Synthesis and structure-activity relationship of berkeleylactone A-derived antibiotics

Berkeleylactone A is a potent 16-membered macrolactone antibiotic, recently isolated from a coculture of Berkeley Pit Lake fungi. Although its antimicrobial activity has already been investigated, little is known about the structure-activity relationship. Based on our previous synthetic studies, a s...

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Published inOrganic & biomolecular chemistry Vol. 2; no. 39; pp. 7821 - 7832
Main Authors Malatinský, Tomáš, Valachová, Dominika, Pin eková, Lucia, Scherhaufer, David, Olejníková, Petra, Májeková, Magdaléna, Vargová, Jarmila, Gaálová-Radochová, Barbora, Bujdáková, Helena, Nová iková, Jana, Farley, Alistair J. M, Berkeš, Dušan, Jakubec, Pavol, Kolarovi, Andrej, Caletková, O ga
Format Journal Article
LanguageEnglish
Published CAMBRIDGE Royal Soc Chemistry 12.10.2022
Royal Society of Chemistry
Subjects
Antibiotics
Antiinfectives and antibacterials
Antimicrobial activity
Chemistry
Chemistry, Organic
Drug resistance
Methicillin
Physical Sciences
Science & Technology
Staphylococcus aureus
ANALOGS
MACROLIDES
INHIBITORS
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Summary:Berkeleylactone A is a potent 16-membered macrolactone antibiotic, recently isolated from a coculture of Berkeley Pit Lake fungi. Although its antimicrobial activity has already been investigated, little is known about the structure-activity relationship. Based on our previous synthetic studies, a series of berkeleylactone A derivatives were synthesized and evaluated for their in vitro antimicrobial activities against methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MRSA) strains. Our data confirmed the essential role of the embedded conjugated system and suggest a reversible sulfa-protection of the Michael acceptor as a viable option. Structurally simplified achiral macrolactam 8 showed the best inhibitory activity against S. aureus L12 (MRSA) with MIC 50 values of 0.39 μg mL −1 , 8-fold lower than those of berkeleylactone A. These studies may be of value in the development of more advanced candidates for antibiotic applications. A series of berkeleylactone A derivatives was prepared and evaluated for in vitro antimicrobial activities. Our data confirmed the essential role of the embedded Michael acceptor and suggested its reversible sulfa-protection.
Bibliography:Electronic supplementary information (ESI) available. See DOI
https://doi.org/10.1039/d2ob01452a
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ISSN:1477-0520
1477-0539
DOI:10.1039/d2ob01452a