Activity of RBx 11760, a novel biaryl oxazolidinone, against Clostridium difficile
RBx 11760, a novel oxazolidinone, was investigated for in vitro and in vivo activity against Clostridium difficile. The in vitro activity of RBx 11760 and three other agents against 50 diverse C. difficile clinical isolates and other obligate anaerobic bacteria was determined. The effect of RBx 1176...
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| Veröffentlicht in: | Journal of antimicrobial chemotherapy 2011-05, Vol.66 (5), p.1087-1095 |
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| creator | MATHUR, Tarun KUMAR, Manoj BARMAN, Tarani K RAM KUMAR, G KALIA, Vandona SINGHA, Smita RAJ, V. Samuel UPADHYAY, Dilip J DAS, Biswajit BHATNAGAR, Pradip K |
| description | RBx 11760, a novel oxazolidinone, was investigated for in vitro and in vivo activity against Clostridium difficile.
The in vitro activity of RBx 11760 and three other agents against 50 diverse C. difficile clinical isolates and other obligate anaerobic bacteria was determined. The effect of RBx 11760 on sporulation and toxin production was determined against different C. difficile isolates. We used a hamster infection model to investigate the efficacy of RBx 11760, vancomycin and metronidazole. The mechanism of action of RBx 11760 against C. difficile ATCC 43255 was determined by macromolecular synthesis inhibition.
RBx 11760 MICs were in the range of 0.5-1 mg/L for C. difficile isolates, and it demonstrated concentration-dependent killing of C. difficile ATCC 43255 and C. difficile 6387 up to 2-4× MIC (1-2 mg/L). RBx 11760, at concentrations as low as 0.25-0.5 mg/L, resulted in a significant reduction in de novo toxin production as well as sporulation in different C. difficile isolates. In contrast, vancomycin, metronidazole and linezolid had little or no effect on toxin production and appeared to promote the formation of spores. In the hamster infection model, treatment with RBx 11760 resulted in prolonged survival of animals as compared with vancomycin or metronidazole, which correlated well with the histopathology results. Macromolecular labelling results suggest that RBx 11760 is a potent inhibitor of bacterial protein synthesis.
RBx 11760 showed excellent in vitro and in vivo activity against C. difficile, and it could be a promising novel candidate for future drug development against C. difficile infection. |
| doi_str_mv | 10.1093/jac/dkr033 |
| format | Article |
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The in vitro activity of RBx 11760 and three other agents against 50 diverse C. difficile clinical isolates and other obligate anaerobic bacteria was determined. The effect of RBx 11760 on sporulation and toxin production was determined against different C. difficile isolates. We used a hamster infection model to investigate the efficacy of RBx 11760, vancomycin and metronidazole. The mechanism of action of RBx 11760 against C. difficile ATCC 43255 was determined by macromolecular synthesis inhibition.
RBx 11760 MICs were in the range of 0.5-1 mg/L for C. difficile isolates, and it demonstrated concentration-dependent killing of C. difficile ATCC 43255 and C. difficile 6387 up to 2-4× MIC (1-2 mg/L). RBx 11760, at concentrations as low as 0.25-0.5 mg/L, resulted in a significant reduction in de novo toxin production as well as sporulation in different C. difficile isolates. In contrast, vancomycin, metronidazole and linezolid had little or no effect on toxin production and appeared to promote the formation of spores. In the hamster infection model, treatment with RBx 11760 resulted in prolonged survival of animals as compared with vancomycin or metronidazole, which correlated well with the histopathology results. Macromolecular labelling results suggest that RBx 11760 is a potent inhibitor of bacterial protein synthesis.
RBx 11760 showed excellent in vitro and in vivo activity against C. difficile, and it could be a promising novel candidate for future drug development against C. difficile infection.</description><identifier>ISSN: 0305-7453</identifier><identifier>EISSN: 1460-2091</identifier><identifier>DOI: 10.1093/jac/dkr033</identifier><identifier>PMID: 21393140</identifier><identifier>CODEN: JACHDX</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Animals ; Anti-Bacterial Agents - administration & dosage ; Anti-Bacterial Agents - pharmacology ; Antibiotics ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Bacterial infections ; Bacterial Toxins - biosynthesis ; Biological and medical sciences ; Chemotherapy ; Clostridium difficile ; Clostridium difficile - drug effects ; Clostridium difficile - isolation & purification ; Clostridium Infections - drug therapy ; Clostridium Infections - microbiology ; Cricetinae ; Disease Models, Animal ; Gastroenterology. Liver. Pancreas. Abdomen ; Gram-positive bacteria ; Humans ; Medical sciences ; Mesocricetus ; Metronidazole - administration & dosage ; Molecular structure ; Other diseases. Semiology ; Oxazolidinones - administration & dosage ; Oxazolidinones - pharmacology ; Pharmacology. Drug treatments ; Protein synthesis ; Spores, Bacterial - drug effects ; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus ; Toxins ; Vancomycin - administration & dosage</subject><ispartof>Journal of antimicrobial chemotherapy, 2011-05, Vol.66 (5), p.1087-1095</ispartof><rights>2015 INIST-CNRS</rights><rights>Copyright Oxford Publishing Limited(England) May 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c411t-d6436ba75a795065f703492e9958dfce934191ec3eaf0ef5b14546eba9748aeb3</citedby><cites>FETCH-LOGICAL-c411t-d6436ba75a795065f703492e9958dfce934191ec3eaf0ef5b14546eba9748aeb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24147681$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21393140$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MATHUR, Tarun</creatorcontrib><creatorcontrib>KUMAR, Manoj</creatorcontrib><creatorcontrib>BARMAN, Tarani K</creatorcontrib><creatorcontrib>RAM KUMAR, G</creatorcontrib><creatorcontrib>KALIA, Vandona</creatorcontrib><creatorcontrib>SINGHA, Smita</creatorcontrib><creatorcontrib>RAJ, V. Samuel</creatorcontrib><creatorcontrib>UPADHYAY, Dilip J</creatorcontrib><creatorcontrib>DAS, Biswajit</creatorcontrib><creatorcontrib>BHATNAGAR, Pradip K</creatorcontrib><title>Activity of RBx 11760, a novel biaryl oxazolidinone, against Clostridium difficile</title><title>Journal of antimicrobial chemotherapy</title><addtitle>J Antimicrob Chemother</addtitle><description>RBx 11760, a novel oxazolidinone, was investigated for in vitro and in vivo activity against Clostridium difficile.
The in vitro activity of RBx 11760 and three other agents against 50 diverse C. difficile clinical isolates and other obligate anaerobic bacteria was determined. The effect of RBx 11760 on sporulation and toxin production was determined against different C. difficile isolates. We used a hamster infection model to investigate the efficacy of RBx 11760, vancomycin and metronidazole. The mechanism of action of RBx 11760 against C. difficile ATCC 43255 was determined by macromolecular synthesis inhibition.
RBx 11760 MICs were in the range of 0.5-1 mg/L for C. difficile isolates, and it demonstrated concentration-dependent killing of C. difficile ATCC 43255 and C. difficile 6387 up to 2-4× MIC (1-2 mg/L). RBx 11760, at concentrations as low as 0.25-0.5 mg/L, resulted in a significant reduction in de novo toxin production as well as sporulation in different C. difficile isolates. In contrast, vancomycin, metronidazole and linezolid had little or no effect on toxin production and appeared to promote the formation of spores. In the hamster infection model, treatment with RBx 11760 resulted in prolonged survival of animals as compared with vancomycin or metronidazole, which correlated well with the histopathology results. Macromolecular labelling results suggest that RBx 11760 is a potent inhibitor of bacterial protein synthesis.
RBx 11760 showed excellent in vitro and in vivo activity against C. difficile, and it could be a promising novel candidate for future drug development against C. difficile infection.</description><subject>Animals</subject><subject>Anti-Bacterial Agents - administration & dosage</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Antibiotics</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Bacterial infections</subject><subject>Bacterial Toxins - biosynthesis</subject><subject>Biological and medical sciences</subject><subject>Chemotherapy</subject><subject>Clostridium difficile</subject><subject>Clostridium difficile - drug effects</subject><subject>Clostridium difficile - isolation & purification</subject><subject>Clostridium Infections - drug therapy</subject><subject>Clostridium Infections - microbiology</subject><subject>Cricetinae</subject><subject>Disease Models, Animal</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gram-positive bacteria</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Mesocricetus</subject><subject>Metronidazole - administration & dosage</subject><subject>Molecular structure</subject><subject>Other diseases. Semiology</subject><subject>Oxazolidinones - administration & dosage</subject><subject>Oxazolidinones - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein synthesis</subject><subject>Spores, Bacterial - drug effects</subject><subject>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</subject><subject>Toxins</subject><subject>Vancomycin - administration & dosage</subject><issn>0305-7453</issn><issn>1460-2091</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0V1LHDEUBuAgirtue9MfIEEQQZyas_maXNrFj4JQkPZ6yGSSkjU70WRGdv31TdltBW-8Cpw8HM45L0JfgHwFoujlUpvL7jERSvfQFJgg1Zwo2EdTQgmvJON0go5yXhJCBBf1IZrMgSoKjEzRw5UZ_IsfNjg6_PBtjQGkIBdY4z6-2IBbr9Mm4LjWrzH4zvext-X3t_Z9HvAixDykUh5XuPPOeeOD_YQOnA7Zft69M_Tr5vrn4q66_3H7fXF1XxkGMFSdYFS0WnItFS-DOUkoU3OrFK87Z6yiDBRYQ612xDreAuNM2FYryWptWzpDZ9u-Tyk-jzYPzcpnY0PQvY1jbmqlQIia0o-lAKmAs7rIk3dyGcfUlzUKYkpRWYuCzrfIpJhzsq55Sn5V7tQAaf4m0pREmm0iBR_vOo7tynb_6b8ICjjdAZ2NDi7p3vj85hgwKWqgfwAVipIe</recordid><startdate>20110501</startdate><enddate>20110501</enddate><creator>MATHUR, Tarun</creator><creator>KUMAR, Manoj</creator><creator>BARMAN, Tarani K</creator><creator>RAM KUMAR, G</creator><creator>KALIA, Vandona</creator><creator>SINGHA, Smita</creator><creator>RAJ, V. Samuel</creator><creator>UPADHYAY, Dilip J</creator><creator>DAS, Biswajit</creator><creator>BHATNAGAR, Pradip K</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7T7</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20110501</creationdate><title>Activity of RBx 11760, a novel biaryl oxazolidinone, against Clostridium difficile</title><author>MATHUR, Tarun ; KUMAR, Manoj ; BARMAN, Tarani K ; RAM KUMAR, G ; KALIA, Vandona ; SINGHA, Smita ; RAJ, V. 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Antiparasitic agents</topic><topic>Bacterial infections</topic><topic>Bacterial Toxins - biosynthesis</topic><topic>Biological and medical sciences</topic><topic>Chemotherapy</topic><topic>Clostridium difficile</topic><topic>Clostridium difficile - drug effects</topic><topic>Clostridium difficile - isolation & purification</topic><topic>Clostridium Infections - drug therapy</topic><topic>Clostridium Infections - microbiology</topic><topic>Cricetinae</topic><topic>Disease Models, Animal</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gram-positive bacteria</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Mesocricetus</topic><topic>Metronidazole - administration & dosage</topic><topic>Molecular structure</topic><topic>Other diseases. Semiology</topic><topic>Oxazolidinones - administration & dosage</topic><topic>Oxazolidinones - pharmacology</topic><topic>Pharmacology. 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Samuel</au><au>UPADHYAY, Dilip J</au><au>DAS, Biswajit</au><au>BHATNAGAR, Pradip K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Activity of RBx 11760, a novel biaryl oxazolidinone, against Clostridium difficile</atitle><jtitle>Journal of antimicrobial chemotherapy</jtitle><addtitle>J Antimicrob Chemother</addtitle><date>2011-05-01</date><risdate>2011</risdate><volume>66</volume><issue>5</issue><spage>1087</spage><epage>1095</epage><pages>1087-1095</pages><issn>0305-7453</issn><eissn>1460-2091</eissn><coden>JACHDX</coden><abstract>RBx 11760, a novel oxazolidinone, was investigated for in vitro and in vivo activity against Clostridium difficile.
The in vitro activity of RBx 11760 and three other agents against 50 diverse C. difficile clinical isolates and other obligate anaerobic bacteria was determined. The effect of RBx 11760 on sporulation and toxin production was determined against different C. difficile isolates. We used a hamster infection model to investigate the efficacy of RBx 11760, vancomycin and metronidazole. The mechanism of action of RBx 11760 against C. difficile ATCC 43255 was determined by macromolecular synthesis inhibition.
RBx 11760 MICs were in the range of 0.5-1 mg/L for C. difficile isolates, and it demonstrated concentration-dependent killing of C. difficile ATCC 43255 and C. difficile 6387 up to 2-4× MIC (1-2 mg/L). RBx 11760, at concentrations as low as 0.25-0.5 mg/L, resulted in a significant reduction in de novo toxin production as well as sporulation in different C. difficile isolates. In contrast, vancomycin, metronidazole and linezolid had little or no effect on toxin production and appeared to promote the formation of spores. In the hamster infection model, treatment with RBx 11760 resulted in prolonged survival of animals as compared with vancomycin or metronidazole, which correlated well with the histopathology results. Macromolecular labelling results suggest that RBx 11760 is a potent inhibitor of bacterial protein synthesis.
RBx 11760 showed excellent in vitro and in vivo activity against C. difficile, and it could be a promising novel candidate for future drug development against C. difficile infection.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>21393140</pmid><doi>10.1093/jac/dkr033</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Anti-Bacterial Agents - administration & dosage Anti-Bacterial Agents - pharmacology Antibiotics Antibiotics. Antiinfectious agents. Antiparasitic agents Bacterial infections Bacterial Toxins - biosynthesis Biological and medical sciences Chemotherapy Clostridium difficile Clostridium difficile - drug effects Clostridium difficile - isolation & purification Clostridium Infections - drug therapy Clostridium Infections - microbiology Cricetinae Disease Models, Animal Gastroenterology. Liver. Pancreas. Abdomen Gram-positive bacteria Humans Medical sciences Mesocricetus Metronidazole - administration & dosage Molecular structure Other diseases. Semiology Oxazolidinones - administration & dosage Oxazolidinones - pharmacology Pharmacology. Drug treatments Protein synthesis Spores, Bacterial - drug effects Stomach. Duodenum. Small intestine. Colon. Rectum. Anus Toxins Vancomycin - administration & dosage |
| title | Activity of RBx 11760, a novel biaryl oxazolidinone, against Clostridium difficile |
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