title: 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.
authors.affiliation: Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
authors.forename: Ian
authors.initials: I
authors.lastname: Glassford
authors.affiliation: Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
authors.forename: Miseon
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
authors.forename: Bharat
authors.initials: B
authors.lastname: Wagh
authors.affiliation: Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
authors.forename: Venkata
authors.initials: V
authors.lastname: Velvadapu
authors.affiliation: Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
authors.forename: Tapas
authors.initials: T
authors.lastname: Paul
authors.affiliation: Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
authors.forename: Gary
authors.initials: G
authors.lastname: Sandelin
authors.affiliation: Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: DeBrosse
authors.affiliation: Center for Pharmaceutical Biotechnology, University of Illinois , Chicago, Illinois 60607, United States.
authors.forename: Dorota
authors.initials: D
authors.lastname: Klepacki
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Meagan C
authors.initials: MC
authors.lastname: Small
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
authors.affiliation: Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
authors.forename: Rodrigo B
authors.initials: RB
authors.lastname: Andrade
keywords: Total synthesis; antibiotic resistance; desmethyl analogues; ketolide antibiotics; molecular modeling; telithromycin