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Inhibition of Yersinia pestis DNA adenine methyltransferase in vitro by a stibonic acid compound: identification of a potential novel class of antimicrobial agents
Author(s) -
McKelvie JC,
Richards MI,
Harmer JE,
Milne TS,
Roach PL,
Oyston PCF
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02134.x
Subject(s) - yersinia pestis , biology , virulence , dna , dna methylation , methyltransferase , methylation , enzyme , biochemistry , microbiology and biotechnology , gene expression , gene
Background and Purpose Multiple antibiotic resistant strains of plague are emerging, driving a need for the development of novel antibiotics effective against Y ersinia pestis . DNA adenine methylation regulates numerous fundamental processes in bacteria and alteration of DNA adenine methlytransferase ( D am) expression is attenuating for several pathogens, including Y . pestis . The lack of a functionally similar enzyme in humans makes D am a suitable target for development of novel therapeutics for plague. Experimental Approach Compounds were evaluated for their ability to inhibit D am activity in a high‐throughput screening assay. DNA was isolated from Y ersinia grown in the presence of lead compounds and restricted to determine the effect of inhibitors on DNA methylation. Transcriptional analysis was undertaken to determine the effect of an active inhibitor on virulence‐associated phenotypes. Key Results We have identified a series of aryl stibonic acids which inhibit D am in vitro . The most active, 4‐stibonobenzenesulfonic acid, exhibited a competitive mode of inhibition with respect to DNA and a K i of 6.46 n M . One compound was found to inhibit DNA methylation in cultured Y . pestis . The effects of this inhibition on the physiology of the cell were widespread, and included altered expression of known virulence traits, including iron acquisition and T ype III secretion. Conclusions and Implications We have identified a novel class of potent D am inhibitors. Treatment of bacterial cell cultures with these inhibitors resulted in a decrease in DNA methylation. Expression of virulence factors was affected, suggesting these inhibitors may attenuate bacterial infectivity and function as antibiotics.