3 research outputs found
Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl Telithromycin
Novel sources of antibiotics are required to keep pace
with the
inevitable onset of bacterial resistance. Continuing with our macrolide
desmethylation strategy as a source of new antibiotics, we report
the total synthesis, molecular modeling, and biological evaluation
of 4,10-didesmethyl telithromycin (<b>4</b>), a novel desmethyl
analogue of the third-generation drug telithromycin (<b>2</b>). Telithromycin is an FDA-approved ketolide antibiotic derived from
erythromycin (<b>1</b>). We found 4,10-didesmethyl telithromycin
(<b>4</b>) to be four times more active than previously prepared
4,8,10-tridesmethyl congener (<b>3</b>) in MIC assays. While
less potent than telithromycin (<b>2</b>), the inclusion of
the C-8 methyl group has improved biological activity, suggesting
that it plays an important role in antibiotic function
Desmethyl Macrolides: Synthesis and Evaluation of 4,10-Didesmethyl Telithromycin
Novel sources of antibiotics are required to keep pace
with the
inevitable onset of bacterial resistance. Continuing with our macrolide
desmethylation strategy as a source of new antibiotics, we report
the total synthesis, molecular modeling, and biological evaluation
of 4,10-didesmethyl telithromycin (<b>4</b>), a novel desmethyl
analogue of the third-generation drug telithromycin (<b>2</b>). Telithromycin is an FDA-approved ketolide antibiotic derived from
erythromycin (<b>1</b>). We found 4,10-didesmethyl telithromycin
(<b>4</b>) to be four times more active than previously prepared
4,8,10-tridesmethyl congener (<b>3</b>) in MIC assays. While
less potent than telithromycin (<b>2</b>), the inclusion of
the C-8 methyl group has improved biological activity, suggesting
that it plays an important role in antibiotic function
Desmethyl Macrolides: Synthesis and Evaluation of 4‑Desmethyl Telithromycin
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 (<b>6</b>), a novel desmethyl analogue of the
third-generation ketolide antibiotic telithromycin (<b>2</b>) and our final analogue in this series. While 4-desmethyl telithromycin
(<b>6</b>) was found to be equipotent with telithromycin (<b>2</b>) 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 <b>6</b> 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 <b>6</b> with <i>E. coli</i> ribosomes confirmed <b>6</b> is indeed binding the ribosome