Targeted synthesis of novel β-lactam antibiotics by laccase-catalyzed reaction of aromatic substrates selected by pre-testing for their antimicrobial and cytotoxic activity

Applied Microbiology and Biotechnology
Annett MikolaschUlrike Lindequist

Abstract

The rapidly increasing problem of antimicrobial-drug resistance requires the development of new antimicrobial agents. The laccase-catalyzed amination of dihydroxy aromatics is a new and promising method to enlarge the range of currently available antibiotics. Thirty-eight potential 1,2- and 1,4-hydroquinoid laccase substrates were screened for their antibacterial and cytotoxic activity to select the best substrates for laccase-catalyzed coupling reaction resulting in potent antibacterial derivatives. As a result, methyl-1,4-hydroquinone and 2,3-dimethyl-1,4-hydroquinone were used as parent compounds and 14 novel cephalosporins, penicillins, and carbacephems were synthesized by amination with amino-β-lactam structures. All purified products were stable in aqueous buffer and resistant to the action of β-lactamases, and in agar diffusion and broth micro-dilution assays, they inhibited the growth of several Gram-positive bacterial strains including multidrug-resistant Staphylococcus aureus and Enterococci. Their in vivo activity and cytotoxicity in a Staphylococcus-infected, immune-suppressed mouse model are discussed.

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Mar 3, 2007·Chemical & Pharmaceutical Bulletin·Annett MikolaschUlrike Lindequist
Jun 4, 2008·Chemical & Pharmaceutical Bulletin·Annett MikolaschFrieder Schauer
Jul 2, 2008·Chemical & Pharmaceutical Bulletin·Annett MikolaschUlrike Lindequist
Aug 1, 2008·Applied Microbiology and Biotechnology·Annett MikolaschFrieder Schauer
Apr 17, 2013·Biotechnology and Applied Biochemistry·Annett MikolaschUlrike Lindequist
Nov 19, 2013·Antimicrobial Resistance and Infection Control·Angela HuttnerDidier Pittet

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