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Desmethyl Macrolide Analogues to Address Antibiotic Resistance: Total Synthesis and Biological Evaluation of 4,8,10-Tridesmethyl Telithromycin.

ABSTRACT: There is an urgent need to discover new drugs to address the pressing problem of antibiotic-resistance. Macrolide antibiotics such as erythromycin (1) are safe, broad-spectrum antibiotics used in the clinic since 1954. Herein we report the synthesis and evaluation of 4,8,10-tridesmethyl telithromycin (3), a novel desmethyl analogue of the 3rd-generation drug telithromycin (2), which is a semisynthetic derivative of 1. Analogue 3 was found to possess antibiotic activity and was superior to telithromycin (2) when tested against resistant strains of S. aureus possessing an A→T mutation at position 2058 (E. coli numbering).

SUBMITTER: Velvadapu V

PROVIDER: S-EPMC3105755 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description: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.

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Desmethyl Macrolides: Synthesis and Evaluation of 4,8-Didesmethyl Telithromycin.

Project description: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 (5), a novel desmethyl analogue of the third-generation ketolide antibiotic telithromycin (2), which is an FDA-approved semisynthetic derivative of erythromycin (1). We found 4,8-didesmethyl telithromycin (5) to be eight times more active than previously prepared 4,8,10-tridesmethyl congener (3) and two times more active than 4,10-didesmethyl regioisomer (4) in MIC assays. While less potent than telithromycin (2) and paralleling the observations made in the previous study of 4,10-didesmethyl analogue (4), the inclusion of a single methyl group improves biological activity thus supporting its role in antibiotic activity.

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