Discovery and Mechanistic Study of Novel Mycobacterium tuberculosis ClpP1P2 Inhibitors

Caseinolytic
protease P (ClpP) responsible for the proteolysis
of damaged or misfolded proteins plays a critical role in proteome
homeostasis. MtbClpP1P2, a ClpP enzyme complex, is required for survival
in Mycobacterium tuberculosis, and
it is therefore considered as a promising target for the development
of antituberculosis drugs. Here, we discovered that cediranib and
some of its derivatives are potent MtbClpP1P2 inhibitors and suppress M. tuberculosis growth. Protein pull-down and loss-of-function
assays validated the in situ targeting of MtbClpP1P2 by cediranib
and its active derivatives. Structural and mutational studies revealed
that cediranib binds to MtbClpP1P2 by binding to an allosteric pocket
at the equatorial handle domain of the MtbClpP1 subunit, which represents
a unique binding mode compared to other known ClpP modulators. These
findings provide us insights for rational drug design of antituberculosis
therapies and implications for our understanding of the biological
activity of MtbClpP1P2.