities of their simple salt and dicarboxylate precursors. The chelates incorporating 3,6,9-trioxaundecanedioic acid (tdda) were the most effective, and the varied toxicity depended on the metal centre. Whole-genome sequencing was carried out on reference Pseudomonas aeruginosa strain, PAO1. This strain was exposed to sub-lethal doses of lead metal-tdda-phen complexes to form mutants with induced resistance properties. Various mutations were detected in the mutant P. aeruginosa genome, causing amino acid changes to proteins involved in cellular respiration, the polyamine biosynthetic pathway, and virulence mechanisms. This study provides insights into acquired resistance mechanisms of pathogenic organisms exposed to novel Cu(II), Mn(II), and Ag(I) complexes incorporating phen with tdda for further development of these potential complexes as alternative clinical therapeutic drugs to treat AMR.