Hennessen Fabienne, Miethke Marcus, Zaburannyi Nestor, Loose Maria, Lukežič Tadeja, Bernecker Steffen, Hüttel Stephan, Jansen Rolf, Schmiedel Judith, Fritzenwanker Moritz, Imirzalioglu Can, Vogel Jörg, Westermann Alexander J, Hesterkamp Thomas, Stadler Marc, Wagenlehner Florian, Petković Hrvoje, Herrmann Jennifer, Müller Rolf
Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), and Department of Pharmacy, Saarland University Campus E8.1, 66123 Saarbrücken, Germany.
German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 38124 Braunschweig, Germany.
Antibiotics (Basel). 2020 Sep 18;9(9):619. doi: 10.3390/antibiotics9090619.
The reassessment of known but neglected natural compounds is a vital strategy for providing novel lead structures urgently needed to overcome antimicrobial resistance. Scaffolds with resistance-breaking properties represent the most promising candidates for a successful translation into future therapeutics. Our study focuses on chelocardin, a member of the atypical tetracyclines, and its bioengineered derivative amidochelocardin, both showing broad-spectrum antibacterial activity within the ESKAPE (, and species) panel. Further lead development of chelocardins requires extensive biological and chemical profiling to achieve favorable pharmaceutical properties and efficacy. This study shows that both molecules possess resistance-breaking properties enabling the escape from most common tetracycline resistance mechanisms. Further, we show that these compounds are potent candidates for treatment of urinary tract infections due to their in vitro activity against a large panel of multidrug-resistant uropathogenic clinical isolates. In addition, the mechanism of resistance to natural chelocardin was identified as relying on efflux processes, both in the chelocardin producer and in the pathogen Resistance development in led primarily to mutations in , causing increased expression of the efflux pump. Most importantly, amidochelocardin overcomes this resistance mechanism, revealing not only the improved activity profile but also superior resistance-breaking properties of this novel antibacterial compound.
重新评估已知但被忽视的天然化合物是提供克服抗菌耐药性急需的新型先导结构的重要策略。具有抗耐药性的骨架是成功转化为未来治疗药物最有希望的候选物。我们的研究聚焦于非典型四环素成员之一的螯合卡菌素及其生物工程衍生物氨基螯合卡菌素，二者在ESKAPE（粪肠球菌、金黄色葡萄球菌、肺炎克雷伯菌、鲍曼不动杆菌、铜绿假单胞菌和阴沟肠杆菌）菌属中均表现出广谱抗菌活性。螯合卡菌素的进一步先导物开发需要广泛的生物学和化学分析，以实现良好的药物性质和疗效。本研究表明，这两种分子均具有抗耐药性，能够避开最常见的四环素耐药机制。此外，我们表明，由于这些化合物对大量耐多药尿路致病性临床分离株具有体外活性，它们是治疗尿路感染的有力候选物。此外，在螯合卡菌素产生菌和病原体中，对天然螯合卡菌素的耐药机制均被确定为依赖于外排过程。粪肠球菌中的耐药性发展主要导致tetK基因突变，导致tetK外排泵表达增加。最重要的是，氨基螯合卡菌素克服了这种耐药机制，不仅揭示了这种新型抗菌化合物改善的活性谱，还揭示了其优越的抗耐药性。
