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Antimicrobial Agents and Chemotherapy, August 2000, p. 2217-2221, Vol. 44, No. 8
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

In Vitro Antimicrobial Activities of Novel Anilinouracils Which Selectively Inhibit DNA Polymerase III of Gram-Positive Bacteria

Jennifer S. Daly,1,2,* Theodore J. Giehl,1 Neal C. Brown,3 Chengxin Zhi,3,dagger George E. Wright,3,dagger and Richard T. Ellison III1,2

Division of Infectious Diseases and Immunology, Department of Medicine1 and Department of Pharmacology and Molecular Toxicology,3 University of Massachusetts Medical School, and UMass Memorial Health Care,2 Worcester, Massachusetts 01655

Received 15 November 1999/Returned for modification 12 March 2000/Accepted 24 May 2000

The 6-anilinouracils are novel dGTP analogs that selectively inhibit the replication-specific DNA polymerase III of gram-positive eubacteria. Two specific derivatives, IMAU (6-[3'-iodo-4'-methylanilino]uracil) and EMAU (6-[3'-ethyl-4'-methylanilino]uracil), were substituted with either a hydroxybutyl (HB) or a methoxybutyl (MB) group at their N3 positions to produce four agents: HB-EMAU, MB-EMAU, HB-IMAU, and MB-IMAU. These four new agents inhibited Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, and Enterococcus faecium. Time-kill assays and broth dilution testing confirmed bactericidal activity. These anilinouracil derivatives represent a novel class of antimicrobials with promising activities against gram-positive bacteria that are resistant to currently available agents, validating replication-specific DNA polymerase III as a new target for antimicrobial development.

* Corresponding author. Mailing address: Division of Infectious Diseases and Immunology, UMass Memorial Health Care, 55 Lake Ave. N., Worcester, MA 01655. Phone: (508) 856-3158. Fax: (506) 856-5981. E-mail: dalyj01{at}ummhc.org.

dagger Present address: GLSynthesis, Inc., Worcester, MA 01605.

Antimicrobial Agents and Chemotherapy, August 2000, p. 2217-2221, Vol. 44, No. 8
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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