Structure–Activity Relationship of PseudouridimycinFocusing on the Improvement of Chemical Stability

In recent years, the spread of drug-resistant bacterial infections has driven a critical demand for new antimicrobial agents with novel mechanisms of action. Pseudouridimycin (PUM) is a nucleoside antibiotic that inhibits bacterial DNA-dependent RNA polymerase (RNAP) by binding in the conserved active site that is distinct from the mutable allosteric sites targeted by the clinically approved rifamycin-class of antibiotics. However, translational development of PUM is compromised by its poor intrinsic chemical stability and competitive modality of inhibition with respect to UTP, which will require further augmentation of binding affinity. We have conducted structure–activity relationship (SAR) studies on PUM by approaching these two problems through the rational design of analogs based on the known PUM·RNAP X-ray cocrystal structure and through elucidation of the decomposition mechanisms.