title: Assessment of 6'- and 6'''-N-acylation of aminoglycosides as a strategy to overcome bacterial resistance.
abstract: Amongst the many synthetic aminoglycoside analogues that were developed to regain the efficacy of this class of antibiotics against resistant bacterial strains, the 1-N-acylated analogues are the most clinically used. In this study we demonstrate that 6'-N-acylation of the clinically used compound tobramycin and 6'''-N-acylation of paromomycin result in derivatives resistant to deactivation by 6'-aminoglycoside acetyltransferase (AAC(6')) which is widely found in aminoglycoside resistant bacteria. When tested against AAC(6')- or AAC(3)-expressing bacteria as well as pathogenic bacterial strains, some of the analogues demonstrated improved antibacterial activity compared to their parent antibiotics. Improvement of the biological performance of the N-acylated analogues was found to be highly dependent on the specific aminoglycoside and acyl group. Our study indicates that as for 1-N-acylation, 6'- and 6'''-N-acylation of aminoglycosides offer an additional promising direction in the search for aminoglycosides capable of overcoming infections by resistant bacteria.
authors.affiliation: School of Chemistry, Tel Aviv University, Tel Aviv, 69978, Israel.
authors.forename: Pazit
authors.initials: P
authors.lastname: Shaul
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.forename: Roi
authors.initials: R
authors.lastname: Rutenberg
authors.forename: Maria
authors.initials: M
authors.lastname: Kramer
authors.forename: Yifat
authors.initials: Y
authors.lastname: Berkov-Zrihen
authors.forename: Elinor
authors.initials: E
authors.lastname: Breiner-Goldstein
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
authors.forename: Micha
authors.initials: M
authors.lastname: Fridman
mesh_terms: D000215:Acylation; D000617:Aminoglycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects*; D002236:Carbohydrate Conformation; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004926:Escherichia coli / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects*; D013237:Stereoisomerism
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents