Daptomycin exerts bactericidal effect through induction of excessive ROS production and blocking the function of stress response protein Usp2. Issue 2 (27th July 2021)

• Record Type: Journal Article
• Authors: Po, Kathy Hiu Laam; Chow, Hoi Yee; Cheng, Qipeng; Chan, Bill Kwan‐wai; Deng, Xin; Wang, Shuping; Chan, Edward Wai Chi; Kong, Hang‐Kin; Chan, Kin Fai; Li, Xuechen; Chen, Sheng
• Is Part Of: Natural sciences. Volume 1:Issue 2(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-07-27
• Subjects: bacteriacidal mechansims -- daptomycin -- ROS -- stress response -- Usp2; Science -- Periodicals; 505
• DOI: 10.1002/ntls.10023
• Languages: English
• ISSNs: 2698-6248

Abstract

Abstract: Daptomycin, as a lipopeptide antibiotic, exhibits high potency in the treatment of infections caused by clinically relevant drug‐resistant Gram‐positive pathogens, such as methicillin‐resistant Staphylococcus aureus and vancomycin‐resistant Enterococci . However, its bactericidal mechanism of action remains controversial. In this study, we report that daptomycin kills bacteria through triggering overproduction of deleterious reactive oxygen species (ROS). This outcome is attributed to daptomycin binding to the universal stress response protein (Usp2) and subsequent blocking its function, triggering stress, and anti‐ROS response. Based on these findings, we conclude that daptomycin causes bacterial cell death by simultaneously triggering ROS production through inflicting cell membrane damages and inhibiting antioxidant defense by blocking Usp2 function. This study depicts molecular mechanisms underlying the bactericidal effect of daptomycin, a combination of triggering ROS production and inhibiting anti‐ROS response. Key points: Novel bactericidal mechanism of daptomycin by ROS Identification of first bacterial protein target, Usp2, for daptomycin Deciphering the dual role of Usp2 on daptomycin mediated bacterial killing Abstract : Novel bactericidal mechanism of daptomycin by ROS. Identification of first bacterial protein target, Usp2, for daptomycin. Deciphering the dual role of Usp2 on daptomycin mediated bacterial killing. Mechanism of action of daptomycin. Daptomycin works by binding to Usp2 so that the hydrophobic lipid tail of the drug can be inserted to bacterial cell membrane. In the presence of calcium ions, aggregation of membrane‐bound daptomycin occurs, resulting in membrane damage. These events in turn triggers over‐production of ROS. The binding to Usp2 protein, which is an essential protein that mediates onset of bacterial oxidative stress response, might block the function of this protein, rendering the organism not able to express anti‐ROS response, thereby predisposing cell death due to excessive production of ROS.