Antibacterial activities of gallium Ga(III) against E. coli are substantially impacted by ferric Fe(III) uptake systems and multidrug resistance (MDR) in combination with oxygen levels.

The continued emergence and spread of antimicrobial resistance (AMR) - particularly multidrug resistant (MDR) bacteria - is an increasing threat driving the search for additional and alternative antimicrobial agents. WHO has categorised bacterial risk levels and includes Escherichia coli among the highest priority, making this both a convenient "model" bacterium as well as a clinically highly relevant species on which to base investigations of antimicrobials. Among many compounds examined for use as antimicrobials, Ga(III) complexes have shown promise. Nonetheless, spectrum of activities, susceptibility of bacterial species, mechanisms of antimicrobial action and bacterial characteristics influencing antibacterial actions are far from being completely understood - these are important considerations for any implementation as an effective antibacterial agent. In this investigation, we show that alteration in growth conditions to physiologically-relevant lowered oxygen (anaerobic) conditions substantially increases minimum inhibitory concentrations (MIC) of Ga(III) required to inhibit growth for 46 wild-type E. coli strains. Several studies have implicated a "Trojan horse hypothesis" wherein bacterial Fe uptake systems have been linked to promotion of Ga(III) uptake and resultant enhanced antibacterial activity. Our studies show that, conversely, carriage of "accessory" Fe uptake systems (Fe_acc) significantly increased the concentrations of Ga(III) required for antibacterial action. Similarly, it is shown that MDR strains are more resistant to Ga(III). Increased tolerance of Fe_acc/MDR strains was apparent under anaerobic conditions. This phenomenon of heightened tolerance has not previously been shown although the mechanisms remain to be defined. Nonetheless, this further highlights the significant contributions of bacterial metabolism, fitness and AMR characteristics and their implications in evaluating novel antimicrobials.

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