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TitleAn inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials.
Journal, issue, pagesPLoS Pathog, Vol. 20, Issue 7, Page e1012376, Year 2024
Publish dateJul 15, 2024
AuthorsHaomin Huang / Shenghai Chang / Tao Cui / Man Huang / Jiuxin Qu / Huimin Zhang / Ting Lu / Xing Zhang / Chun Zhou / Youjun Feng /
PubMed AbstractAntimicrobial 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), ...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.
External linksPLoS Pathog / PubMed:39008531 / PubMed Central
MethodsEM (single particle)
Resolution2.19 - 2.53 Å
Structure data

35008

8hsy

EMDB-35008, PDB-8hsy:
Acyl-ACP Synthetase structure
Method: EM (single particle) / Resolution: 2.53 Å

36725

8jyl

EMDB-36725, PDB-8jyl:
Acyl-ACP Synthetase structure bound to C10-AMS
Method: EM (single particle) / Resolution: 2.33 Å

36731

8jyu

EMDB-36731, PDB-8jyu:
Acyl-ACP Synthetase structure bound to Decanoyl-AMP
Method: EM (single particle) / Resolution: 2.19 Å

Chemicals


ChemComp, No image

ChemComp-VUL:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-AMP:
ADENOSINE MONOPHOSPHATE / AMP*YM

ChemComp-DKA:
DECANOIC ACID

Source
  • vibrio harveyi (bacteria)
KeywordsCYTOSOLIC PROTEIN / Acyl-ACP synthetase / Tool enzyme / LIGASE

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