Restriction of the conformational dynamics of the cyclic acyldepsipeptide antibiotics improves their antibacterial activity.

ABSTRACT: The cyclic acyldepsipeptide (ADEP) antibiotics are a new class of antibacterial agents that kill bacteria via a mechanism that is distinct from all clinically used drugs. These molecules bind and dysregulate the activity of the ClpP peptidase. The potential of these antibiotics as antibacterial drugs has been enhanced by the elimination of pharmacological liabilities through medicinal chemistry efforts. Here, we demonstrate that the ADEP conformation observed in the ADEP-ClpP crystal structure is fortified by transannular hydrogen bonding and can be further stabilized by judicious replacement of constituent amino acids within the peptidolactone core structure with more conformationally constrained counterparts. Evidence supporting constraint of the molecule into the bioactive conformer was

SUBMITTER: Carney DW 

PROVIDER: S-EPMC4004210 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature