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.2018-02-262018-02-262017ChemMedChem: chemistry enabling drug discovery, 2017; 12(23):1969-19761860-71791860-7187http://hdl.handle.net/2440/110591The 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.en© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, WeinheimAntibiotics; BCG; MRSA; natural products; structure–activity relationshipsJournal article003007836110.1002/cmdc.2017004510004174924000102-s2.0-85035080640388752Polyak, S. [0000-0002-8458-5194]Abell, A. [0000-0002-0604-2629]George, J. [0000-0002-7330-2160]