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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.


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