Photoaffinity Approach Reveals Antibiotic Adjuvant Activity toward Pseudomonas aeruginosa

Laura C Miller Conrad
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Abstract

Pseudomonas aeruginosa is an emerging public health threat. A common Gram‐negative source of secondary infections, it has few effective treatment options, which are currently being undermined by the rise of resistance. New therapies are urgently needed. We had previously pursued an antivirulence strategy to block the production of pyocyanin, a redox‐active virulence factor. A photoaffinity analog of an antipyocyanin compound was developed to interrogate the inhibitor’s molecular mechanism of action. In the process, antibiotic adjuvant activity was suggested by the proteomics results. Using susceptibility assays, we found that these compounds amplify the bactericidal activity of colistin, a well‐characterized antibiotic, suggesting they may represent a first‐in‐class antibiotic adjuvant therapy. Analogs have the potential to not only widen the therapeutic index of cationic antibiotic peptides like colistin, but to be effective against colistin‐resistant strains. Multidrug‐resistant infections with P. aeruginosa are currently treated with colistin and the related polymyxin b, however, resistance to these drugs is also increasingly encountered. The adjuvants have the potential to preserve the life‐saving therapy of colistin when used in a combination therapy.
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光亲和方法揭示铜绿假单胞菌的抗生素佐剂活性
铜绿假单胞菌是一种新出现的公共卫生威胁。铜绿假单胞菌是一种常见的革兰氏阴性菌,可引起继发性感染,但它的有效治疗方案却很少,目前抗药性的增加又削弱了它的治疗效果。我们迫切需要新的疗法。此前,我们一直在寻求一种抗病毒策略,以阻断具有氧化还原作用的毒力因子--焦花青素的产生。我们开发了一种抗焦花青素化合物的光亲和类似物,以探究抑制剂的分子作用机制。在此过程中,蛋白质组学结果表明了抗生素的辅助活性。通过药敏试验,我们发现这些化合物放大了可乐定(一种特性良好的抗生素)的杀菌活性,这表明它们可能代表了第一类抗生素辅助疗法。类似物不仅有可能扩大阳离子抗生素肽(如秋水仙碱)的治疗指数,还能有效抑制耐秋水仙碱菌株。铜绿假单胞菌对多种药物产生耐药性,目前主要使用秋水仙素和相关的多粘菌素 b 进行治疗,但对这些药物产生耐药性的情况也越来越多。辅助剂在联合疗法中使用时,有可能保留可乐定的救命疗法。
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