Gallium and its competing roles with iron in biological systems

Abstract

Gallium, a group IIIa metal, shares chemical properties with iron. Studies have shown that gallium-based compounds have potential therapeutic activity against certain cancers and infectious microorganisms. By functioning as an iron mimetic, gallium perturbs iron-dependent proliferation processes in tumor cells. Gallium's action on iron homeostasis leads to disruption of ribonucleotide reductase, mitochondrial function, and the regulation of transferrin receptor and ferritin. In addition, gallium nitrate stimulates an increase in mitochondrial reactive oxygen species in cells which triggers downstream upregulation of metallothionein and hemoxygenase-1. Gallium's anti-infective activity against bacteria and fungi results from disruption of microbial iron utilization through mechanisms which include gallium binding to siderophores and downregulation of bacterial iron uptake. Gallium compounds lack cross-resistance to conventional chemotherapeutic drugs and antibiotics thus making them attractive agents for drug development. This review will focus on the mechanisms of action of gallium with emphasis on its interaction with iron and iron proteins.

Metal Complexes, an Untapped Source of Antibiotic Potential?

“…Despite these promising results, there is a general lack of knowledge around the exact molecular mechanisms of action of gallium-based compounds. As mentioned earlier, Ga(III) has very similar properties to Fe(III) and can disrupt a variety of iron-dependent functions as it cannot be reduced under physiological conditions [60]. Recent studies by the group of Hongzhe Sun elucidated the molecular targets of gallium.…”

Antimicrobial Metal Nanomaterials: From Passive to Stimuli‐Activated Applications

“…[ 46 ] 2) Generation of ROS, either directly in the case of redox‐active metals, or through damage to the Fe–S clusters within proteins, which liberate redox‐active Fe ions. [ 46 ] 3) Inhibition of nutrient uptake, for example gallium ions have recently been shown to kill bacteria through a “trojan horse” mechanism, whereby the cells mistake it for Fe 3+ ions, due to the similar chemical properties [ 125 ] and the cell becomes inactivated through inhibition of metabolic activity as the bacteria are unable to reduce the Ga 3+ . [ 126 ] 4) Damage to the membrane can occur as the positive metal cations interact with the electronegative membrane as well as some integral proteins such as those involved in the electron transport chain.…”

Bioactive glasses as delivery systems for antimicrobial agents

“…The role of gallium (Ga 3+ ) as an antibacterial agent is attributed to the chemical similarity of its 3+ oxidation state to Fe 3+ (Kelson et al . ; Chitambar ). The reduction of Fe 2+ is a key step in many intracellular processes and since many proteins require Fe 3+ as a key cofactor, Ga 3+ can also function as an Fe 3+ analogue.…”

“…The reduction of Fe 2+ is a key step in many intracellular processes and since many proteins require Fe 3+ as a key cofactor, Ga 3+ can also function as an Fe 3+ analogue. However, unlike Fe 3+ , under physiological conditions, Ga 3+ cannot be reduced to Ga 2+ (Chitambar ). Hence, since most microbes require iron to survive, gallium has the potential to function as an antibacterial agent with very broad spectrum activity by targeting bacterial Fe 3+ metabolisms.…”