Recent Advances in the Rational Design and Optimization of Antibacterial Agents

Abstract

This review discusses next-generation antibacterial agents developed using rational, or targeted, drug design strategies. The focus of this review is on small-molecule compounds that have been designed to bypass developing bacterial resistance, improve the antibacterial spectrum of activity, and/or to optimize other properties, including physicochemical and pharmacokinetic properties. Agents are discussed that affect known antibacterial targets, such as the bacterial ribosome, nucleic acid binding proteins, and proteins involved in cell-wall biosynthesis; as well as some affecting novel bacterial targets which do not have currently marketed agents. The discussion of the agents focuses on the rational design strategies employed and the synthetic medicinal chemistry and structure-based design techniques utilized by the scientists involved in the discoveries, including such methods as ligand- and structure-based strategies, structure-activity relationship (SAR) expansion strategies, and novel synthetic organic chemistry methods. As such, the discussion is limited to small-molecule therapeutics that have confirmed macromolecular targets and encompasses only a fraction of all antibacterial agents recently approved or in late-stage clinical trials. The antibacterial agents selected have been recently approved for use on the U.S. or European markets or have shown promising results in phase 2 or phase 3 U.S.

Keywords: Antibacterial; optimization; rational design; resistance; semi-synthesis; targeted.

Figure 1

Cephem ring, structure and positional numbering.

Figure 2

Advanced generation cephalosporins recently approved or in clinical trials. A. Ceftaroline fosamil. B. Ceftobiprole medocaril (prodrug moiety in red). C. Ceftolozane. D. S-649266

Figure 3

Marketed, mechanism-based β-lactamase inhibitors. A. Clavulanic Acid. B. Tazobactam. C. Sulbactam.

Figure 4

Next generation β-lactamase inhibitors recently approved or in clinical trials. A. Avibactam. B. Relebactam. C. Vaborbactam.

Figure 5

Avibactam (cyan carbons) and relebactam (green carbons) shown bound into the active site of beta-lactamases, SHV-1 from K. pneumoniae [PDB ID 4ZAM] and AmpC from P. aeruginosa [PDB ID 4NK3), respectively.

Figure 6

RPX7009 bound to AmpC from E. cloacae [PDB ID 4XUX].

Figure 7

Oxazolidinones currently marketed or in clinical trials. A. Linezolid. B. Tedizolid. C. Radezolid. D. MRX-I. E. Cadezolid.

Figure 8

Next generation bacterial topoisomerase inhibitors. A. Zoliflodacin. B. Gepotidacin. C. Finafloxacin. D. Nemonoxacin. E. Delafloxacin. F. Zabofloxacin. G. Avarofloxacin.

Figure 9

Tetracycline (cyan carbons) shown binding to the bacterial ribosome, 30S subunit [PDB ID 1HNW]. Hydrogen bonds are shown as dashed, yellow lines.

Figure 10

Next generation tetracyclines & glycylcyclines marketed or in clinical trials. A. Tigecycline. B. Omadacycline. C. Eravacycline.

Figure 11

Advanced generation macrolides. A. Telithromycin. B. Cethromycin. C. Solithromycin.

Figure 12

Plazomicin.

Figure 13

Bacterial DHFR inhibitors. A. Trimethoprim. B. Iclaprim.

Figure 14

Inhibitors of the bacterial FAS2 pathway. A. Debio 1452. Debio 1450 is a reported prodrug of Debio 1452, with undisclosed structure. B. CG-400549.