Targeting Enterococcus faecalis HMG-CoA reductase with a non-statin inhibitor
Sucharita Bose1,2, C Nicklaus Steussy1, Daneli López-Pérez3,4
1Department of Biological Sciences, Purdue University, 915 West State Street, West Lafayette, IN, 47907, USA.
Communications Biology
|April 3, 2023
Summary
Researchers identified a novel compound that selectively inhibits bacterial HMG-CoA reductase (HMGR), a key enzyme in pathogenic bacteria. This non-statin inhibitor offers a promising avenue for developing new antibiotics against Gram-positive bacteria.
Area of Science:
- Biochemistry
- Microbiology
- Drug Discovery
Background:
- HMG-CoA reductase (HMGR) is a critical enzyme in the bacterial mevalonate pathway and a target for novel antibiotics.
- Existing statin drugs are ineffective against bacterial HMGR.
- Gram-positive pathogenic bacteria pose a significant public health threat.
Purpose of the Study:
- To determine the crystal structure of Enterococcus faecalis HMGR (efHMGR).
- To identify and characterize novel inhibitors of bacterial HMGR.
- To develop selective inhibitors for potential antibiotic development.
Main Methods:
- X-ray crystallography was used to determine the structures of apo and liganded efHMGR.
- High-throughput in-vitro screening was employed to identify inhibitors.
- Structural analysis of efHMGR in complex with a novel inhibitor.
Main Results:
- The crystal structure of efHMGR revealed unique features.
- A potent competitive inhibitor (compound 315) of efHMGR was identified.
- Compound 315 binds to the mevalonate-binding site and is selective for bacterial HMGR over human HMGR.
Conclusions:
- A selective, non-statin inhibitor of bacterial HMGR was discovered.
- This inhibitor occupies a conserved active site, offering potential for broad-spectrum antibacterial development.
- The findings provide a foundation for optimizing lead compounds and developing new antibacterial drugs.
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