Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 61, Issue 24, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202117724
Keywords
Antibiotic Compound Screening; Cofactors; Enzyme Characterisation; Proteomics; Pyridoxal Phosphate-Dependent Enzymes
Categories
Funding
- European Research Council (ERC)
- European Union's Horizon 2020 research and innovation program [725085]
- Studienstiftung des deutschen Volkes
- Projekt DEAL
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This study systematically investigates pyridoxal phosphate-dependent enzymes (PLP-DEs) in bacteria, discovering an unknown enzyme essential for bacterial growth and confirming its inhibition by a marketed drug. The research provides a foundation for developing novel antibiotic targets and corresponding inhibitors.
Unprecedented bacterial targets are urgently needed to overcome the resistance crisis. Herein we systematically mine pyridoxal phosphate-dependent enzymes (PLP-DEs) in bacteria to focus on a target class which is involved in crucial metabolic processes. For this, we tailored eight pyridoxal (PL) probes bearing modifications at various positions. Overall, the probes exceeded the performance of a previous generation and provided a detailed map of PLP-DEs in clinically relevant pathogens including challenging Gram-negative strains. Putative PLP-DEs with unknown function were exemplarily characterized via in-depth enzymatic assays. Finally, we screened a panel of PLP binders for antibiotic activity and unravelled the targets of hit molecules. Here, an uncharacterized enzyme, essential for bacterial growth, was assigned as PLP-dependent cysteine desulfurase and confirmed to be inhibited by the marketed drug phenelzine. Our approach provides a basis for deciphering novel PLP-DEs as essential antibiotic targets along with corresponding ways to decipher small molecule inhibitors.
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