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Title: Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections
Authors: Tan, Liang;Tao, Yunliang;Wang, Ting;Zou, Feng;Zhang, Shuhua;Kou, Qunhuan;Niu, Ao;Chen, Qian;Chu, Wenjing;Chen, Xiaoyan;Wang, Haidong;Yang, Yushe
subject: a syndrome comprising;acute intravascular hemolysis;african child;and the passage of;blackwater fever;bwf;commonly as;dark;fever;haemoglobinopathies;has been recognized most;hemoglobinuria;historically;Malaria;or red-colored urine
Year: 2017
Abstract: 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 ...
volume: Volume 64
issue: Issue 7
month: April
Appears in Collections:Clinical infectious diseases 2017

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