Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins—a class of natural products with weak activity and limited spectrum—to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria. G0775 inhibits the essential bacterial type I signal peptidase, a new antibiotic target, through an unprecedented molecular mechanism. It circumvents existing antibiotic resistance mechanisms and retains activity against contemporary multidrug-resistant Gram-negative clinical isolates in vitro and in several in vivo infection models. These findings demonstrate that optimized arylomycin analogues such as G0775 could translate into new therapies to address the growing threat of multidrug-resistant Gram-negative infections.Chemical optimization of arylomycins results in an inhibitor of bacterial type I signal peptidase that shows activity both against multidrug-resistant clinical isolates of Gram-negative bacteria in vitro and in several in vivo infection models.

中文翻译：

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优化的芳霉素是一类新的革兰氏阴性抗生素

耐多药细菌正在以惊人的速度传播，尽管做出了广泛的努力，但五十多年来没有一种新的具有抗革兰氏阴性细菌活性的抗生素获得批准。天然产物及其衍生物在对抗革兰氏阴性病原体方面具有关键作用。在这里，我们报告了对芳霉素（一类活性较弱且光谱有限的天然产物）的化学优化，以获得 G0775，一种对革兰氏阴性菌具有强效广谱活性的分子。G0775 通过前所未有的分子机制抑制必需的细菌 I 型信号肽酶，这是一种新的抗生素靶点。它绕过了现有的抗生素耐药机制，并在体外和几种体内感染模型中保留了对当代多重耐药革兰氏阴性临床分离株的活性。