Silver-based N-heterocyclic carbene (NHC) complexes as emerging strategies against antimicrobial resistance

Antimicrobial resistance (AMR) is a major and growing problem in global health, reducing the effectiveness of routine antibiotics and driving the increased prevalence of infectious diseases across the globe. The swift proliferation of resistant bacterial strains is largely a consequence of the overuse and misuse of antimicrobial agents; this is underscored by the estimated 1.27 million deaths directly linked to AMR, alongside the nearly 4.95 million deaths associated with AMR in 2019. Mechanisms by which bacteria gain resistance include degradation of the drug through enzymatic action, modification of the site of action for the antimicrobial drug, activation of efflux pumps, diminished susceptibility to antimicrobial agents and biofilm growth, all of which ultimately reduce the efficiency of the traditional treatment measures. Over the past few years, there has been increasing interest in the use of metal-based antimicrobial agents, as these potential agents can simultaneously target bacteria via multiple mechanisms (e.g., disrupting bacterial membranes, generating reactive oxygen species (ROS), denaturing proteins, and interfering with DNA replication). As one of the metals studied, silver has demonstrated a high level of efficacy against bacteria with a broad antimicrobial spectrum. Silver ions, silver nanoparticles and organometallic complexes containing silver have been widely studied for their antibacterial activity and ability to prevent the development of bacterial resistance. Of these, N-heterocyclic carbene (NHC)-silver complexes have received special attention because of their excellent stability and ability to release silver ions in a controlled and sustained manner under physiological conditions. These properties have been correlated with increased antimicrobial activity in preclinical in vitro and in limited in vivo models, and thus translation to clinical application is premature. It is important to note that in vivo pharmacokinetics, toxicity characterization and well-designed clinical trials are critical requirements for determining the real therapeutic utility of Ag-NHC complexes as next generation antimicrobial agents.