Tailored Pyridoxal Probes Unravel Novel Cofactor‐Dependent Targets and Antibiotic Hits in Critical Bacterial Pathogens
Abstract: 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.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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Tailored Pyridoxal Probes Unravel Novel Cofactor‐Dependent Targets and Antibiotic Hits in Critical Bacterial Pathogens ; day:12 ; month:04 ; year:2022 ; extent:1
Angewandte Chemie / International edition. International edition ; (12.04.2022) (gesamt 1)
- Creator
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Pfanzelt, Martin
Maher, Thomas E.
Absmeier, Ramona M.
Schwarz, Markus
Sieber, Stephan A.
- DOI
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10.1002/anie.202117724
- URN
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urn:nbn:de:101:1-2022041315084295502443
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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15.08.2025, 7:24 AM CEST
Data provider
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Associated
- Pfanzelt, Martin
- Maher, Thomas E.
- Absmeier, Ramona M.
- Schwarz, Markus
- Sieber, Stephan A.
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Elucidating the mechanism of action of the natural product xanthocillin X & tailored cofactor traps for the in situ detection of hemithioacetal-forming pyridoxal kinases
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Design and application of natural product derived probes for activity based protein profiling
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Functionalised Cofactor Mimics for Interactome Discovery and Beyond
Tailored Phenyl Esters Inhibit ClpXP and Attenuate Staphylococcus aureus α‐Hemolysin Secretion
Elucidating the mechanism of action of the natural product xanthocillin X & tailored cofactor traps for the in situ detection of hemithioacetal-forming pyridoxal kinases
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