Reinterpreting the mechanism of inhibition of Mycobacterium tuberculosis D-alanine:D-alanine ligase by D-cycloserine.

ABSTRACT: d-Cycloserine is a second-line drug approved for use in the treatment of patients infected with Mycobacterium tuberculosis, the etiologic agent of tuberculosis. The unique mechanism of action of d-cycloserine, compared with those of other clinically employed antimycobacterial agents, represents an untapped and exploitable resource for future rational drug design programs. Here, we show that d-cycloserine is a slow-onset inhibitor of MtDdl and that this behavior is specific to the M. tuberculosis enzyme orthologue. Furthermore, evidence is presented that indicates d-cycloserine binds exclusively to the C-terminal d-alanine binding site, even in the absence of bound d-alanine at the N-terminal binding site. Together, these results led us to propose a new model of d-alanine:d-alanine ligase i

SUBMITTER: Prosser GA 

PROVIDER: S-EPMC3944805 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature