Synthesis and Characterization of Novel Zn Complexes of 8-Hydroxyquinolines to Disrupt Zn Homeostasis to Kill Multidrug-Resistant Staphylococcus aureus

Abstract

Antimicrobial resistance (AMR) poses a significant challenge to global health, which is further heightened by the declining number of promising antimicrobial agents in the pharmaceutical pipeline. To address this issue, an urgent need is to discover and develop a variety of antimicrobial agents with novel mechanisms that are distinct from traditional antibiotics as the most rational countermeasure against AMR. Within this framework, metal-based compounds have emerged as potentially very promising candidates as these can offer mechanistic pathways often drastically different from their organic counterparts. A comprehensive screening of 906 metal-containing compounds by the Community for Open Antimicrobial Drug Discovery (CO-ADD) has highlighted Zn complexes along with complexes containing several other metals as standout candidates in the realm of "active and non-toxic" agents against pathogenic organisms. The design, synthesis, and biological evaluation of novel Zn complexes for antimicrobial applications is an underexploited area of research. Hence, the research work was focused on Zn-based complexes. The research findings show that all the new Zn compounds that have been synthesized in this work exhibit dual antibacterial mechanisms and can target unexplored cellular components. They penetrate bacterial membranes, disrupt metal homeostasis by translocating antimicrobial Zn(II) ions, and sequester essential metals – unlike conventional antibiotics and other compounds like hydroxychloroquine. These zinc-based compounds have demonstrated potent activity against different Staphylococcus aureus strains, even antibiotic-resistant bacterial strains. When comparing these Zn-based compounds to conventional antibiotics like ciprofloxacin, it is noteworthy that they show lower tendencies for resistance development. The results indicate that Zn-based therapeutics may emerge as a promising frontier in the battle against AMR due to their distinctive antimicrobial mechanisms of action and remarkable antimicrobial potency.