title: Antibacterial agent discovery using thymidylate synthase biolibrary screening.
abstract: Thymidylate synthase (TS, ThyA) catalyzes the reductive methylation of 2'-deoxyuridine 5'-monophosphate to 2'-deoxythymidine 5'-monophosphate, an essential precursor for DNA synthesis. A specific inhibition of this enzyme induces bacterial cell death. As a second round lead optimization design, new 1,2-naphthalein derivatives have been synthesized and tested against a TS-based biolibrary, including human thymidylate synthase (hTS). Docking studies have been performed to rationalize the experimentally observed affinity profiles of 1,2-naphthalein compounds toward Lactobacillus casei TS and hTS. The best TS inhibitors have been tested against a number of clinical isolates of Gram-positive-resistant bacterial strains. Compound 3,3-bis(3,5-dibromo-4-hydroxyphenyl)-1H,3H-naphtho[1,2-c]furan-1-one (5) showed significant antibacterial activity, no in vitro toxicity, and dose-response effects against Staphylococcus epidermidis (MIC=0.5-2.5 microg/mL) clinical isolate strains, which are resistant to at least 17 of the best known antibacterial agents, including vancomycin. So far this compound can be regarded as a leading antibacterial agent.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Via Campi 183, 41100 Modena, Italy. costimp@unimore.it
authors.forename: M Paola
authors.initials: MP
authors.lastname: Costi
authors.forename: Arianna
authors.initials: A
authors.lastname: Gelain
authors.forename: Daniela
authors.initials: D
authors.lastname: Barlocco
authors.forename: Stefano
authors.initials: S
authors.lastname: Ghelli
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Soragni
authors.forename: Fabiano
authors.initials: F
authors.lastname: Reniero
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rossi
authors.forename: Antonio
authors.initials: A
authors.lastname: Ruberto
authors.forename: Claude
authors.initials: C
authors.lastname: Guillou
authors.forename: Antonio
authors.initials: A
authors.lastname: Cavazzuti
authors.forename: Chiara
authors.initials: C
authors.lastname: Casolari
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferrari
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D002954:Citrobacter / Q000187:drug effects; D003455:Cryptococcus neoformans / Q000201:enzymology; D016208:Databases, Factual; D024901:Drug Resistance, Multiple, Bacterial; D016983:Enterococcus / Q000187:drug effects / Q000302:isolation & purification; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007780:Lacticaseibacillus casei / Q000201:enzymology; D008089:Listeria monocytogenes / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013210:Staphylococcus / Q000187:drug effects / Q000302:isolation & purification; D013291:Streptococcus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014709:Vero Cells
chemical_list: C514369:1,1-bis(3,5-dibromo-4-hydroxyphenyl)-1H-naphtho(1,2-c)furan-3-one; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001572:Benzofurans; D009281:Naphthalenes; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase