Single-Molecule FRET Studies of the Hybridization Mechanism during Noncovalent Adsorption and Desorption of DNA on Graphene Oxide

Remarkable observations on the adsorption and desorption mechanisms of single-stranded oligonucleotides and the hybridization of double-stranded DNA (ds-DNA) on a graphene oxide (GO) surface have been made using ensemble and single-molecule fluorescence methods. Probe and target DNAs labeled individually with fluorescence resonance energy transfer (FRET) pairs and having similar adsorption affinities toward the GO surface are used to provide detailed insights into the hybridization mechanism. Single-molecule FRET results reveal an “in situ” DNA hybridization mechanism, i.e., hybridization between the probe and target DNAs to form a ds-DNA, and simultaneous desorption from the GO surface thereafter. These results also demonstrate that the electrostatic interaction between DNA and GO is of little importance to the overall theory of interaction and the largest effects are from solvation forces, specifically the hydrophobic effect. This investigation improves the fundamental understanding of the DNA hybridization dynamics on the GO surface, opening new windows in the field of biophysics as well as in sensing and therapeutic applications

Desmethyl Macrolides: Synthesis and Evaluation of 4,8,10-Tridesmethyl Cethromycin

Antibiotic-resistant bacteria are emerging at an alarming rate in both hospital and community settings. Motivated by this issue, we have prepared desmethyl (i.e., replacing methyl groups with hydrogens) analogues of third-generation macrolide drugs telithromycin (TEL, <b>2</b>) and cethromycin (CET, <b>6</b>), both of which are semisynthetic derivatives of flagship macrolide antibiotic erythromycin (<b>1</b>). Herein, we report the total synthesis, molecular modeling, and biological evaluation of 4,8,10-tridesmethyl cethromycin (<b>7</b>). In MIC assays, CET analogue <b>7</b> was found to be equipotent with TEL (<b>2</b>) against a wild-type <i>E. coli</i> strain, more potent than previously disclosed desmethyl TEL congeners <b>3</b>, <b>4</b>, and <b>5</b>, but 4-fold less potent than TEL (<b>2</b>) against a mutant <i>E. coli</i> A2058G strain

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