There is an urgent need for new antibacterial drugs that are effective against infections caused by multidrug-resistant pathogens. Novel nonfluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) have the potential to become such drugs because they display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. Bacterial topoisomerase inhibitors that are built on a tetrahydropyran ring linked to a bicyclic aromatic moiety through a syn-diol linker show potent anti-Gram-positive activity, covering isolates with clinically relevant resistance phenotypes. For instance, analog 49c was found to be a dual DNA gyrase-topoisomerase IV inhibitor, with broad antibacterial activity and low propensity for spontaneous resistance development, but suffered from high hERG K(+) channel block. On the other hand, analog 49e displayed lower hERG K(+) channel block while retaining potent in vitro antibacterial activity and acceptable frequency for resistance development. Furthermore, analog 49e showed moderate clearance in rat and promising in vivo efficacy against Staphylococcus aureus in a murine infection model.

Novel antibacterial drugs that are effective against infections caused by multidrug resistant pathogens are urgently needed. In a previous report, we have shown that tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. During the course of our optimization program, lead compound 5 was deprioritized due to adverse findings in cardiovascular safety studies. In the effort of mitigating these findings and optimizing further the pharmacological profile of this class of compounds, we have identified a subseries of tetrahydropyran-based molecules that are potent DNA gyrase and topoisomerase IV inhibitors and display excellent antibacterial activity against Gram positive pathogens, including clinically relevant resistant isolates. One representative of this class, compound 32d, elicited only weak inhibition of hERG K(+) channels and hNaV1.5 Na(+) channels, and no effects were observed on cardiovascular parameters in anesthetized guinea pigs. In vivo efficacy in animal infection models has been demonstrated against Staphylococcus aureus and Streptococcus pneumoniae strains.

There is an urgent unmet medical need for novel antibiotics that are effective against a broad range of bacterial species, especially multidrug resistant ones. Tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent activity against Gram-positive pathogens and no target-mediated cross-resistance with fluoroquinolones. We report our research efforts aimed at expanding the antibacterial spectrum of this class of molecules toward difficult-to-treat Gram-negative pathogens. Physicochemical properties (polarity and basicity) were considered to guide the design process. Dibasic tetrahydropyran-based compounds such as 6 and 21 are potent inhibitors of both DNA gyrase and topoisomerase IV, displaying antibacterial activities against Gram-positive and Gram-negative pathogens (Staphylococcus aureus, Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii). Compounds 6 and 21 are efficacious in clinically relevant murine infection models.

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.

The promotion of colonization with vancomycin-resistant enterococci (VRE) is one potential side effect during treatment of Clostridium difficile-associated diarrhea (CDAD), resulting from disturbances in gut microbiota. Cadazolid (CDZ) is an investigational antibiotic with potent in vitro activity against C. difficile and against VRE and is currently in clinical development for the treatment of CDAD. We report that CDZ treatment did not lead to intestinal VRE overgrowth in mice.C urrent antibiotic treatment of Clostridium difficile-associated diarrhea (CDAD) is mostly done with oral metronidazole (MDZ) and vancomycin (VAN), while only VAN is approved by the FDA. Both drugs promote overgrowth of vancomycin-resistant enterococci (VRE) in the gut and long-term colonization on treatment (1). Recently, the antibiotic fidaxomicin (FDX) was approved by the FDA as a new treatment option for CDAD. Its clinical impact on VRE overgrowth is still unclear. Colonization with VRE represents a major source for VRE bloodstream infections, endocarditis, and urinary tract infections, a particular problem in intensive care units (ICUs) (2-5). Infections caused by VRE are more serious and are associated with a higher mortality rate than those caused by vancomycin-sensitive enterococci (6-9). VRE control appears to be highly challenging. Therefore, preventing VRE colonization represents an important health care goal, particularly in the ICU. FIG 1Mice were pretreated with cadazolid, vancomycin, fidaxomicin, or metronidazole once daily at the indicated doses per kilogram body weight per day (vehicle-treated group, 0 mg/kg) from day Ϫ2 to day ϩ2 and infected with VRE on day 0. Results are expressed as change in log CFU per cecum (versus vehicle group) at 3 days postinfection. Shown are 25% to 75% interquartile range (box), median (intersection), and minimum-maximum (t bar) values for each group. Data were pooled from two similar, independent experiments. API, active pharmacological ingredient. *, P Ͻ 0.05; ***, P Ͻ 0.001. (10), exhibited efficacy and potency in prevention of CDAD similar or superior to VAN, MDZ, and FDX in the mouse model for CDAD (10, 11). CDZ exhibited potent in vitro activity not only against C. difficile clinical isolates but also against VRE (MIC 90 , 2 g/ml) (12, 13), while having a limited impact on bacteria of the normal gut microflora in the in vitro human gut model (14). Recently, a phase 2 trial in CDAD showed clinical cure rates with CDZ treatment similar to those with VAN treatment, while having lower recurrence rates, resulting in higher sustained cure rates (15).In order to investigate the impact of CDZ on intestinal VRE expansion, a mouse model for VRE colonization was employed (1; see Supplementary Material and Methods in the supplemental material). All animal housing and experiments were conducted in agreement with the Swiss Federal Ordinance for animal protection, the animal welfare guidelines from the Cantonal Veterinary Office Basellandschaft, and the Actelion Pharmaceuticals, Ltd., internal anim...