ABSTRACT
Clostridioides difficile (C. difficile) is one of the leading causes of healthcare-associated infections worldwide. The increasing incidence of strains resistant to currently available therapies highlights the need for alternative treatment options with a novel mode of action. Oxazolidinones that are connected to a quinolone moiety with a pyrrolidine linker, such as compound 1, are reported to exhibit potent broadspectrum antibacterial activity. In an effort to optimize this class of compounds for the treatment of C. difficile infection (CDI), we have identified cadazolid (9), a first-in-class quinoxolidinone antibiotic, which is a potent inhibitor of C. difficile protein synthesis. In order to achieve narrow-spectrum coverage of clinically most relevant strains without affecting the gut microbiota, an emphasis was placed on abolishing activity against commensals of the intestinal microbiome while retaining good coverage of pathogenic C. difficile, including hypervirulent and epidemic strains.
Subject(s)
Anti-Bacterial Agents , Clostridioides difficile , Clostridium Infections , Microbial Sensitivity Tests , Structure-Activity Relationship , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/chemical synthesis , Clostridioides difficile/drug effects , Clostridium Infections/drug therapy , Animals , Humans , Drug Discovery , Gastrointestinal Microbiome/drug effects , Mice , OxazolidinonesABSTRACT
UDP-3-O-((R)-3-hydroxymyristoyl)-N-glucosamine deacetylase (LpxC) is as an attractive target for the discovery and development of novel antibacterial drugs to address the critical medical need created by multidrug resistant Gram-negative bacteria. By using a scaffold hopping approach on a known family of methylsulfone hydroxamate LpxC inhibitors, several hit series eliciting potent antibacterial activities against Enterobacteriaceae and Pseudomonas aeruginosa were identified. Subsequent hit-to-lead optimization, using cocrystal structures of inhibitors bound to Pseudomonas aeruginosa LpxC as guides, resulted in the discovery of multiple chemical series based on (i) isoindolin-1-ones, (ii) 4,5-dihydro-6H-thieno[2,3-c]pyrrol-6-ones, and (iii) 1,2-dihydro-3H-pyrrolo[1,2-c]imidazole-3-ones. Synthetic methods, antibacterial activities and relative binding affinities, as well as physicochemical properties that allowed compound prioritization are presented. Finally, in vivo properties of lead molecules which belong to the most promising pyrrolo-imidazolone series, such as 18d, are discussed.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Escherichia coli Infections/drug therapy , Gram-Negative Bacteria/drug effects , Hydroxamic Acids/therapeutic use , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Escherichia coli/drug effects , Female , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacokinetics , Klebsiella pneumoniae/drug effects , Mice, Inbred ICR , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/enzymology , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Pyrroles/therapeutic useABSTRACT
LpxC inhibitors were optimized starting from lead compounds with limited efficacy and solubility and with the goal to provide new options for the treatment of serious infections caused by Gram-negative pathogens in hospital settings. To enable the development of an aqueous formulation for intravenous administration of the drug at high dose, improvements in both solubility and antibacterial activity in vivo were prioritized early on. This lead optimization program resulted in the discovery of compounds such as 13 and 30, which exhibited high solubility and potent efficacy against Gram-negative pathogens in animal infection models.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Escherichia coli Infections/drug therapy , Hydroxamic Acids/therapeutic use , Administration, Intravenous , Animals , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Gram-Negative Bacteria/drug effects , Hepatocytes/metabolism , Hydroxamic Acids/administration & dosage , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacokinetics , Mice , Microbial Sensitivity Tests , Molecular Structure , Rats , SolubilityABSTRACT
Our strategy to combat resistant bacteria consisted of targeting the GyrB/ParE ATP-binding sites located on bacterial DNA gyrase and topoisomerase IV and not utilized by marketed antibiotics. Screening around the minimal ethyl urea binding motif led to the identification of isoquinoline ethyl urea 13 as a promising starting point for fragment evolution. The optimization was guided by structure-based design and focused on antibacterial activity in vitro and in vivo, culminating in the discovery of unprecedented substituents able to interact with conserved residues within the ATP-binding site. A detailed characterization of the lead compound highlighted the potential for treatment of the problematic fluoroquinolone-resistant MRSA, VRE, and S. pneumoniae, and the possibility to offer patients an intravenous-to-oral switch therapy was supported by the identification of a suitable prodrug concept. Eventually, hERG K-channel block was identified as the main limitation of this chemical series, and efforts toward its minimization are reported.
