title: A Derivative of the Thiopeptide GE2270A Highly Selective against Propionibacterium acnes.
abstract: A chemical derivative of the thiopeptide GE2270A, designated NAI003, was found to possess a substantially reduced antibacterial spectrum in comparison to the parent compound, being active against just a few Gram-positive bacteria. In particular, NAI003 retained low MICs against all tested isolates of Propionibacterium acnes and, to a lesser extent, against Enterococcus faecalis. Furthermore, NAI003 showed a time- and dose-dependent killing of both a clindamycin-resistant and a clindamycin-sensitive P. acnes isolate. Gel shift experiments indicated that, like the parent compound, NAI003 retained the ability to bind to elongation factors Tu (EF-Tus) derived from Escherichia coli, E. faecalis, or P. acnes, albeit with reduced efficiency. In contrast, EF-Tus derived from the NAI003-insensitive Staphylococcus aureus or Streptococcus pyogenes did not bind this compound. These results were confirmed by in vitro studies using a hybrid translation system, which indicated that NAI003 can inhibit most efficiently protein synthesis driven by the P. acnes EF-Tu. P. acnes mutants resistant to NAI003 were isolated by direct plating. With one exception, all analyzed strains carried mutations in the tuf gene, encoding EF-Tu. Because of its selective effect on P. acnes in comparison to resident skin flora, NAI003 represents a promising candidate for the topical treatment of acne, which has already completed a phase 1 clinical study.
authors.affiliation: Laboratory of Genetics, School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy attilio.fabbretti@unicam.it sdonadio@naicons.com.
authors.forename: Attilio
authors.initials: A
authors.lastname: Fabbretti
authors.affiliation: Laboratory of Genetics, School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
authors.forename: Cheng-Guang
authors.initials: CG
authors.lastname: He
authors.affiliation: Naicons Srl, Milan, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gaspari
authors.affiliation: Naicons Srl, Milan, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Maffioli
authors.affiliation: Laboratory of Genetics, School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Brandi
authors.affiliation: Laboratory of Genetics, School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Spurio
authors.affiliation: Naicons Srl, Milan, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Sosio
authors.affiliation: Naicons Srl, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Jabes
authors.affiliation: Naicons Srl, Milan, Italy attilio.fabbretti@unicam.it sdonadio@naicons.com.
authors.forename: Stefano
authors.initials: S
authors.lastname: Donadio
mesh_terms: D000287:Administration, Topical; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002981:Clindamycin / Q000494:pharmacology; D004352:Drug Resistance, Microbial / Q000187:drug effects; D008826:Microbial Sensitivity Tests / Q000379:methods; D010444:Peptide Elongation Factor Tu / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011425:Propionibacterium acnes / Q000187:drug effects* / Q000378:metabolism; D012867:Skin / Q000382:microbiology; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic; D013844:Thiazoles; D002981:Clindamycin; D010444:Peptide Elongation Factor Tu; C068122:GE 2270 A