Mechanism Beta and Inhibition of Enzymes Involved in Antibiotic Resistance

Metallo Beta-lactamase (MBL) fold hydrolytic enzymes play critical roles in antibiotic resistance and in the regulation of gene expression. The substrates for these enzymes vary substantially, including Beta-lactam antibiotics and nucleic acids (both DNA and RNA). However, they have conserved core folds and active site chemistry, the latter remarkably so given the diversity in their reactions they catalyse. MBL fold enzymes are current potential drug targets both from perspectives of extending antibiotic lifetime and for combatting cellular 'resistance' to cancer drugs such as cis-platin. They also play critical roles in the processing of mRNA. This project concerns the development of fundamental knowledge of catalysis by MBL fold hydroxylases and application of the knowledge to identify template inhibitors, which can be modified to enable selective inhibition of specific family members. The work builds on structural studies on MBL fold hydroxylases (Beta-lactamases and nucleases) in Oxford as well as studies on small-molecule analogues of transition states during hydrolytic reactions[1-4]. The work will thus involve structure based design, synthesis, as well as assays with isolated enzymes and in cells. It is anticipated the work will provide mechanistic insights as well as enabling biological functional assignment studies.