title: Design, synthesis and biological evaluation of monobactams as antibacterial agents against gram-negative bacteria.
abstract: A series of monobactam derivatives were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative strains, taking Aztreonam and BAL30072 as the leads. Six conjugates (12a-f) bearing PIH-like siderophore moieties were created to enhance the bactericidal activities against Gram-negative bacteria based on Trojan Horse strategy, and all of them displayed potencies against susceptible Gram-negative strains with MIC ≤ 8 μg/mL. SAR revealed that the polar substituents on the oxime side chain were beneficial for activities against resistant Gram-negative bacteria. Compounds 19c and 33a-b exhibited the promising potencies against ESBLs-producing E. coli and Klebsiella pneumoniae with MICs ranging from 2 μg/mL to 8 μg/mL. These results offered powerful information for further strategic optimization in search of the antibacterial candidates against MDR Gram-negative bacteria.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
authors.forename: Hai-Gen
authors.initials: HG
authors.lastname: Fu
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
authors.forename: Xin-Xin
authors.initials: XX
authors.lastname: Hu
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
authors.forename: Cong-Ran
authors.initials: CR
authors.lastname: Li
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Li
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
authors.forename: Yan-Xiang
authors.initials: YX
authors.lastname: Wang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
authors.forename: Chong-Wen
authors.initials: CW
authors.lastname: Bi
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Tang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China. Electronic address: xuefuyou@126.com.
authors.forename: Xue-Fu
authors.initials: XF
authors.lastname: You
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China. Electronic address: songdanqingsdq@hotmail.com.
authors.forename: Dan-Qing
authors.initials: DQ
authors.lastname: Song
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001398:Aztreonam / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008997:Monobactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; C552042:BAL 30072; D008997:Monobactams; D013844:Thiazoles; D001398:Aztreonam
keywords: Antibacterial activity; Click chemistry; Monobactam; Siderophore; Structure–activity relationship