The OXA-class of β-lactamases. A structural view on antibiotic resistance

Abstract

Antibiotic resistance is a topic that concerns everyone, and by 2050 deaths due to antibiotic resistant bacteria may surpass number of deaths due to cancer. The OXA-class of antibiotic resistance enzymes is a formidable threat, but has not received the same attention as other resistance enzymes. The goal of the project was to understand antibiotic resistance enzymes at an atomic scale and to develop molecules that may inactivate OXA enzymes responsible for antibiotic resistance.

We studied the OXA-class of antibiotic resistance enzymes, which makes bacteria resistant to important antibiotics including the carbapenem meropenem. The main method was protein crystallography. In order to identify new inhibitors, molecules that disrupts the OXA-48 enzyme activity, we screened a library of 490 small molecules by combining biophysical and biochemical methods. Based on three-dimensional structural information from protein and inhibitor interactions, over 50 new compounds were synthesized, and we characterized inhibitor properties towards OXA-48. We determined more than 40 complexes of OXA-48 bound to new compounds. We also enzymatically characterized the new OXA-436 enzyme, and determined three-dimensional structures of OXA-181 and OXA-245. Results from these studies have expanded our knowledge on how OXA-class enzymes contribute to antibiotic resistance crisis, and our work on developing new compounds, active as inhibitors against OXA-48 lays a foundation for new inhibitor drugs, and understanding of antibiotic resistance at the atomic level.