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Cadazolid, a New Antibiotic with Potent Activity Against Clostridium Difficile Inhibits Protein Synthesis Also in P-1658 Linezolid-Resistant Strains

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Cadazolid, a New Antibiotic with Potent Activity Against Clostridium Difficile Inhibits Protein Synthesis Also in P-1658 Linezolid-Resistant Strains Cadazolid, a New Antibiotic with Potent Activity Against Clostridium difficile Inhibits Protein Synthesis also in P-1658 Linezolid-Resistant Strains P. Caspers, D. Ritz, H.H. Locher, T. Bruyère, S. Schroeder, P. Pfaff, A. Knezevic, M. Dos Santos, C. Hubschwerlen, W. Keck Actelion Pharmaceuticals Ltd, Allschwil, Switzerland Toxin formation studies: The effect on toxin production of sub-MIC and supra- Macromolecular labeling: Cadazolid inhibits primarily de novo protein synthesis in C. difficile; INTRODUCTION MIC antibiotic concentrations was measured in stationary phase cultures of toxigenic C. difficile. Cell viability (colony count) and toxin A/B content (ELISA, weak inhibition of nucleic acid synthesis Clostridium difficile (CD) is a Gram-positive, anaerobic, toxin and spore RIDASCREEN®) were determined after 24h. Total toxin produced (in forming bacterium that is the most common cause of antibiotic- supernatant and cell pellet) within 24 hours in untreated culture was set as 100%. associated diarrhea (CDAD) and colitis. CDAD results from overgrowth of toxin-producing strains in the colon following disturbance of the indigenous protective enteric microflora. New hypervirulent and epidemic strains of C. difficile have been discovered that are characterized by acquired resistance to fluoroquinolones such as moxifloxacin. Current antibiotic therapies for CDAD include vancomycin RESULTS and metronidazole, which have limited treatment success in severe disease and high recurrence rates of up to 30% [1]. Only one new Cadazolid is a potent inhibitor of translation in C. antibiotic, fidaxomicin [2] has been approved in the last 30 years for R this indication and there remains a need for new drugs with improved difficile cell-free extracts, including LZD strains Figure 3. Inhibition of protein and DNA synthesis shown against wild-type and a Lzd-R and FQ-R strain efficacy. Table 2. Macromolecular labeling: Inhibition of protein, nucleic acid and Cadazolid shows weak activity in bacterial DNA Cadazolid (CDZ, formerly ACT-179811) is a new antibiotic and its cell wall synthesis in different C. difficile strains compared to MICs. structure is shown in Figure 1. CDZ showed potent in vitro activity topoisomerase assays Test Strain (phenotype) Cadazolid Linezolid Moxifloxacin Vancomycin against C. difficile clinical isolates [3] and in a human gut model of Table 3. Activity of Cadazolid and comparators in DNA topoisomerase CDAD, while having only a very limited impact on bacteria of the 43602 (LZDS, FQS) 0.09 1.7 >64 nt assays (IC [mM]) Protein 50 S R normal gut microflora [3] and was selected for clinical development in A-1179 (LZD , FQ ) 0.08 1.8 >64 nt 4) synthesis Enzyme Cadazolid Linezolid Ciprofloxacin Moxifloxacin Etoposide CDAD. CDZ has recently shown promising Phase II study results A-1291 (LZDR, FQS) 0.19 11.8 >64 nt IC50 [μg/ml] DNA gyrase (E. coli) 1) 8-32 >256 0.125-2 0.5 nt A-1410 (LZDR, FQR) 0.31 68.0 >32 nt (ECCMID 2013 late breaker poster LB-2956). DNA topoIV (E. coli) 2) 32->50 >256 2-8 8 nt 43602 (LZDS, FQS) 12.0 >128 2.4 nt The present study provides further information on the mode of action DNA DNA gyrase (C. difficile) 1) >50 >256 >256 32-128 nt A-1179 (LZDS, FQR) 17.6 >128 46.0 nt (MoA) of CDZ on CD. synthesis DNA gyrase (C. difficile) 2) >50 >256 >256 32-128 nt A-1291 (LZDR, FQS) 14.3 >128 6.0 nt O IC50 [μg/ml] 3) R R DNA topo I (human) >50 nt >1028 nt >1028 F A-1410 (LZD , FQ ) 18.6 >128 43.0 nt O DNA topo II (human) 3) >50 nt 512 >256 32-128 N O O H O Cell wall 43602 (LZDS, FQS) >32 >128 >128 1.4 N O ATCC 1)Supercoiling, 2)Decatenation, 3) Relaxation assays. 4)Maximal solubility of cadazolid in assay buffer (2-5% Strain ATCC 43602 ATCC 9689 A-1363 ATCC 43596 A-1290 A-1291 A-1410 A-1412 synthesis F A-1410 (LZDR, FQR) >32 >128 >128 4.7 DMSO): 50 µM; nt: not tested. O H 700057 IC [μg/ml] N OH 50 MIC LZDS FQS LZDS FQS LZDS FQS LZDS FQS LZDR FQS LZDR FQS LZDR FQS LZDR FQR LZDR FQR 43602 (LZDS, FQS) 0.125 2 2 1 Cadazolid (as well as ciprofloxacin) demonstrated no inhibition in LZD 2 4 4 2 16 32 16 64 64 A-1179 (LZDS, FQR) 0.125 1 32 1 C. difficile gyrase assays within its limited solubility range in CIP 16 16 16 16 16 16 16 64 64 MICTable3. [μg/ml ]Macromolecular labeling: Effect on protein, nucleic acid and cell A-1291 (LZDR, FQS) 0.25 16 1 2 Figure 1. Chemical structure of cadazolid CDZ 0.25 0.125 0.125 0.125 0.125 0.25 0.5 0.5 0.5 wall synthesis in different C. difficile strains compared to MICs. assay buffer (max 50 mM). Nevertheless, cadazolid showed A-1410 (LZDR, FQR) 0.5 64 32 1 measurable inhibitory effects of E. coli gyrase and topoIV. Figure 2. Inhibition of protein synthesis assayed by CFTA. IC50 and MIC Mean IC values in mg/ml are given. LZDS, linezolid susceptible; LZDR, linezolid resistant; FQS, values [mg/ml] are shown for LZD, CIP and CDZ against CD strains with various 50 fluoroquinolone susceptible; FQR, fluoroquinolone resistant; nt: not tested phenotypes. Assays and ranges of at least three independent experiments are shown. METHODS S R ATCC, American Type Culture Collection; LZD , linezolid susceptible; LZD , linezolid CONCLUSIONS resistant; FQS, fluoroquinolone susceptible; FQR, fluoroquinolone resistant; CFTA Cadazolid showed strong inhibition of protein synthesis in C. General: C. difficile reference strains were obtained from the ATCC and NCTC. assays for ciprofloxacin were not done in strains ATCC9689 and A-1363. difficile with IC50s ~ 15 to 220 times lower than linezolid. Linezolid non-susceptible CD clinical isolates were kindly provided by Prof. M. Cadazolid (CDZ), a new antibiotic acts primarily by Wilcox, Leeds, UK and by Prof. D. Gerding, Chicago, USA. CDZ (purity 98.8%) In contrast to linezolid, cadazolid strongly inhibits protein inhibition of protein synthesis, with inhibition of nucleic was synthesized at Actelion Pharmaceuticals Ltd. Other antibiotics were obtained Cadazolid potently inhibits in vitro translation in coupled cell-free synthesis also in linezolid-resistant strains. acid synthesis as weaker secondary mode of action. from Sigma-Aldrich. Standard MICs were determined by agar dilution following the transcription-translation assays (CFTA) C. difficile extracts derived Cadazolid inhibits nucleic acid synthesis only at considerably CDZ strongly inhibits protein synthesis in C. difficile guidelines of the CLSI [4]. from LZD-susceptible and -resistant strains. higher concentrations. extracts from LZDS as well as LZDR strains in agreement C. difficile cell-free coupled transcription-translation assay (CFTA): Bacterial S12 CFTA IC values correlate well with MICs, which suggests that 50 Cadazolid does not inhibit cell wall biosynthesis. with potent antibacterial activity against linezolid-resistant extracts were prepared according to a simplified E. coli procedure [5]. The firefly inhibition of protein synthesis is the primary mode of action for luciferase reporter gene was resynthesized with codons optimized for C. difficile strains. cadazolid in these strains. and placed under the control of the Abr310 promoter derived from C. The improvement of inhibitory activity may be mediated by acetobutylicum for efficient translation [6]. Extracts were mixed with reporter Cadazolid inhibits C. difficile toxin formation plasmid DNA (500 ng/mL) and CFTA buffer. Reactions were incubated at 37 °C for additional binding sites of CDZ on the ribosome. Further 30 min and Bright Glo solution (luciferase substrate) was added. The Cadazolid inhibits translation, not transcription structural studies are needed. luminescence was immediately measured using a Tecan SpectralFluor Plus The strong inhibitory effect of CDZ on C. difficile toxin Reader (GeniosPro) instrument. IC values were calculated from the data. 50 Table 1. E. coli in vitro transcription/translation and translation only; synthesis in the absence of killing may be explained by its In vitro RNA production: To discriminate between transcription, translation and DNA inhibitory IC [mM] values. inhibition of de novo protein synthesis (more efficient than interacting compounds, in vitro-produced luciferase mRNA was added to in vitro 50 other antibiotics with a different mode of action, such as translation experiments. pSP-luc+NF Fusion Vector plasmid DNA was used for the E. coli RNA Transcription T7 RNA polymerase No transcription RiboMAX™ large scale RNA production system-SP6 (Promega). The in vitro- polymerase vancomycin and metronidazole). A better control of toxin produced luciferase mRNA was purified using the RNeasy Plus Mini Kit (Qiagen), Translation E. coli ribosomes E. coli ribosomes E. coli ribosomes and spore formation may result in improved treatment and the concentration of the purified mRNA determined at an optical density (OD) response in CDAD patients. a) b) Purified luciferase of 260 nm. Luciferase gene pBestluc pT7-luc c) mRNA The clinical efficacy and safety of CDZ has been evaluated DNA supercoiling and decatenation assays: DNA gyrase supercoiling inhibition Linezolid 2-6 7.3 10.3 in a clinical Phase 2 study. assays were performed with relaxed pBR322 DNA (Inspiralis, UK) as a substrate Cadazolid 0.37 1.0 2.9 and DNA topoisomerase IV relaxation assays with supercoiled pBR322 (Inspiralis, Rifaximin 0.10 >40 >40 UK) as a substrate. Reactions were carried out at 37 °C for 1 h and aliquots were (transcription inhibitor) loaded on a 1% agarose gel. For supercoiling inhibition assays (SCIA), IC was 50 Mitramycin A <1.0 <1.0 >40 References determined visually as being the compound concentration at which the supercoiled (DNA interacting) [1] Ananthakrishnan A. Clostridium difficile infection: epidemiology, risk factors and band was reduced by 50%. For relaxation inhibition assays (RIA), IC50 was defined a) E.
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