Resisting the gallium "Trojan horse": Experimental evolutionary insights into microbial resistance

Given the increasing challenge of multidrug-resistant infections, there is a significant push to explore alternative treatments beyond conventional antibiotics. Historically, heavy metals have served as antimicrobial agents, and the current review focuses on elucidating their mechanisms of action and effectiveness against multidrug-resistant pathogens. Among these, gallium has emerged as a particularly promising antimicrobial agent with the potential to address the growing threat of antibiotic resistance. Using a "Trojan horse" strategy, gallium leverages its chemical similarity to iron to deceive pathogens. Because their ionic properties are nearly identical, pathogens readily import gallium through their native iron uptake systems. Once inside, the gallium is unable to perform iron's necessary functions and instead acts as a poison, disrupting the microbe's metabolism and ultimately causing its death. However, the question remains whether pathogens might adapt genetically, potentially leading to more harmful strains resistant to gallium's effects. Given the significant threat posed by multidrug-resistant pathogens, such as Escherichia coli, Staphylococcus aureus, and Candida tropicalis, this review explores new approaches to combating antimicrobial resistance. This hybrid review uses experimental evolution to identify the adaptive mechanisms that allow bacteria and Candida to overcome gallium's therapeutic "Trojan horse" effect. Studying gallium resistance is important for medical applications, as it provides critical insights into combating drug-resistant pathogens.