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

Tomáš Malatinský; Dominika Valachová; Lucia Pinčeková; David Scherhaufer; Petra Olejníková; Magdaléna Májeková; Jarmila Vargová; Barbora Gaálová-Radochová; Helena Bujdáková; Jana Nováčiková; Alistair J. M. Farley; Dušan Berkeš; Pavol Jakubec; Andrej Kolarovič; Oľga Caletková

doi:10.1039/D2OB01452A

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

Tomáš Malatinský,^a Dominika Valachová,^a Lucia Pinčeková,^a David Scherhaufer,^a Petra Olejníková,^b Magdaléna Májeková,^c Jarmila Vargová,^d Barbora Gaálová-Radochová,^d Helena Bujdáková,^d Jana Nováčiková,^e Alistair J. M. Farley,^f Dušan Berkeš,

^a Pavol Jakubec,^a Andrej Kolarovič

^g and Oľga Caletková

*^a

Author affiliations

* Corresponding authors

^a Institute of Organic Chemistry, Catalysis and Petrochemistry, Slovak University of Technology, Radlinského 9, 812 37 Bratislava, Slovakia
E-mail: olga.caletkova@stuba.sk

^b Institute of Biochemistry and Microbiology, Slovak University of Technology, Radlinského 9, 812 37 Bratislava, Slovakia

^c Institute of Experimental Pharmacology & Toxicology, Centre of Experimental Medicine SAS, Dúbravská cesta 9, 841 04 Bratislava, Slovakia

^d Department of Microbiology and Virology, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská dolina, Ilkovičova 6, 842 15 Bratislava, Slovakia

^e Central Laboratories, Slovak University of Technology, Radlinského 9, 812 37 Bratislava, Slovakia

^f The Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK

^g Department of Chemistry, Faculty of Education, Trnava University, Priemyselná 4, 918 43 Trnava, Slovakia

Abstract

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 MIC₅₀ 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.

Organic & Biomolecular Chemistry

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

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

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