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dc.contributor.authorTarantino, Paul M. Jr.
dc.contributor.authorZhi, Chengxin
dc.contributor.authorWright, George E.
dc.contributor.authorBrown, Neal C.
dc.date2022-08-11T08:09:36.000
dc.date.accessioned2022-08-23T16:37:23Z
dc.date.available2022-08-23T16:37:23Z
dc.date.issued1999-08-03
dc.date.submitted2008-02-29
dc.identifier.citationAntimicrob Agents Chemother. 1999 Aug;43(8):1982-7.
dc.identifier.issn0066-4804 (Print)
dc.identifier.pmid10428923
dc.identifier.urihttp://hdl.handle.net/20.500.14038/39004
dc.description.abstract6-Anilinouracils are selective inhibitors of DNA polymerase III, the enzyme required for the replication of chromosomal DNA in gram-positive bacteria (N. C. Brown, L. W. Dudycz, and G. E. Wright, Drugs Exp. Clin. Res. 12:555-564, 1986). A new class of 6-anilinouracils based on N-3 alkyl substitution of the uracil ring was synthesized and analyzed for activity as inhibitors of the gram-positive bacterial DNA polymerase III and the growth of gram-positive bacterial pathogens. Favorable in vitro properties of N-3-alkyl derivatives prompted the synthesis of derivatives in which the R group at N-3 was replaced with more-hydrophilic methoxyalkyl and hydroxyalkyl groups. These hydroxyalkyl and methoxyalkyl derivatives displayed K(i) values in the range from 0.4 to 2.8 microM against relevant gram-positive bacterial DNA polymerase IIIs and antimicrobial activity with MICs in the range from 0.5 to 15 microg/ml against a broad spectrum of gram-positive bacteria, including methicillin-resistant staphylococci and vancomycin-resistant enterococci. Two of these hydrophilic derivatives displayed protective activity in a simple mouse model of lethal staphylococcal infection.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10428923&dopt=Abstract ">Link to article in PubMed</a>
dc.subjectAniline Compounds
dc.subjectAnimals
dc.subjectAnti-Bacterial Agents
dc.subjectBacillus subtilis
dc.subjectBacterial Proteins
dc.subjectCattle
dc.subjectDNA Polymerase III
dc.subjectEnterococcus faecalis
dc.subjectEnterococcus faecium
dc.subjectEnzyme Inhibitors
dc.subjectFemale
dc.subjectGram-Positive Bacteria
dc.subjectKinetics
dc.subjectMice
dc.subjectMicrobial Sensitivity Tests
dc.subjectStaphylococcal Infections
dc.subjectStaphylococcus aureus
dc.subjectStructure-Activity Relationship
dc.subjectUracil
dc.subjectMedical Molecular Biology
dc.subjectPharmacology
dc.subjectToxicology
dc.titleInhibitors of DNA polymerase III as novel antimicrobial agents against gram-positive eubacteria
dc.typeJournal Article
dc.source.journaltitleAntimicrobial agents and chemotherapy
dc.source.volume43
dc.source.issue8
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1182&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/183
dc.identifier.contextkey441948
refterms.dateFOA2022-08-23T16:37:23Z
html.description.abstract<p>6-Anilinouracils are selective inhibitors of DNA polymerase III, the enzyme required for the replication of chromosomal DNA in gram-positive bacteria (N. C. Brown, L. W. Dudycz, and G. E. Wright, Drugs Exp. Clin. Res. 12:555-564, 1986). A new class of 6-anilinouracils based on N-3 alkyl substitution of the uracil ring was synthesized and analyzed for activity as inhibitors of the gram-positive bacterial DNA polymerase III and the growth of gram-positive bacterial pathogens. Favorable in vitro properties of N-3-alkyl derivatives prompted the synthesis of derivatives in which the R group at N-3 was replaced with more-hydrophilic methoxyalkyl and hydroxyalkyl groups. These hydroxyalkyl and methoxyalkyl derivatives displayed K(i) values in the range from 0.4 to 2.8 microM against relevant gram-positive bacterial DNA polymerase IIIs and antimicrobial activity with MICs in the range from 0.5 to 15 microg/ml against a broad spectrum of gram-positive bacteria, including methicillin-resistant staphylococci and vancomycin-resistant enterococci. Two of these hydrophilic derivatives displayed protective activity in a simple mouse model of lethal staphylococcal infection.</p>
dc.identifier.submissionpathoapubs/183
dc.contributor.departmentDepartment of Pharmacology and Molecular Toxicology
dc.source.pages1982-7


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