Identification of a Mycobacterium tuberculosis Cyclic Dinucleotide Phosphodiesterase Inhibitor

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.