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Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2024 Apr 25; Vol. 67 (8), pp. 6610-6623. Date of Electronic Publication: 2024 Apr 10. - Publication Year :
- 2024
-
Abstract
- Inhibition of the biosynthesis of bacterial heptoses opens novel perspectives for antimicrobial therapies. The enzyme GmhA responsible for the first committed biosynthetic step catalyzes the conversion of sedoheptulose 7-phosphate into d- glycero -d- manno -heptose 7-phosphate and harbors a Zn <superscript>2+</superscript> ion in the active site. A series of phosphoryl- and phosphonyl-substituted derivatives featuring a hydroxamate moiety were designed and prepared from suitably protected ribose or hexose derivatives. High-resolution crystal structures of GmhA complexed to two N -formyl hydroxamate inhibitors confirmed the binding interactions to a central Zn <superscript>2+</superscript> ion coordination site. Some of these compounds were found to be nanomolar inhibitors of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity of their own, they demonstrated in vitro lipopolysaccharide heptosylation inhibition in Enterobacteriaceae as well as the potentiation of erythromycin and rifampicin in a wild-type Escherichia coli strain. These inhibitors pave the way for a novel treatment of Gram-negative infections.
- Subjects :
- Humans
Gram-Negative Bacteria drug effects
Microbial Sensitivity Tests
Structure-Activity Relationship
Enzyme Inhibitors pharmacology
Enzyme Inhibitors chemistry
Enzyme Inhibitors chemical synthesis
Escherichia coli drug effects
Escherichia coli enzymology
Crystallography, X-Ray
Drug Synergism
Hep G2 Cells
Models, Molecular
Hydroxamic Acids chemistry
Hydroxamic Acids pharmacology
Hydroxamic Acids chemical synthesis
Zinc chemistry
Anti-Bacterial Agents pharmacology
Anti-Bacterial Agents chemistry
Anti-Bacterial Agents chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 67
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38598312
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.4c00037