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

Huang, Haomin1,2,3; Chang, Shenghai4; Cui, Tao5; Huang, Man1,2,3; Qu, Jiuxin6; Zhang, Huimin7; Lu, Ting8; Zhang, Xing4; Zhou, Chun9; Feng, Youjun1,2,3,6

2024-07-01

10.1371/journal.ppat.1012376

PLOS PATHOGENS   影响因子和分区

1553-7366

1553-7374

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 & Aring;) and C10-AMP intermediate (2.19 & Aring;) in addition to its apo form (2.53 & Aring;). Apart from our measurements for C10-AMS' Ki value of around 0.6 mu M, 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 proof of principle that inhibiting salvage of eFA by AasS reverses the FAS II bypass. This facilitates the development of next-generation of anti-bacterial therapeutics, esp. the dual therapy consisting of C10-AMS scaffold derivatives combined with certain FAS II inhibitors.

SCI

英语

通讯

National Natural Science Foundation of China["32141001","31830001"] ; National Science Fund for Distinguished Young Scholar[32125003] ; National Key Research & Development Program of China["2023YFC2307100","2023YFC2300021"]

Microbiology ; Parasitology ; Virology

Microbiology ; Parasitology ; Virology

WOS:001267886000001

PUBLIC LIBRARY SCIENCE

Web of Science

1.Zhejiang Univ, Affiliated Hosp 2, Sch Med, Key Lab Multiple Organ Failure,Minist Educ, Hangzhou, Zhejiang, Peoples R China
2.Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Microbiol, Hangzhou, Zhejiang, Peoples R China
3.Zhejiang Univ, Affiliated Hosp 2, Gen Intens Care Unit, Sch Med, Hangzhou, Zhejiang, Peoples R China
4.Zhejiang Univ, Ctr Cryoelectron Microscopy, Hangzhou, Zhejiang, Peoples R China
5.Northwestern Polytech Univ, Sch Life Sci, Xian, Shaanxi, Peoples R China
6.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Natl Clin Res Ctr Infect Dis, Dept Clin Lab,Affiliated Hosp 2, Shenzhen, Guangdong, Peoples R China
7.Univ Illinois, Canc Ctr Illinois, Urbana, IL USA
8.Univ Illinois, Dept Bioengn, Urbana, IL USA
9.Zhejiang Univ, Sch Med, Sch Publ Hlth, Hangzhou, Zhejiang, Peoples R China

Huang, Haomin,Chang, Shenghai,Cui, Tao,et al. An inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials[J]. PLOS PATHOGENS,2024,20(7).

Huang, Haomin.,Chang, Shenghai.,Cui, Tao.,Huang, Man.,Qu, Jiuxin.,...&Feng, Youjun.(2024).An inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials.PLOS PATHOGENS,20(7).

Huang, Haomin,et al."An inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials".PLOS PATHOGENS 20.7(2024).