Zhang Zinan, Ortega Dominic, Rush Anthony, Blankenship Lauren R, Cheng Zi Jun, Moore Rebecca E, Tran Minh L N, Sandoval Lucero G, Aboulhosn Kareem, Watanabe Seiichiro, Cortez Kendra S, Perlman David H, Semmelhack Martin F, Miller Conrad Laura C
Department of Chemistry, Princeton University, Washington Road, Princeton, New Jersey 08544, United States.
Department of Chemistry, San José State University, 1 Washington Square, San Jose, California 95192, United States.
ACS Infect Dis. 2021 Mar 12;7(3):535-543. doi: 10.1021/acsinfecdis.0c00160. Epub 2021 Feb 15.
Infections with are a looming threat to public health. New treatment strategies are needed to combat this pathogen, for example, by blocking the production of virulence factors like pyocyanin. A photoaffinity analogue of an antipyocyanin compound was developed to interrogate the inhibitor's molecular mechanism of action. While we sought to develop antivirulence inhibitors, the proteomics results suggested that the compounds had antibiotic adjuvant activity. Unexpectedly, 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. Analogues have the potential not only to widen the therapeutic index of cationic antimicrobial peptides like colistin, but also to be effective against colistin-resistant strains, strengthening our arsenal to combat infections.
感染是对公共卫生的一个潜在威胁。需要新的治疗策略来对抗这种病原体，例如通过阻断绿脓菌素等毒力因子的产生。开发了一种抗绿脓菌素化合物的光亲和类似物，以探究该抑制剂的分子作用机制。虽然我们试图开发抗毒力抑制剂，但蛋白质组学结果表明这些化合物具有抗生素佐剂活性。出乎意料的是，我们发现这些化合物增强了多粘菌素（一种特征明确的抗生素）的杀菌活性，这表明它们可能代表了一类新型的抗生素佐剂疗法。类似物不仅有可能扩大多粘菌素等阳离子抗菌肽的治疗指数，而且对耐多粘菌素菌株也有效，从而增强我们对抗感染的手段。
