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Type: Journal article
Title: Biosynthetically guided structure-activity relationship studies of Merochlorin A, an antibiotic marine natural product
Author: López-Pérez, B.
Pepper, H.
Ma, R.
Fawcett, B.
Pehere, A.
Wei, Q.
Ji, Z.
Polyak, S.
Dai, H.
Song, F.
Abell, A.
Zhang, L.
George, J.
Citation: ChemMedChem: chemistry enabling drug discovery, 2017; 12(23):1969-1976
Publisher: Wiley
Issue Date: 2017
ISSN: 1860-7179
Statement of
Borja López-Pérez, Henry P. Pepper, Rong Ma, Benjamin J. Fawcett, Ashok D. Pehere, Qi Wei, Zengchun Ji, Steven W. Polyak, Huanqin Dai, Fuhang Song, Andrew D. Abell, Lixin Zhang, and Jonathan H. George
Abstract: 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 {(±)-(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-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.
Keywords: Antibiotics; BCG; MRSA; natural products; structure–activity relationships
Rights: © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/cmdc.201700451
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