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How Clavulanic Acid Inhibits Serine β-Lactamases
Pauline A Lang1,2, Mariska de Munnik1,2, Abraham O Oluwole3,4
1Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, United Kingdom.
Chembiochem : a European Journal of Chemical Biology
|July 25, 2024
Summary
Clavulanic acid inhibits serine β-lactamases (SBLs) via acyl enzyme complex formation and oxazolidine ring opening. Fragmentation of clavulanic acid is not essential for SBL inhibition in vivo.
Area of Science:
- Biochemistry
- Enzymology
- Medicinal Chemistry
Background:
- Clavulanic acid is a vital inhibitor of serine β-lactamases (SBLs), enzymes conferring antibiotic resistance.
- Understanding the precise inhibition mechanism is crucial for developing new antibacterial agents.
Purpose of the Study:
- To elucidate the mechanism of clavulanic acid inhibition against representative Ambler class A, C, and D SBLs.
- To investigate the role of clavulanic acid fragmentation in SBL inhibition under varying pH conditions.
Main Methods:
- Utilized denaturing and non-denaturing mass spectrometry (MS) to study enzyme-inhibitor interactions.
- Analyzed inhibition mechanisms of TEM-116, Escherichia coli AmpC, and OXA-10 SBLs with clavulanic acid.
Main Results:
- Results indicate clavulanic acid primarily inhibits SBLs through acyl enzyme complex formation and oxazolidine ring opening, without significant fragmentation at neutral pH.
- Acidic conditions, common in LC-MS, promote clavulanic acid fragmentation, contrasting with neutral pH observations.
- Slow fragmentation was observed with TEM-116 under prolonged neutral conditions.
Conclusions:
- Clavulanic acid scaffold fragmentation is likely not essential for SBL inhibition in vivo.
- Developing inhibitors that form stable covalent complexes through fragmentation may offer therapeutic potential.
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