Recent contributions of structure-based drug design to the development of antibacterial compounds

Abstract

According to a Pew Research study published in February 2015, there are 37 antibacterial programs currently in clinical trials in the United States. Protein structure-based methods for guiding small molecule design were used in at least 34 of these programs. Typically, this occurred at an early stage (drug discovery and/or lead optimization) prior to an Investigational New Drug (IND) application, although sometimes in retrospective studies to rationalize biological activity. Recognizing that structure-based methods are resource-intensive and often require specialized equipment and training, the NIAID has funded two Structural Genomics Centers to determine structures of infectious disease species proteins with the aim of supporting individual investigators' research programs with structural biology methods.

Figure 1. New β-lactamase inhibitors

(a) Chemical diagram of Avibactam. (b) Chemical diagram of Tazobactam. (c) Overlay of the protein structure OXA-24 from Acinetobacter baumannii bound to Avibactam (PDB: 4WM9) and Tazobactam (PDB: 3ZNT). Avibactam is a non β-lactam containing compound which binds OXA- 24 in similar ring-open conformation to the β-lactam containing compound Tazobactam. Avibactam structures shown with green carbons. Tazobactam structures shown with cyan carbons. (d) Surface of OXA-24 from A. baumannii bound to Avibactam. A hydrophobic bridge in Class-D β -lactamases covers the active site thus restricting access. Surface colored by atom (blue=nitrogen, red=oxygen, green=carbon).