title: Synthesis and evaluation of hetero- and homodimers of ribosome-targeting antibiotics: antimicrobial activity, in vitro inhibition of translation, and drug resistance.
abstract: In this study, we describe the synthesis of a full set of homo- and heterodimers of three intact structures of different ribosome-targeting antibiotics: tobramycin, clindamycin, and chloramphenicol. Several aspects of the biological activity of the dimeric structures were evaluated including antimicrobial activity, inhibition of in vitro bacterial protein translation, and the effect of dimerization on the action of several bacterial resistance mechanisms that deactivate tobramycin and chloramphenicol. This study demonstrates that covalently linking two identical or different ribosome-targeting antibiotics may lead to (i) a broader spectrum of antimicrobial activity, (ii) improved inhibition of bacterial translation properties compared to that of the parent antibiotics, and (iii) reduction in the efficacy of some drug-modifying enzymes that confer high levels of resistance to the parent antibiotics from which the dimers were derived.
authors.affiliation: School of Chemistry, Tel Aviv University , Tel Aviv, 6997801, Israel.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Berkov-Zrihen
authors.forename: Keith D
authors.initials: KD
authors.lastname: Green
authors.forename: Kristin J
authors.initials: KJ
authors.lastname: Labby
authors.forename: Mark
authors.initials: M
authors.lastname: Feldman
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garneau-Tsodikova
authors.forename: Micha
authors.initials: M
authors.lastname: Fridman
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002701:Chloramphenicol / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002981:Clindamycin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019281:Dimerization; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D015394:Molecular Structure; D014176:Protein Biosynthesis / Q000187:drug effects*; D012270:Ribosomes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014031:Tobramycin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D002981:Clindamycin; D002701:Chloramphenicol; D014031:Tobramycin