title: Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections.
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 ED50of 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.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tan
authors.affiliation: College of Biological, Chemical Sciences and Engineering, Jiaxing University , Jiaxing, Zhejiang Province 314001, China.
authors.forename: Yunliang
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Department of Microbiology, Sichuan Primed Bio-Tech Group Co., Ltd. , Chengdu, Sichuan Province 610041, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Sichuan Primed Bio-Tech Group Co., Ltd. , Chengdu, Sichuan Province 610041, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zou
authors.affiliation: Department of Microbiology, Sichuan Primed Bio-Tech Group Co., Ltd. , Chengdu, Sichuan Province 610041, China.
authors.forename: Shuhua
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: Qunhuan
authors.initials: Q
authors.lastname: Kou
authors.affiliation: Department of Pharmacology, School of Pharmacy, China Pharmaceutical University , Nanjing, Jiangsu Province 210009, China.
authors.forename: Ao
authors.initials: A
authors.lastname: Niu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Chu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: Xiaoyan
authors.identifier: 0000-0002-6559-8627
authors.initials: X
authors.lastname: Chen
authors.affiliation: College of Biological, Chemical Sciences and Engineering, Jiaxing University , Jiaxing, Zhejiang Province 314001, China.
authors.forename: Haidong
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|University of Chinese Academy of Sciences , Beijing 100049, China.
authors.forename: Yushe
authors.identifier: 0000-0002-1007-2492
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery; D024901:Drug Resistance, Multiple, Bacterial; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008997:Monobactams / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D011728:Pyridones / Q000097:blood / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; C552042:BAL 30072; D008997:Monobactams; D011728:Pyridones; D013844:Thiazoles