Selective Inhibition of Bacterial Intramolecular Trans-Sialidases via a Multidisciplinary Computational/Experimental Approach

forthcoming

SELECT-IT aims to develop small molecules that specifically target bacterial intramolecular trans(IT)-sialidases. IT-sialidases from Ruminococcus species have been related to progression of inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Following elucidation of the yet unknown mechanisms of action of IT-sialidases, I will rationally design candidate inhibitors, synthesise and characterise them, and assess their binding modes, inhibition efficacy and target selectivity. Inspired by strategies previously successful for antiviral drugs like Tamiflu, SELECT-IT will modify existing molecules such as Siastatin B, DANA, and 2,7-anhydro-Neu5Ac, as starting points to develop candidates that selectively inhibits bacterial sialidases while sparing human ones. The inhibitors will undergo systematic refinement through computer simulation (molecular dynamics, QM/MM and metadynamics) and experimental techniques (biochemical assays and NMR spectroscopy) to ensure high specificity. SELECT-IT aims to develop targeted inhibitors for managing bacterial infections linked to IBD and CRC, contributing directly to the creation of new therapeutic options.