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J Med Chem ; 67(8): 6610-6623, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38598312

RESUMEN

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 Zn2+ 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 Zn2+ 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.


Asunto(s)
Antibacterianos , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Humanos , Bacterias Gramnegativas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Cristalografía por Rayos X , Sinergismo Farmacológico , Células Hep G2 , Modelos Moleculares , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/síntesis química , Zinc/química
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