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Biosynthetically Guided Structure–Activity Relationship Studies of Merochlorin A, an Antibiotic Marine Natural Product
Author(s) -
LópezPérez Borja,
Pepper Henry P.,
Ma Rong,
Fawcett Benjamin J.,
Pehere Ashok D.,
Wei Qi,
Ji Zengchun,
Polyak Steven W.,
Dai Huanqin,
Song Fuhang,
Abell Andrew D.,
Zhang Lixin,
George Jonathan H.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700451
Subject(s) - enterococcus faecium , natural product , microbiology and biotechnology , bacillus subtilis , antibiotics , bacteria , staphylococcus aureus , bacillus anthracis , mycobacterium tuberculosis , chemistry , biology , antibacterial activity , stereochemistry , tuberculosis , medicine , genetics , pathology
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 merochlorin A 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 12 c {(±)‐(3a R ,4 S ,5 R ,10b S )‐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‐6 H ‐5,10b‐methanobenzo[ e ]azulene‐6,11‐dione} was found to inhibit the growth of Bacillus Calmette–Guérin (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.