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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Structure-based optimization of MurF inhibitors
Geoffrey F Stamper1, Kenton L Longenecker, Elizabeth H Fry
1Global Pharmaceutical Research & Development, Department of Structural Biology, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. geoffrey.stamper@abbott.com
Abstract:
The D-Ala-D-Ala adding enzyme (MurF) from Streptococcus pneumoniae catalyzes the ATP-dependent formation of the UDP-MurNAc-pentapeptide, a critical component of the bacterial cell wall. MurF is a potential target for antibacterial design because it is unique to bacteria and performs an essential non-redundant function in the bacterial cell. The recent discovery and subsequent cocrystal structure determination of MurF in complex with a new class of inhibitors served as a catalyst to begin a medicinal chemistry program aimed at improving their potency. We report here a multidisciplinary approach to this effort that allowed for rapid generation of cocrystal structures, thereby providing the crystallographic information critical for driving the inhibitor optimization process. This effort resulted in the discovery of low-nanomolar inhibitors of this bacterial enzyme.
Insights
Researchers developed potent, low-nanomolar inhibitors targeting the essential bacterial enzyme MurF (D-Ala-D-Ala adding enzyme). This advancement offers a promising new avenue for antibacterial drug discovery against Streptococcus pneumoniae.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Structural Biology
Background:
- The D-Ala-D-Ala adding enzyme (MurF) from Streptococcus pneumoniae is essential for bacterial cell wall synthesis.
- MurF is a validated antibacterial target due to its essential, non-redundant function and bacterial specificity.
- Previous work identified a new class of MurF inhibitors and determined their cocrystal structure.
Purpose of the Study:
- To initiate a medicinal chemistry program to enhance the potency of existing MurF inhibitors.
- To leverage structural information for rational drug design and optimization.
Main Methods:
- A multidisciplinary approach combining medicinal chemistry and structural biology.
- Rapid generation and analysis of cocrystal structures of MurF with inhibitors.
- Structure-guided design and iterative optimization of inhibitor compounds.
Main Results:
- Successful optimization of MurF inhibitors.
- Discovery of novel inhibitors with low-nanomolar potency.
- Detailed crystallographic insights guiding the optimization process.
Conclusions:
- The multidisciplinary, structure-guided approach is effective for rapid optimization of antibacterial inhibitors.
- Low-nanomolar inhibitors of MurF were discovered, representing significant progress in antibacterial drug development.
- These findings provide a strong foundation for further development of MurF-targeted therapeutics.
