JAC Advance Access originally published online on May 18, 2004
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Journal of Antimicrobial Chemotherapy 2004 54(1):100-108; doi:10.1093/jac/dkh256
JAC vol.54 no.1 © The British Society for Antimicrobial Chemotherapy 2004; all rights reserved.
Differential gene expression in a Bacteroides fragilis metronidazole-resistant mutant
1 Department of Microbiology and Immunology, The Brody School of Medicine, East Carolina University, Greenville, NC, USA; 2 Departamento de Microbiologia, ICB-UFMG, Belo Horizonte, MG, Brazil
* Corresponding author. Tel: +55-31-3499-27-59; Fax: +55-31-3499-27-30; Email: macedo{at}icb.ufmg.br
Objectives: The current work focused on molecular changes in a spontaneous Bacteroides fragilismutant selected by low concentrations of metronidazole as an adaptive response to the drug.
Methods: A metronidazole-resistant strain derived from B. fragilis ATCC 25285 was selected by passage in the presence of drug using 0–4 mg/L gradient plates. Using a combination of proteomics for identification of differentially expressed proteins by two-dimensional electrophoresis and selected mutational analyses by single cross-over insertion and an allelic exchange, we have identified genes involved in the adaptive response to metronidazole.
Results: There are significant changes in the protein profiles of resistant strains. These changes appeared to affect a wide range of metabolic proteins including lactate dehydrogenase (up-regulated) and flavodoxin (down-regulated), which may be involved in electron transfer reactions. Also, the enzymic activity of the pyruvate–ferredoxin oxidoreductase (PorA) complex was impaired. Mutant strains lacking the genes for flavodoxin and PorA were less susceptible to metronidazole than the sensitive parent, and a double flavodoxin/PorA mutant had even less susceptibility but none of the mutants were as resistant as the spontaneous metronidazole-resistant strain.
Conclusions: Overall, the data indicated that there were global changes in the regulation of the physiology of the metronidazole-resistant strain. In addition, flavodoxin was identified as an important contributor to metronidazole sensitivity in B. fragilis.
Keywords: proteomics , anaerobes , drug resistance
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