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Desmethyl macrolides: synthesis and evaluation of 4-desmethyl telithromycin.


ABSTRACT: Novel sources of antibiotics are needed to address the serious threat of bacterial resistance. Accordingly, we have launched a structure-based drug design program featuring a desmethylation strategy wherein methyl groups have been replaced with hydrogens. Herein we report the total synthesis, molecular modeling, and biological evaluation of 4-desmethyl telithromycin (6), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (2) and our final analogue in this series. While 4-desmethyl telithromycin (6) was found to be equipotent with telithromycin (2) against wild-type bacteria, it was 4-fold less potent against the A2058G mutant. These findings reveal that strategically replacing the C4-methyl group with hydrogen (i.e., desmethylation) did not address this mechanism of resistance. Throughout the desmethyl series, the sequential addition of methyls to the 14-membered macrolactone resulted in improved bioactivity. Molecular modeling methods indicate that changes in conformational flexibility dominate the increased biological activity; moreover, they reveal 6 adopts a different conformation once bound to the A2058G ribosome, thus impacting noncovalent interactions reflected in a lower MIC value. Finally, fluorescence polarization experiments of 6 with E. coli ribosomes confirmed 6 is indeed binding the ribosome.

SUBMITTER: Glassford I 

PROVIDER: S-EPMC4160760 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Desmethyl macrolides: synthesis and evaluation of 4-desmethyl telithromycin.

Glassford Ian I   Lee Miseon M   Wagh Bharat B   Velvadapu Venkata V   Paul Tapas T   Sandelin Gary G   DeBrosse Charles C   Klepacki Dorota D   Small Meagan C MC   MacKerell Alexander D AD   Andrade Rodrigo B RB  

ACS medicinal chemistry letters 20140716 9


Novel sources of antibiotics are needed to address the serious threat of bacterial resistance. Accordingly, we have launched a structure-based drug design program featuring a desmethylation strategy wherein methyl groups have been replaced with hydrogens. Herein we report the total synthesis, molecular modeling, and biological evaluation of 4-desmethyl telithromycin (6), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (2) and our final analogue in this series  ...[more]

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