AAC
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tarantino, P. M.
Right arrow Articles by Brown, N. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tarantino, P. M., Jr.
Right arrow Articles by Brown, N. C.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, August 1999, p. 1982-1987, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Inhibitors of DNA Polymerase III as Novel Antimicrobial Agents against Gram-Positive Eubacteria

Paul M. Tarantino Jr.,dagger Chengxin Zhi, George E. Wright,dagger and Neal C. Brown*

Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical School, Worcester, Massachusetts 01655

Received 14 December 1998/Returned for modification 22 March 1999/Accepted 2 June 1999

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 Ki values in the range from 0.4 to 2.8 µM against relevant gram-positive bacterial DNA polymerase IIIs and antimicrobial activity with MICs in the range from 0.5 to 15 µg/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.


* Corresponding author. Mailing address: Dept. of Pharmacology and Molecular Toxicology, University of Massachusetts Medical School, Worcester, MA 01655. Phone: (508) 856-2152. Fax: (508) 856-5080. E-mail: neal.brown{at}ummed.edu.

dagger Present address: GLSynthesis, Inc., 222 Maple Ave., Shrewsbury, MA 01545.


Antimicrobial Agents and Chemotherapy, August 1999, p. 1982-1987, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.



This article has been cited by other articles:




Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
Clin. Vaccine Immunol. Clin. Microbiol. Rev.
J. Clin. Microbiol. ALL ASM JOURNALS

Copyright © 1999 by the American Society for Microbiology. All rights reserved.