Gallium to the rescue?

 Although it has received less publicity than it should, anti-microbial resistance remains a threat to treatment for bacterial infections. There may be no silver bullet in sight, but another element may ride to the rescue. A recent European Parliamentary Research Service posting reports:

Antimicrobial-resistant infections are predicted to become the second biggest cause of death worldwide by 2050. Despite increasing investment in the development of new antimicrobials, awareness campaigns on antimicrobial misuse and abuse, and monitoring of antimicrobial use and resistance in animals, humans and the environment, antimicrobial resistance continues to grow and the last three decades have not seen even one novel antimicrobial class reach the market. Could the answer lie in a ‘Trojan horse’ strategy to disrupt a natural physiological process common to all bacteria?

In Homer’s telling of the fall of Troy, following an unsuccessful 10‑year siege, the Greeks offered the Trojans a large wooden horse. Once the gift was inside the city walls, out came an army, led by Odysseus, who destroyed the city and ended the war. While it may seem far-fetched to use an old Greek myth as an analogy for the fight against antimicrobial resistance (AMR), the market dearth of new antimicrobials, despite millions of euros invested, means bold new strategies are needed.

The Trojan horse that could be ‘offered’ to antimicrobial-resistant bacteria is gallium. This metal-based nanoparticle strategy exploits an essential living requirement for all living beings: iron acquisition. As an essential micronutrient, during an infection iron is used as a pawn in a tug of war between humans and bacteria: our organism sequesters iron in red blood cells, as well as in heme, ferritin and lactoferrin molecules; in parallel, bacteria secrete iron chellators (siderophores and heme carriers) that bind host ferric iron (Fe(III)) and transport it to the bacterial cell. Using gallium (Ga(III)) as an antimicrobial would mean tricking the bacteria into believing they have acquired iron. Gallium is an iron-mimetic metal, of similar electric charge, ion diameter and biochemistry to iron. It can enter bacterial cells through iron membrane receptors, like a Trojan horse, and then replace iron in physiological processes. However, unlike iron, it cannot be reduced to divalent gallium. Therefore, it inhibits essential cell biochemical processes that depend on iron as a co-factor, quickly becoming toxic for the bacteria and leading to its death.

Gallium is not a novel promise. This FDA-approved drug for cancer treatment was shown more than 10 years ago to successfully inhibit the virulence of Acinetobacter baummannii, a nosocomial bacterial pathogen that has become resistant to virtually all known antimicrobials, including ‘last resort‘ ones. Since then, gallium’s antimicrobial activity has been demonstrated for other multidrug-resistant (MDR) bacteria considered by the World Health Organization (WHO) to be critical priority pathogens for the development of new antimicrobials. These include Pseudomonas aeruginosa, Enterobacterales species and Mycobacterium tuberculosis, responsible for tuberculosis, the second most deadly communicable disease (after COVID-19), causing 1.5 million deaths per year. More specifically, gallium was effective in a pilot phase Ib trial involving 20 patients with cystic fibrosis and chronic P. aeruginosa lung infections.