A New-Class Antibacterial—Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV

Abstract

The introduction into clinical practice of an ATPase inhibitor of bacterial DNA gyrase and topoisomerase IV (topo IV) would represent a new-class agent for the treatment of resistant bacterial infections. Novobiocin, the only historical member of this class, established the clinical proof of concept for this novel mechanism during the late 1950s, but its use declined rapidly and it was eventually withdrawn from the market. Despite significant and prolonged effort across the biopharmaceutical industry to develop other agents of this class, novobiocin remains the only ATPase inhibitor of gyrase and topo IV ever to progress beyond Phase I. In this review, we analyze the historical attempts to discover and develop agents within this class and highlight factors that might have hindered those efforts. Within the last 15 years, however, our technical understanding of the molecular details of the inhibition of the gyrase and topo IV ATPases, the factors governing resistance development to such inhibitors, and our knowledge of the physical properties required for robust clinical drug candidates have all matured to the point wherein the industry may now address this mechanism of action with greater confidence. The antibacterial spectrum within this class has recently been extended to begin to include serious Gram negative pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae. In spite of this recent technical progress, adverse economics associated with antibacterial R&D over the last 20 years has diminished industry's ability to commit the resources and perseverance needed to bring new-class agents to launch. Consequently, a number of recent efforts in the ATPase class have been derailed by organizational rather than scientific factors. Nevertheless, within this context we discuss the unique opportunity for the development of ATPase inhibitors of gyrase and topo IV as new-class antibacterial agents with broad spectrum potential.

Design, synthesis, and biological evaluation of 1‐ethyl‐3‐(thiazol‐2‐yl)urea derivatives as Escherichia coli DNA gyrase inhibitors

“…The crystal structures of DNA gyrase in complexes with ethylurea‐based inhibitors show that their Asp73 ( E. coli numbering) side‐chain carboxylate forms two hydrogen bonds with the two NH groups of the ethylurea moiety, while the nitrogen atom of the central scaffold forms an additional hydrogen bond with a conserved water molecule (Figure ). With this hydrogen bonding motif, ethylurea‐based DNA gyrase inhibitors mimic the binding of the adenine ring of ATP, while additional interactions are formed with the amino acids of the lipophilic floor of the ATP binding site and with the Arg76 and Arg136 side‐chains …”

“…The GyrB and ParE subunits have the ATPase activities which are necessary for providing the energy for the supercoiling and decatenation reactions of the catalytic GyrA and ParC subunits. The aminocoumarin antibiotic novobiocin interacts with the ATP binding sites of GyrB and ParE, but it was withdrawn from the market because of its toxicity and lack of efficacy . In recent years, several structural classes of GyrB and ParE inhibitors have been discovered through high‐throughput screening, virtual screening, and de‐novo design, in both industry and academia .…”

Synthesis and Evaluation of N‐Phenylpyrrolamides as DNA Gyrase B Inhibitors

“…The main reason for this situation is the rapid adaptation of bacteria to antibiotics, which results in the development of resistance soon after antibacterial drugs are introduced into clinical use . Another problem is the low number of new approved antibacterial drugs in recent decades, which is associated with strict regulatory requirements and the relatively low benefit–cost ratio for antibacterial research and development relative to other pharmacological fields …”

Novel Bacterial Topoisomerase Inhibitors with Potent Broad-Spectrum Activity against Drug-Resistant Bacteria

“…Research efforts over the past few years have focused on the development of novel classes of antibacterials with a dual-targeting mechanism of action that is distinct from currently used antibiotics, with the twin objectives of avoiding cross-resistance and reducing the emergence of de novo resistance. The essential bacterial type II topoisomerase enzymes, DNA gyrase, and topoisomerase IV are well-validated drug targets for antibiotic pharmacology as evidenced by the fluoroquinolone and aminocoumarin classes of antibiotics (5)(6)(7)(8). These enzymes are responsible for introducing negative supercoils into DNA and for the decatenation of DNA.…”