Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 1999 Aug;43(8):1982-7.
doi: 10.1128/AAC.43.8.1982.

Inhibitors of DNA polymerase III as novel antimicrobial agents against gram-positive eubacteria

P M Tarantino Jr  1 , C Zhi, G E Wright, N C Brown
Affiliations

Inhibitors of DNA polymerase III as novel antimicrobial agents against gram-positive eubacteria

P M Tarantino Jr et al. Antimicrob Agents Chemother. 1999 Aug.

Abstract

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.

PubMed Disclaimer

Figures

FIG. 1
FIG. 1
Structures and mechanisms of action of AUs which selectively inhibit the gram-positive pol III. (A) Relevant domains of the AU molecule. (B) Equivalence of the base-pairing domains of the guanine (left) and AU (right) molecules. (C) The AU molecule inhibits its pol III target by sequestering it into an inactive DNA-drug-protein complex. PUR, purine; PYR, pyrimidine. (D) Structures of two relevant AUs, EMAU and TMAU.
FIG. 2
FIG. 2
Bactericidal activities of N-3 methoxyalkyl- and hydroxyalkyl-EMAUs against S. aureus (Smith strain). Each of the four agents was tested, as indicated, at its MIC and at four times (4×) its MIC. The MICs of the agents for this strain were as follows: HE-EMAU, 8 mg/ml; ME-EMAU, 16 mg/ml; HP-EMAU, 8 mg/ml; and MP-EMAU, 8 mg/ml. (A) Activities of HE-EMAU and ME-EMAU. (B) Activities of HP-EMAU and MP-EMAU.
See this image and copyright information in PMC

References

    1. Barnes M H, Brown N C. Antibody to B. subtilis DNA polymerase III: use in the purification of enzyme and the study of its structure. Nucleic Acids Res. 1979;6:1203–1219. - PMC - PubMed
    1. Barnes M H, Leo C, Brown N C. DNA polymerase III of gram-positive eubacteria is a zinc metalloprotein conserving an essential finger-like domain. Biochemistry. 1998;37:15254–15260. - PubMed
    1. Barnes M H, Tarantino P M, Spacciapoli P, Yu H, Brown N C, Dybvig K. DNA polymerase III of Mycoplasma pulmonis: isolation and characterization of the enzyme and its structural gene, polC. Mol Microbiol. 1994;13:843–854. - PubMed
    1. Brown, N. C. Unpublished data.
    1. Brown N C, Dudycz L W, Wright G E. Rational design of substrate analogues targeted to selectively inhibit replication-specific DNA polymerases. Drugs Exp Clin Res. 1986;12:555–564. - PubMed

Publication types

MeSH terms

LinkOut - more resources