Evaluation of the metS and murB loci for antibiotic discovery using targeted antisense RNA expression analysis in Bacillus anthracis.

Evaluation of the metS and murB loci for antibiotic discovery using targeted antisense RNA expression analysis in Bacillus anthracis. Research Abstract Details 

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Evaluation of the metS and murB loci for antibiotic discovery using targeted antisense RNA expression analysis in Bacillus anthracis. Abstract Text:

G C Kedar,Vickie Brown-Driver,Daniel R Reyes,Mark T Hilgers,Mark A Stidham,Karen Joy Shaw,John Finn,Robert J Haselbeck,

The biowarfare-relevant bacterial pathogen Bacillus anthracis contains two paralogs each of the metS and murB genes, which encode the important antibiotic target functions methionyl-tRNA synthetase and UDP-N-acetylenolpyruvoylglucosamine reductase, respectively. Empirical screens were conducted to detect and characterize gene fragments of each of these four genes that could cause growth reduction of B. anthracis when inducibly expressed from a plasmid-borne promoter. Numerous such gene fragments that were overwhelmingly in the antisense orientation were identified for the metS1 and murB2 alleles, while no such orientation bias was seen for the metS2 and murB1 alleles. Gene replacement mutagenesis was used to confirm the essentiality of the metS1 and murB2 alleles, and the nonessentiality of the metS2 and murB1 alleles, for vegetative growth. Induced transcription of RNA from metS1 and murB2 antisense-oriented gene fragments resulted in specific reduction of mRNA of their cognate genes. Attenuation of MetS1 enzyme expression hypersensitized B. anthracis cells to a MetS-specific antimicrobial compound but not to other antibiotics that affect cell wall assembly, fatty acid biosynthesis, protein translation, or DNA replication. Antisense-dependent reduction of MurB2 enzyme expression caused hypersensitivity to beta-lactam antibiotics, a synergistic response that has also been noted for the MurA-specific antibiotic fosfomycin. These experiments form the basis of mode-of-action detection assays that can be used in the discovery of novel MetS- or MurB-specific antibiotic drugs that are effective against B. anthracis or other gram-positive bacterial pathogens.

Evaluation of the metS and murB loci for antibiotic discovery using targeted antisense RNA expression analysis in Bacillus anthracis. Publishing Authors By Initials

GC Kedar,V Brown-Driver,DR Reyes,MT Hilgers,MA Stidham,KJ Shaw,J Finn,RJ Haselbeck,

For similar nucleic acids, nucleotides, and nucleosides: antisense elements (genetics): rna, antisense research abstracts see: nucleic acids, nucleotides, and nucleosides: antisense elements (genetics): rna, antisense research

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Evaluation of the metS and murB loci for antibiotic discovery using targeted antisense RNA expression analysis in Bacillus anthracis. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Antimicrobial agents and chemotherapy

VOLUME: 51

Page Numbers: 1708-18

Journal Abbreviation:

ISSN: 0066-4804

DAY: 5

MONTH: 03

YEAR: 2007

Evaluation of the metS and murB loci for antibiotic discovery using targeted antisense RNA expression analysis in Bacillus anthracis. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 315061

Evaluation of the metS and murB loci for antibiotic discovery using targeted antisense RNA expression analysis in Bacillus anthracis. Keywords Mesh Terms:

KEYWORDS: RNA, Antisense

MESH TERMS: physiology

Chemical & Substance for Abstract: Evaluation of the metS and murB loci for antibiotic discovery using targeted antisense RNA expression analysis in Bacillus anthracis. Information

Substance Name: Methionine-tRNA Ligase

Registry Number: EC 6.1.1.10

Grant and Affiliation Information for Evaluation of the metS and murB loci for antibiotic discovery using targeted antisense RNA expression analysis in Bacillus anthracis.

AFFILIATION: Trius Therapeutics Inc, San Diego, CA 92121, USA.

Country: United States

AGENCY: United States NIAID

GRANT: R44 AI053009

ACRONYM: AI

MEDLINETA: Antimicrob Agents Chemother

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