Addison

Research Project: I develop antimicrobial prodrugs to selectively suppress β-lactam-resistant bacteria by hijacking β-lactamase enzymatic reactivity attendant to those resistant bacteria. This development takes a non-canonical approach by tailoring prodrug design to maintain chemical recognition with β-lactamases while minimizing chemical recognition with penicillin-binding-proteins to allow for growth suppression and pharmacophore delivery to  β-lactamase harboring cells. Techniques and approaches I use to probe the chemical design and reactivity of proposed prodrugs include molecular dynamic (MD) simulations and ΔGbinding analyses, quantification of prodrug activation rates with recombinant β-lactamases, monitoring structural changes of prodrug activation in whole cell bacteria by 1H NMR, and defining EC50 for prodrugs against lab-variety and clinical isolates expressing a variety of β-lactamases. Successful outcomes of this design approach have been realized by the quantification of the selective suppression of clinical, pathogenic bacteria when grown in a mixture with other model commensal bacteria, the first of its kind to demonstrate this activity.