Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil.
Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
Front Cell Infect Microbiol. 2019 Dec 11;9:414. doi: 10.3389/fcimb.2019.00414. eCollection 2019.
There are only few drugs available to treat fungal infections, and the lack of new antifungals, along with the emergence of drug-resistant strains, results in millions of deaths/year. An unconventional approach to fight microbial infection is to exploit nutritional vulnerabilities of microorganism metabolism. The metal gallium can disrupt iron metabolism in bacteria and cancer cells, but it has not been tested against fungal pathogens such as and . Here, we investigate activity of gallium nitrate III [Ga(NO)] against these human pathogens, to reveal the gallium mechanism of action and understand the interaction between gallium and clinical antifungal drugs. Ga(NO) presented a fungistatic effect against azole-sensitive and -resistant strains (MIC = 32.0 mg/L) and also had a synergistic effect with caspofungin, but not with azoles and amphotericin B. Its antifungal activity seems to be reliant on iron-limiting conditions, as the presence of iron increases its MIC value and because we observed a synergistic interaction between gallium and iron chelators against . We also show that an mutant (Δ) unable to grow in the absence of iron is more susceptible to gallium, reinforcing that gallium could act by disrupting iron homeostasis. Furthermore, we demonstrate that gallium has a fungistatic effect against different species of ranging from 16.0 to 256.0 mg/L, including multidrug-resistant , and . Our findings indicate that gallium can inhibit fungal pathogens under iron-limiting conditions, showing that Ga(NO) could be a potential therapy not only against bacteria but also as an antifungal drug.
目前可用于治疗真菌感染的药物寥寥无几，由于缺乏新的抗真菌药物以及耐药菌株的出现，每年导致数百万人死亡。一种对抗微生物感染的非常规方法是利用微生物代谢的营养脆弱性。金属镓可以破坏细菌和癌细胞中的铁代谢，但尚未在真菌病原体如 和 中进行测试。在这里，我们研究了硝酸镓 III [Ga(NO)] 对这些人类病原体的活性，以揭示镓的作用机制并了解镓与临床抗真菌药物的相互作用。Ga(NO) 对唑类敏感和耐药 的菌株均具有抑菌作用（MIC = 32.0 mg/L），并且与卡泊芬净具有协同作用，但与唑类和两性霉素 B 没有协同作用。其抗真菌活性似乎依赖于铁限制条件，因为铁的存在会增加其 MIC 值，并且我们观察到镓与铁螯合剂对 的协同相互作用。我们还表明，无法在没有铁的情况下生长的 突变体（Δ）对镓更敏感，这进一步证实了镓可以通过破坏铁稳态来发挥作用。此外，我们证明镓对不同种属的 具有抑菌作用，其 MIC 值为 16.0 至 256.0 mg/L，包括多药耐药性 ，和 。我们的研究结果表明，在铁限制条件下，镓可以抑制真菌病原体 ，表明 Ga(NO) 不仅可以作为治疗细菌的潜在疗法，也可以作为抗真菌药物。
