Antibacterial Activities of Ga(III) against E. coli Are Substantially Impacted by Fe(III) Uptake Systems and Multidrug Resistance in Combination with Oxygen Levels

Abstract

The continued emergence and spread of antimicrobial resistance (AMR), particularly multidrug resistant (MDR) bacteria, are increasing threats driving the search for additional and alternative antimicrobial agents. The World Health Organization (WHO) has categorized bacterial risk levels and includes Escherichia coli among the highest priority, making this both a convenient model bacterium and 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, the 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 of an effective antibacterial agent. In this investigation, we show that an alteration in growth conditions to physiologically relevant lowered oxygen (anaerobic) conditions substantially increases the minimum inhibitory concentrations (MICs) 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 the promotion of Ga­(III) uptake and result in enhanced antibacterial activity. Our studies show that, conversely, the 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). The 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.

Antimicrobial Properties of Gallium(III)- and Iron(III)-Loaded Polysaccharides Affecting the Growth of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa, In Vitro

“…Because of the physiological relevance of oxygen levels, a separate experiment was carried out to investigate the effect of reduced oxygen level in atmosphere on the MIC of Ga-CMC. It was reported that the oxygen levels in infection usually are much lower than ambient atmosphere 50 . For example, it is about 5% O2 equivalent in perfused tissues while a near anaerobic condition is found in sites of inflammatory damage.…”

Advantageous Reactivity of Unstable Metal Complexes: Potential Applications of Metal-Based Anticancer Drugs for Intratumoral Injections

“…In addition, the ability of Ga(III) to inhibit bone resorption and Ca(II) release has been reported [135], but the link between Ga(III) and Ca(II) remains much less explored than the similarities between Ga(III) and Fe(III) [124,125]. Recently, inorganic Ga(III) salts and Ga(III) complexes with organic ligands have emerged as potent antibacterial and antifungal agents with low toxicity to animals and humans [136][137][138][139][140][141][142][143]. Such beneficial antimicrobial activities are likely to be based on the differences in both Fe and Ca metabolism between microbial and mammalian cells [138,144].…”

Gallium Complex-Functionalized P4HB Fibers: A Trojan Horse to Fight Bacterial Infection

“…While these results cannot be directly extrapolated to other bacterial strains or to the effect of GaPPIX in wound healing scenarios, they provide important information on the effect of the environment. 46 S. aureus, on the other hand, was not shown to have a reduced susceptibility to GaPPIX when cultured in cell culture media of different iron concentrations. 42 This is of high clinical relevance since it suggests that the availability of iron from red blood cells within a wound might not impair the antibacterial efficacy of GaPPIX.…”

“…Further, in competition with an Fe 3+ -supplemented medium, a 60-fold excess of Ga over Fe was necessary to achieve an antibacterial effect. While these results cannot be directly extrapolated to other bacterial strains or to the effect of GaPPIX in wound healing scenarios, they provide important information on the effect of the environment S.…”