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

• Published in: Applied microbiology and biotechnology Vol. 100; no. 11; pp. 4885 - 4899
• Main Authors: Mikolasch, Annett, Hildebrandt, Oliver, Schlüter, Rabea, Hammer, Elke, Witt, Sabine, Lindequist, Ulrike
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2016
• Subjects: Animals; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - pharmacology; beta-Lactamases - chemistry; beta-Lactamases - pharmacology; beta-Lactams - chemical synthesis; beta-Lactams - pharmacology; Biomedical and Life Sciences; Biotechnological Products and Process Engineering; Biotechnology; Biotransformation; Catalysis; Cephalosporins - chemical synthesis; Cephalosporins - pharmacology; Culture Media - chemistry; Disease Models, Animal; Enterococcus - drug effects; Female; Gram-Positive Bacteria - drug effects; Hydroquinones - chemistry; Industrial Microbiology; Laccase - metabolism; Life Sciences; Mice; Mice, Inbred BALB C; Microbial Genetics and Genomics; Microbial Sensitivity Tests; Microbiology; Penicillins - chemical synthesis; Penicillins - pharmacology; Staphylococcal Infections - drug therapy; Staphylococcus - drug effects; Staphylococcus aureus; Hydroquinone; Amination; Cephalosporin; Penicillin; Laccase
• ISSN: 0175-7598; 1432-0614
• DOI: 10.1007/s00253-016-7288-z

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.