title: Targeted synthesis of novel β-lactam antibiotics by laccase-catalyzed reaction of aromatic substrates selected by pre-testing for their antimicrobial and cytotoxic activity.
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.
authors.affiliation: Institute of Microbiology, Ernst-Moritz-Arndt-University Greifswald, Friedrich-Ludwig-Jahn-Str. 15, 17487, Greifswald, Germany. annett.mikolasch@uni-greifswald.de.
authors.forename: Annett
authors.initials: A
authors.lastname: Mikolasch
authors.affiliation: Institute of Pharmacy, Ernst-Moritz-Arndt-University Greifswald, Friedrich-Ludwig-Jahn-Str. 15, 17487, Greifswald, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hildebrandt
authors.affiliation: Institute of Microbiology, Ernst-Moritz-Arndt-University Greifswald, Friedrich-Ludwig-Jahn-Str. 15, 17487, Greifswald, Germany.
authors.forename: Rabea
authors.initials: R
authors.lastname: Schlüter
authors.affiliation: Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, Friedrich-Ludwig-Jahn-Str. 15a, 17487, Greifswald, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Hammer
authors.affiliation: Baltic Analytics GmbH, Walther-Rathenau-Str. 49a, 17489, Greifswald, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Witt
authors.affiliation: Institute of Pharmacy, Ernst-Moritz-Arndt-University Greifswald, Friedrich-Ludwig-Jahn-Str. 15, 17487, Greifswald, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lindequist
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001711:Biotransformation; D002384:Catalysis; D002511:Cephalosporins / Q000138:chemical synthesis / Q000494:pharmacology; D003470:Culture Media / Q000737:chemistry; D004195:Disease Models, Animal; D016983:Enterococcus / Q000187:drug effects; D005260:Female; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006873:Hydroquinones / Q000737:chemistry; D007218:Industrial Microbiology; D042845:Laccase / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010406:Penicillins / Q000138:chemical synthesis / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy; D013210:Staphylococcus / Q000187:drug effects; D001618:beta-Lactamases / Q000737:chemistry / Q000494:pharmacology; D047090:beta-Lactams / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D002511:Cephalosporins; D003470:Culture Media; D006873:Hydroquinones; D010406:Penicillins; D047090:beta-Lactams; C026739:carbacephems; C062397:2-methyl-1,4-hydroquinone; D042845:Laccase; D001618:beta-Lactamases; C516077:2,3-dimethylhydroquinone
keywords: Amination; Cephalosporin; Hydroquinone; Laccase; Penicillin