Antimicrobial Activity of Gallium Compounds on ESKAPE Pathogens

Abstract

ESKAPE bacteria are a major cause of multidrug-resistant infections, and new drugs are urgently needed to combat these pathogens. Given the importance of iron in bacterial physiology and pathogenicity, iron uptake and metabolism have become attractive targets for the development of new antibacterial drugs. In this scenario, the FDA-approved iron mimetic metal Gallium [Ga(III)] has been successfully repurposed as an antimicrobial drug. Ga(III) disrupts ferric iron-dependent metabolic pathways, thereby inhibiting microbial growth. This work provides the first comparative assessment of the antibacterial activity of Ga(NO3)3 (GaN), Ga(III)-maltolate (GaM), and Ga(III)-protoporphyrin IX (GaPPIX), belonging to the first-, second- and third-generation of Ga(III) formulations, respectively, on ESKAPE species, including reference strains and multidrug-resistant (MDR) clinical isolates. In addition to the standard culture medium Mueller Hinton broth (MHB), iron-depleted MHB (DMHB) and RPMI-1640 supplemented with 10% human serum (HS) (RPMI-HS) were also included in Ga(III)-susceptibility tests, because of their different nutrient and iron contents. All ESKAPE species were resistant to all Ga(III) compounds in MHB and DMHB (MIC > 32 μM), except Staphylococcus aureus and Acinetobacter baumannii, which were susceptible to GaPPIX. Conversely, the antibacterial activity of GaN and GaM was very evident in RPMI-HS, in which the low iron content and the presence of HS better mimic the in vivo environment. In RPMI-HS about 50% of the strains were sensitive (MIC < 32) to GaN and GaM, both compounds showing a similar spectrum of activity, although GaM was more effective than GaN. In contrast, GaPPIX lost its antibacterial activity in RPMI-HS likely due to the presence of albumin, which binds GaPPIX and counteracts its inhibitory effect. We also demonstrated that the presence of multiple heme-uptake systems strongly influences GaPPIX susceptibility in A. baumannii. Interestingly, GaN and GaM showed only a bacteriostatic effect, whereas GaPPIX exerted a bactericidal activity on susceptible strains. Altogether, our findings raise hope for the future development of Ga(III)-based compounds in the treatment of infections caused by multidrug-resistant ESKAPE pathogens.

Potential of Gallium as an Antifungal Agent

“…In this study, we have investigated the antifungal effect of gallium nitrate III, which is an FDA-approved drug (Ganite TM ), and the first generation of gallium compounds. Additionally, there are several other gallium-based metallodrugs and novel gallium agents available and in development (Chitambar, 2010;Hijazi et al, 2018) that can exert distinct antimicrobial effects (Hijazi et al, 2018). In the future, studies should focus on testing if other gallium compounds are more effective and specific against fungal cells and the safety of those drugs for the host.…”

Iron/Heme Metabolism-Targeted Gallium(III) Nanoparticles Are Active against Extracellular and Intracellular Pseudomonas aeruginosa and Acinetobacter baumannii

“…The MICs of Ga(NO 3 ) 3 ranged from 0.5 to 128 g/ml against all A. baumannii strains, whereas the MICs for P. aeruginosa strains ranged from 1 to 4 g/ml. Thus, the susceptibility of A. baumannii to Ga(NO 3 ) 3 is more strain dependent, and resistance to Ga(NO 3 ) 3 is more common than for P. aeruginosa (22).…”

Metal Complexes, an Untapped Source of Antibiotic Potential?

“…On the other hand, bacteriostatic activity of Ga(NO 3 ) 3 and GaM was found against some strains (mainly A. baumannii and P. aeruginosa) in RPMI-1640 supplemented with 10% human serum which better simulates the low iron content and presence of human serum in in vivo environments. Conversely, GaPPIX lost all activity against S. aureus (MIC > 128 µM) and showed more a more variable profile against A. baumannii (MICs = 0.25-128 µM) [56].…”