Reinterpreting the Mechanism of Inhibition of <i>Mycobacterium tuberculosis</i> d‑Alanine:d‑Alanine Ligase by d‑Cycloserine
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Abstract
d-Cycloserine is a second-line
drug approved for use in
the treatment of patients infected with <i>Mycobacterium tuberculosis</i>, 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 <i>M. tuberculosis</i> 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
inhibition by d-cycloserine and suggest new opportunities
for rational drug design against an essential, clinically validated
mycobacterial target