文献类型：期刊文献

英文题名：Biosynthetically Guided Structure-Activity Relationship Studies of MerochlorinA, an Antibiotic Marine Natural Product

作者：Lopez-Perez, Borja[1];Pepper, Henry P.[1];Ma, Rong[2];Fawcett, Benjamin J.[1];Pehere, Ashok D.[1];Wei, Qi[2,3];Ji, Zengchun[2,4];Polyak, Steven W.[5];Dai, Huanqin[7];Song, Fuhang[7];Abell, Andrew D.[1,6];Zhang, Lixin[2,8,9];George, Jonathan H.[1]

机构：[1]Univ Adelaide, Dept Chem, Adelaide, SA 5005, Australia;[2]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[3]Hebei Univ, Coll Life Sci, Baoding 071002, Peoples R China;[4]Tianjin Univ Sci & Technol, Sch Biol Engn, Tianjin 300457, Peoples R China;[5]Univ Adelaide, Dept Mol & Cellular Biol, Adelaide, SA 5005, Australia;[6]Univ Adelaide, Ctr Nanoscale Biophoton, CNBP, Adelaide, SA 5005, Australia;[7]Chinese Acad Sci, Key Lab Pathogen Microbiol & Immunol, Inst Microbiol, Beijing 100101, Peoples R China;[8]Shandong Acad Sci, Inst Biol, Key Biosensor Lab Shandong Prov, Jinan 250014, Shandong, Peoples R China;[9]Qingdao Natl Lab Marine Sci & Technol, Lab Marine Biol & Biotechnol, Qingdao 266061, Peoples R China

年份：2017

卷号：12

期号：23

起止页码：1969

外文期刊名：CHEMMEDCHEM

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000417492400010)】；

基金：This work was supported in part by grants from the Australian Research Council (Discovery Project, DP130101827), the National Natural Science Foundation of China (31430002, 31320103911, and 81460700), the National Key Research and Development Program of China (2017YFD0201203), the National Major Scientific and Technological Special Project for Significant New Drugs Development of China (2015ZX09J15102-004), the Major Natural Science Foundation of Shandong Province of China (ZR2017ZB0206), and the Shandong Taishan Scholar Program of China.

语种：英文

外文关键词：antibiotics; BCG; MRSA; natural products; structure-activity relationships

摘要：The onset of new multidrug-resistant strains of bacteria demands continuous development of antibacterial agents with new chemical scaffolds and mechanisms of action. We present the first structure-activity relationship (SAR) study of 16 derivatives of a structurally novel antibiotic merochlorinA that were designed using a biosynthetic blueprint. Our lead compounds are active against several Gram-positive bacteria such as Staphylococcus aureus (SA), methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium (VRE) and Bacillus subtilis, inhibit intracellular growth of Mycobacterium bovis, and are relatively nontoxic to human cell lines. Furthermore, derivative 12c {(+/-)-(3aR,4S,5R,10bS)-5-bromo-7,9-dimethoxy-4-methyl-4-(4-methylpent-3-en-1-yl)-2-(propan-2-ylidene)-1,2,3,3a,4,5-hexahydro-6H-5,10b-methanobenzo[e]azulene-6,11-dione} was found to inhibit the growth of Bacillus Calmette-Guerin (BCG)-infected cells at concentrations similar to rifampicin. These results outperform the natural product, underscoring the potential of merochlorin analogues as a new class of antibiotics.