Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile- Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence

Authors

Jujun Zhou
John R Horton
Martina Menna
Francesco Fiorentino
Ren Ren
Dan Yu
Taraneh Hajian
Masoud Vedadi
Giulia Mazzoccanti
Alessia Ciogli
Elmar Weinhold
Michael Hüben
Robert M Blumenthal
Xing Zhang
Antonello Mai
Dante Rotili
Xiaodong Cheng

Publication Date

1-12-2023

Journal

Journal of Medicinal Chemistry

Abstract

Antivirulence agents targeting endospore-transmitted Clostridioides difficile infections are urgently needed. C. difficile-specific DNA adenine methyltransferase (CamA) is required for efficient sporulation and affects persistence in the colon. The active site of CamA is conserved and closely resembles those of hundreds of related S-adenosyl-l-methionine (SAM)-dependent methyltransferases, which makes the design of selective inhibitors more challenging. We explored the solvent-exposed edge of the SAM adenosine moiety and systematically designed 42 analogs of adenosine carrying substituents at the C6-amino group (N6) of adenosine. We compare the inhibitory properties and binding affinity of these diverse compounds and present the crystal structures of CamA in complex with 14 of them in the presence of substrate DNA. The most potent of these inhibitors, compound 39 (IC50 ∼ 0.4 μM and KD ∼ 0.2 μM), is selective for CamA against closely related bacterial and mammalian DNA and RNA adenine methyltransferases, protein lysine and arginine methyltransferases, and human adenosine receptors.

Keywords

Animals, Humans, Methyltransferases, Adenosine, Clostridioides difficile, Adenine, S-Adenosylmethionine, DNA, Protein-Arginine N-Methyltransferases, Mammals

Comments

Supplementary Materials

PMID: 36581322