posted on 2021-01-25, 21:30authored byCaroline
W. Karanja, Kofi S. Yeboah, Herman O. Sintim
Immune cells sense bacteria-derived
c-di-GMP and c-di-AMP as well
as host-derived cGAMP, which is synthesized by cGAS upon binding to
the pathogen’s DNA, to mount an immunological response (cytokine
production) via the STING-TBK1 pathway. Successful pathogens, such
as Mycobacterium tuberculosis and group B streptococcus,
harbor phosphodiesterases (PDEs) that can cleave
bacterial c-di-AMP as well as host-derived cGAMP to blunt the host’s
response to infection. Selective inhibitors of bacterial cyclic dinucleotide
(CDN) PDEs are needed as tool compounds to study the role(s) of CDN
PDEs during infection and they could also become bona fide antivirulence
compounds, but there is a paucity of such compounds. Using a high-throughput
assay, we identified six inhibitors of MTB CDN PDE (CdnP). The most
potent inhibitor, C82 with an IC50 of ∼18
μM, did not inhibit the enzymatic activities of three other
bacterial CDN PDEs (Yybt, RocR, and GBS-CdnP), a viral CDN PDE (poxin)
or mammalian ENPP1.