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Research paper thumbnail of Cadazolid does not promote intestinal colonization of vancomycin-resistant enterococci in mice

Antimicrobial Agents and Chemotherapy, 2015

The promotion of colonization with vancomycin-resistant enterococci (VRE) is one potential side e... more The promotion of colonization with vancomycin-resistant enterococci (VRE) is one potential side effect during treatment ofClostridium difficile-associated diarrhea (CDAD), resulting from disturbances in gut microbiota. Cadazolid (CDZ) is an investigational antibiotic with potentin vitroactivity againstC. difficileand 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.

Research paper thumbnail of Dimers of Nostocarboline with Potent Antibacterial Activity

Chemotherapy, 2010

In this study, the in vitro antimicrobial activity and spectrum of new dimeric compounds derived ... more In this study, the in vitro antimicrobial activity and spectrum of new dimeric compounds derived from the cyanobacterial alkaloid nostocarboline were investigated. The mechanism of action and selectivity to bacteria were studied and compared to the cationic antiseptic chlorhexidine. Minimal inhibitory concentrations were determined against clinical isolates and against a panel of microbial reference strains using the CLSI microdilution method. Bacterial membrane damage was addressed by measuring ATP leakage and the mode of action was investigated in Escherichia coli reporter strains. Selectivity was tested by a cytotoxicity assay using MTS. The antimicrobial potency of dimers varied with length of the hydrophobic linker. The most potent compounds, NCD9 and NCD10, had a C10 and C12 linker, respectively, and showed strong activity against Gram-positive bacteria, notably methicillin-resistant Staphylococcus aureus strains. Similar to chlorhexidine, these compounds showed a rapid concentration-dependent bactericidal effect, which correlated with membrane damage as indicated by ATP leakage. NCD9, in contrast to NCD10 and chlorhexidine, lacked activity against yeast strains and showed low cytotoxicity in CHO cells indicating a high degree of selectivity. In E. coli reporter strains, NCD9 induced the DegP response pathway as well as the SOS response, suggesting interaction with both the cell envelope and DNA metabolism. The results presented in this report indicate the potential of this new class of cationic antimicrobial compounds for the design of potent and selective antibacterials with low cytotoxicity.

Research paper thumbnail of In Vitro and In Vivo Antibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

Antimicrobial Agents and Chemotherapy, 2014

Cadazolid is a new oxazolidinone-type antibiotic currently in clinical development 26 for the tre... more Cadazolid is a new oxazolidinone-type antibiotic currently in clinical development 26 for the treatment of Clostridium difficile-associated diarrhea. Here we report 27 investigations on the mode of action and the propensity for spontaneous resistance 28 development in C. difficile strains. Macromolecular labeling experiments indicated that 29 cadazolid acts as a potent inhibitor of protein synthesis, while inhibition of DNA 30 synthesis was also observed, albeit only at substantially higher concentrations. Strong 31 inhibition of protein synthesis was also obtained in strains resistant to linezolid, in 32 agreement with low MICs against such strains. Inhibition of protein synthesis was 33 confirmed in coupled-transcription-translation assays using extracts from different C. 34 difficile strains, including strains resistant to linezolid, while inhibitory effects in DNA 35 topoisomerase assays were weak or not detectable under the assay conditions.

Research paper thumbnail of Cadazolid does not promote intestinal colonization of vancomycin-resistant enterococci in mice

Antimicrobial Agents and Chemotherapy, 2015

The promotion of colonization with vancomycin-resistant enterococci (VRE) is one potential side e... more The promotion of colonization with vancomycin-resistant enterococci (VRE) is one potential side effect during treatment ofClostridium difficile-associated diarrhea (CDAD), resulting from disturbances in gut microbiota. Cadazolid (CDZ) is an investigational antibiotic with potentin vitroactivity againstC. difficileand 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.

Research paper thumbnail of Dimers of Nostocarboline with Potent Antibacterial Activity

Chemotherapy, 2010

In this study, the in vitro antimicrobial activity and spectrum of new dimeric compounds derived ... more In this study, the in vitro antimicrobial activity and spectrum of new dimeric compounds derived from the cyanobacterial alkaloid nostocarboline were investigated. The mechanism of action and selectivity to bacteria were studied and compared to the cationic antiseptic chlorhexidine. Minimal inhibitory concentrations were determined against clinical isolates and against a panel of microbial reference strains using the CLSI microdilution method. Bacterial membrane damage was addressed by measuring ATP leakage and the mode of action was investigated in Escherichia coli reporter strains. Selectivity was tested by a cytotoxicity assay using MTS. The antimicrobial potency of dimers varied with length of the hydrophobic linker. The most potent compounds, NCD9 and NCD10, had a C10 and C12 linker, respectively, and showed strong activity against Gram-positive bacteria, notably methicillin-resistant Staphylococcus aureus strains. Similar to chlorhexidine, these compounds showed a rapid concentration-dependent bactericidal effect, which correlated with membrane damage as indicated by ATP leakage. NCD9, in contrast to NCD10 and chlorhexidine, lacked activity against yeast strains and showed low cytotoxicity in CHO cells indicating a high degree of selectivity. In E. coli reporter strains, NCD9 induced the DegP response pathway as well as the SOS response, suggesting interaction with both the cell envelope and DNA metabolism. The results presented in this report indicate the potential of this new class of cationic antimicrobial compounds for the design of potent and selective antibacterials with low cytotoxicity.

Research paper thumbnail of In Vitro and In Vivo Antibacterial Evaluation of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

Antimicrobial Agents and Chemotherapy, 2014

Cadazolid is a new oxazolidinone-type antibiotic currently in clinical development 26 for the tre... more Cadazolid is a new oxazolidinone-type antibiotic currently in clinical development 26 for the treatment of Clostridium difficile-associated diarrhea. Here we report 27 investigations on the mode of action and the propensity for spontaneous resistance 28 development in C. difficile strains. Macromolecular labeling experiments indicated that 29 cadazolid acts as a potent inhibitor of protein synthesis, while inhibition of DNA 30 synthesis was also observed, albeit only at substantially higher concentrations. Strong 31 inhibition of protein synthesis was also obtained in strains resistant to linezolid, in 32 agreement with low MICs against such strains. Inhibition of protein synthesis was 33 confirmed in coupled-transcription-translation assays using extracts from different C. 34 difficile strains, including strains resistant to linezolid, while inhibitory effects in DNA 35 topoisomerase assays were weak or not detectable under the assay conditions.

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