Department of Biology, University Roma Tre, Rome, Italy.
Antimicrob Agents Chemother. 2012 Nov;56(11):5961-70. doi: 10.1128/AAC.01519-12. Epub 2012 Sep 10.
Multidrug-resistant Acinetobacter baumannii poses a tremendous challenge to traditional antibiotic therapy. Due to the crucial role of iron in bacterial physiology and pathogenicity, we investigated iron metabolism as a possible target for anti-A. baumannii chemotherapy using gallium as an iron mimetic. Due to chemical similarity, gallium competes with iron for binding to several redox enzymes, thereby interfering with a number of essential biological reactions. We found that Ga(NO(3))(3), the active component of an FDA-approved drug (Ganite), inhibits the growth of a collection of 58 A. baumannii strains in both chemically defined medium and human serum, at concentrations ranging from 2 to 80 μM and from 4 to 64 μM, respectively. Ga(NO(3))(3) delayed the entry of A. baumannii into the exponential phase and drastically reduced bacterial growth rates. Ga(NO(3))(3) activity was strongly dependent on iron availability in the culture medium, though the mechanism of growth inhibition was independent of dysregulation of gene expression controlled by the ferric uptake regulator Fur. Ga(NO(3))(3) also protected Galleria mellonella larvae from lethal A. baumannii infection, with survival rates of ≥75%. At therapeutic concentrations for humans (28 μM plasma levels), Ga(NO(3))(3) inhibited the growth in human serum of 76% of the multidrug-resistant A. baumannii isolates tested by ≥90%, raising expectations on the therapeutic potential of gallium for the treatment of A. baumannii bloodstream infections. Ga(NO(3))(3) also showed strong synergism with colistin, suggesting that a colistin-gallium combination holds promise as a last-resort therapy for infections caused by pan-resistant A. baumannii.
耐多药鲍曼不动杆菌对传统抗生素治疗构成了巨大挑战。由于铁在细菌生理和致病性中的关键作用，我们研究了铁代谢作为抗鲍曼不动杆菌化疗的可能靶点，使用镓作为铁模拟物。由于化学相似性，镓与铁竞争结合到几种氧化还原酶上，从而干扰许多必需的生物反应。我们发现，FDA 批准的药物（Ganite）的有效成分 Ga(NO(3))(3)在化学定义的培养基和人血清中抑制了 58 株鲍曼不动杆菌菌株的生长，浓度范围分别为 2 至 80 μM 和 4 至 64 μM。Ga(NO(3))(3)延迟了鲍曼不动杆菌进入指数期，并大大降低了细菌的生长速度。Ga(NO(3))(3)的活性强烈依赖于培养基中铁的可用性，尽管生长抑制机制与铁摄取调节剂 Fur 控制的基因表达失调无关。Ga(NO(3))(3)还保护了大蜡螟幼虫免受致死性鲍曼不动杆菌感染，存活率≥75%。在人类治疗浓度（28 μM 血浆水平）下，Ga(NO(3))(3)抑制了 76%的多药耐药鲍曼不动杆菌分离株在人血清中的生长，抑制率≥90%，这提高了人们对镓治疗鲍曼不动杆菌血流感染的治疗潜力的期望。Ga(NO(3))(3)与多粘菌素也表现出很强的协同作用，表明多粘菌素-镓联合治疗有望成为泛耐药鲍曼不动杆菌感染的最后手段。
