TY - JOUR
T1 - Synthesis and evaluation of hetero- and homodimers of ribosome-targeting antibiotics
T2 - Antimicrobial activity, in vitro inhibition of translation, and drug resistance
AU - Berkov-Zrihen, Yifat
AU - Green, Keith D.
AU - Labby, Kristin J.
AU - Feldman, Mark
AU - Garneau-Tsodikova, Sylvie
AU - Fridman, Micha
PY - 2013/7/11
Y1 - 2013/7/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84880140796&partnerID=8YFLogxK
U2 - 10.1021/jm400707f
DO - 10.1021/jm400707f
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C2 - 23786357
AN - SCOPUS:84880140796
SN - 0022-2623
VL - 56
SP - 5613
EP - 5625
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 13
ER -