5 research outputs found
Desmethyl Macrolides: Synthesis and Evaluation of 4,8-Didesmethyl Telithromycin
There is an urgent need for novel sources of antibiotics
to address
the incessant and inevitable onset of bacterial resistance. To this
end, we have initiated a structure-based drug design program that
features a desmethylation strategy (i.e., replacing methyl groups
with hydrogens). Herein, we report the total synthesis, molecular
modeling, and biological evaluation of 4,8-didesmethyl telithromycin
(<b>5</b>), a novel desmethyl analogue of the third-generation
ketolide antibiotic telithromycin (<b>2</b>), which is an FDA-approved
semisynthetic derivative of erythromycin (<b>1</b>). We found <b>5</b> to be eight times more active than previously prepared 4,8,10-tridesmethyl
congener (<b>3</b>) and two times more active than 4,10-didesmethyl
regioisomer (<b>4</b>) in MIC assays. While less potent than
telithromycin (<b>2</b>) and paralleling the observations made
in the previous study of 4,10-didesmethyl analogue (<b>4</b>), the inclusion of a single methyl group improves biological activity,
thus supporting its role in antibiotic activity
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
Ribosome-Templated Azide–Alkyne Cycloadditions: Synthesis of Potent Macrolide Antibiotics by In Situ Click Chemistry
Over half of all antibiotics target
the bacterial ribosomenature’s
complex, 2.5 MDa nanomachine responsible for decoding mRNA and synthesizing
proteins. Macrolide antibiotics, exemplified by erythromycin, bind
the 50S subunit with nM affinity and inhibit protein synthesis by
blocking the passage of nascent oligopeptides. Solithromycin (<b>1</b>), a third-generation semisynthetic macrolide discovered
by combinatorial copper-catalyzed click chemistry, was synthesized
in situ by incubating either <i>E. coli</i> 70S ribosomes
or 50S subunits with macrolide-functionalized azide <b>2</b> and 3-ethynylaniline (<b>3</b>) precursors. The ribosome-templated
in situ click method was expanded from a binary reaction (i.e., one
azide and one alkyne) to a six-component reaction (i.e., azide <b>2</b> and five alkynes) and ultimately to a 16-component reaction
(i.e., azide <b>2</b> and 15 alkynes). The extent of triazole
formation correlated with ribosome affinity for the <i>anti</i> (1,4)-regioisomers as revealed by measured <i>K</i><sub>d</sub> values. Computational analysis using the site-identification
by ligand competitive saturation (SILCS) approach indicated that the
relative affinity of the ligands was associated with the alteration
of macrolactone+desosamine-ribosome interactions caused by the different
alkynes. Protein synthesis inhibition experiments confirmed the mechanism
of action. Evaluation of the minimal inhibitory concentrations (MIC)
quantified the potency of the in situ click products and demonstrated
the efficacy of this method in the triaging and prioritization of
potent antibiotics that target the bacterial ribosome. Cell viability
assays in human fibroblasts confirmed <b>2</b> and four analogues
with therapeutic indices for bactericidal activity over in vitro mammalian
cytotoxicity as essentially identical to solithromycin (<b>1</b>)