Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections

Conjugating a siderophore
to an antibiotic is a promising strategy
to overcome the permeability-mediated resistance of Gram-negative
pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated
monosulfactams incorporating diverse substituents into the methylene
linker between the 1,3-dihydroxypyridin-4­(1H)-one
and the aminothiazole oxime were designed and synthesized. Structure–activity
relationship studies revealed that a variety of substituents were
tolerated, with isopropyl (compound 12c) and methylthiomethyl
(compound 16a) showing the best efficacy against multidrug-resistant
(MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein
binding test, along with a low clearance and favorable plasma exposure
in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows
an ED50 of 10.20 mg/kg. Taken together, the results indicate
that compound 12c is a promising drug candidate for the
treatment of serious infections caused by MDR Gram-negative pathogens.