Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA.
Sci Transl Med. 2018 Sep 26;10(460). doi: 10.1126/scitranslmed.aat7520.
The lack of new antibiotics is among the most critical challenges facing medicine. The problem is particularly acute for Gram-negative bacteria. An unconventional antibiotic strategy is to target bacterial nutrition and metabolism. The metal gallium can disrupt bacterial iron metabolism because it substitutes for iron when taken up by bacteria. We investigated the antibiotic activity of gallium ex vivo, in a mouse model of airway infection, and in a phase 1 clinical trial in individuals with cystic fibrosis (CF) and chronic airway infections. Our results show that micromolar concentrations of gallium inhibited growth in sputum samples from patients with CF. Ex vivo experiments indicated that gallium inhibited key iron-dependent bacterial enzymes and increased bacterial sensitivity to oxidants. Furthermore, gallium resistance developed slowly, its activity was synergistic with certain antibiotics, and gallium did not diminish the antibacterial activity of host macrophages. Systemic gallium treatment showed antibiotic activity in murine lung infections. In addition, systemic gallium treatment improved lung function in people with CF and chronic lung infection in a preliminary phase 1 clinical trial. These findings raise the possibility that human infections could be treated by targeting iron metabolism or other nutritional vulnerabilities of bacterial pathogens.
缺乏新的抗生素是医学面临的最严峻挑战之一。革兰氏阴性菌的问题尤为突出。一种非传统的抗生素策略是针对细菌的营养和代谢。金属镓可以破坏细菌的铁代谢，因为它在被细菌吸收时替代铁。我们在气道感染的小鼠模型和囊性纤维化（CF）和慢性气道感染患者的 1 期临床试验中，研究了镓的体外抗生素活性。我们的研究结果表明，镓的微摩尔浓度可以抑制 CF 患者痰液样本中的生长。体外实验表明，镓抑制了关键的铁依赖性细菌酶，并增加了细菌对氧化剂的敏感性。此外，镓耐药性的发展缓慢，其活性与某些抗生素具有协同作用，并且镓不会降低宿主巨噬细胞的抗菌活性。全身镓治疗在小鼠肺部感染中显示出抗生素活性。此外，在初步的 1 期临床试验中，全身镓治疗改善了 CF 患者和慢性肺部感染患者的肺功能。这些发现表明，通过靶向铁代谢或细菌病原体的其他营养脆弱性，可能可以治疗人类感染。
