| pubmed-article:18765690 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:18765690 | lifeskim:mentions | umls-concept:C0596988 | lld:lifeskim |
| pubmed-article:18765690 | lifeskim:mentions | umls-concept:C0036576 | lld:lifeskim |
| pubmed-article:18765690 | lifeskim:mentions | umls-concept:C0683598 | lld:lifeskim |
| pubmed-article:18765690 | lifeskim:mentions | umls-concept:C0302614 | lld:lifeskim |
| pubmed-article:18765690 | lifeskim:mentions | umls-concept:C1706050 | lld:lifeskim |
| pubmed-article:18765690 | lifeskim:mentions | umls-concept:C1524063 | lld:lifeskim |
| pubmed-article:18765690 | lifeskim:mentions | umls-concept:C0181090 | lld:lifeskim |
| pubmed-article:18765690 | pubmed:issue | 11 | lld:pubmed |
| pubmed-article:18765690 | pubmed:dateCreated | 2008-10-24 | lld:pubmed |
| pubmed-article:18765690 | pubmed:abstractText | A series of 1-cyclopropyl-8-methoxy-quinazoline-2,4-diones was synthesized and evaluated for lowering the ratio of the antimicrobial MIC in gyrase resistance mutants to that in the gyr(+) (wild type) using isogenic strains of Escherichia coli. Dione features that lowered this ratio were a 3-amino group and C-7 ring structure (3-aminomethyl pyrrolidinyl < 3-aminopyrrolidinyl < diazobicyclo < 2-ethyl piperazinyl). The wild-type MIC was also lowered. With the most active derivative tested, many gyrA resistance mutant types were as susceptible as, or more susceptible than, wild-type cells. The most active 2,4-dione derivatives were also more active with two quinolone-resistant gyrB mutants than with wild-type cells. With respect to lethality, the most bacteriostatic 2,4-dione killed E. coli at a rate that was affected little by a gyrA resistance mutation, and it exhibited a rate of killing similar to its cognate fluoroquinolone at 10x the MIC. Population analysis with wild-type E. coli applied to agar showed that the mutant selection window for the most active 2,4-dione was narrower than that for the cognate fluoroquinolone or for ciprofloxacin. These data illustrate a new approach to guide early-stage antimicrobial selection. Use of antimutant activity (i.e., ratio of the antimicrobial MIC in a mutant strain to the antimicrobial MIC in a wild-type strain) as a structure-function selection criterion can be combined with traditional efforts aimed at lowering antimicrobial MICs against wild-type organisms to more effectively afford lead molecules with activity against both wild-type and mutant cells. | lld:pubmed |
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| pubmed-article:18765690 | pubmed:language | eng | lld:pubmed |
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| pubmed-article:18765690 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:18765690 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:18765690 | pubmed:month | Nov | lld:pubmed |
| pubmed-article:18765690 | pubmed:issn | 1098-6596 | lld:pubmed |
| pubmed-article:18765690 | pubmed:author | pubmed-author:DrlicaKarlK | lld:pubmed |
| pubmed-article:18765690 | pubmed:author | pubmed-author:MalikMuhammad... | lld:pubmed |
| pubmed-article:18765690 | pubmed:author | pubmed-author:RosenJonathan... | lld:pubmed |
| pubmed-article:18765690 | pubmed:author | pubmed-author:KernsRobert... | lld:pubmed |
| pubmed-article:18765690 | pubmed:author | pubmed-author:GermanNadezhd... | lld:pubmed |
| pubmed-article:18765690 | pubmed:issnType | Electronic | lld:pubmed |
| pubmed-article:18765690 | pubmed:volume | 52 | lld:pubmed |
| pubmed-article:18765690 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:18765690 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:18765690 | pubmed:pagination | 3915-21 | lld:pubmed |
| pubmed-article:18765690 | pubmed:dateRevised | 2009-11-18 | lld:pubmed |
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| pubmed-article:18765690 | pubmed:meshHeading | pubmed-meshheading:18765690... | lld:pubmed |
| pubmed-article:18765690 | pubmed:year | 2008 | lld:pubmed |
| pubmed-article:18765690 | pubmed:articleTitle | Use of gyrase resistance mutants to guide selection of 8-methoxy-quinazoline-2,4-diones. | lld:pubmed |
| pubmed-article:18765690 | pubmed:affiliation | Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City,Iowa 52242, USA. | lld:pubmed |
| pubmed-article:18765690 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:18765690 | pubmed:publicationType | Research Support, N.I.H., Extramural | lld:pubmed |
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