An inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials.

Autor: Huang H; Key Laboratory of Multiple Organ Failure, Ministry of Education; Departments of Microbiology and General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China., Chang S; Center of Cryo-Electron Microscopy, Zhejiang University, Hangzhou, Zhejiang, China., Cui T; School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China., Huang M; Key Laboratory of Multiple Organ Failure, Ministry of Education; Departments of Microbiology and General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China., Qu J; Department of Clinical Laboratory, Shenzhen Third People's Hospital, National Clinical Research Center for Infectious Diseases, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China., Zhang H; Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America., Lu T; Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America., Zhang X; Center of Cryo-Electron Microscopy, Zhejiang University, Hangzhou, Zhejiang, China., Zhou C; School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China., Feng Y; Key Laboratory of Multiple Organ Failure, Ministry of Education; Departments of Microbiology and General Intensive Care Unit of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.; Department of Clinical Laboratory, Shenzhen Third People's Hospital, National Clinical Research Center for Infectious Diseases, The Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, China.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2024 Jul 15; Vol. 20 (7), pp. e1012376. Date of Electronic Publication: 2024 Jul 15 (Print Publication: 2024).
DOI: 10.1371/journal.ppat.1012376
Abstrakt: Antimicrobial resistance is an ongoing "one health" challenge of global concern. The acyl-ACP synthetase (termed AasS) of the zoonotic pathogen Vibrio harveyi recycles exogenous fatty acid (eFA), bypassing the requirement of type II fatty acid synthesis (FAS II), a druggable pathway. A growing body of bacterial AasS-type isoenzymes compromises the clinical efficacy of FAS II-directed antimicrobials, like cerulenin. Very recently, an acyl adenylate mimic, C10-AMS, was proposed as a lead compound against AasS activity. However, the underlying mechanism remains poorly understood. Here we present two high-resolution cryo-EM structures of AasS liganded with C10-AMS inhibitor (2.33 Å) and C10-AMP intermediate (2.19 Å) in addition to its apo form (2.53 Å). Apart from our measurements for C10-AMS' Ki value of around 0.6 μM, structural and functional analyses explained how this inhibitor interacts with AasS enzyme. Unlike an open state of AasS, ready for C10-AMP formation, a closed conformation is trapped by the C10-AMS inhibitor. Tight binding of C10-AMS blocks fatty acyl substrate entry, and therefore inhibits AasS action. Additionally, this intermediate analog C10-AMS appears to be a mixed-type AasS inhibitor. In summary, our results provide the proof of principle that inhibiting salvage of eFA by AasS reverses the FAS II bypass. This facilitates the development of next-generation anti-bacterial therapeutics, esp. the dual therapy consisting of C10-AMS scaffold derivatives combined with certain FAS II inhibitors.
Competing Interests: No competing interests are present.
(Copyright: © 2024 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje