1887

Abstract

The two-component regulatory system CiaRH of affects β-lactam susceptibility, autolysis, bacteriocin production, competence development, host colonization and virulence. The system was discovered in a screen for R6 mutants resistant to the β-lactam antibiotic cefotaxime. A mutation in the histidine kinase gene led to this phenotype by enhancing CiaR-mediated gene expression. Additional mutations in have been described in other spontaneous β-lactam-resistant mutants of . R6, but their influence on CiaR-mediated gene regulation has not been determined. Likewise, altered alleles are present in clinical isolates, none of which had been characterized. These novel variants were introduced into R6 to measure their ability to activate CiaR-dependent regulation. The alleles from spontaneous mutants obtained in the laboratory increased the activity of CiaR-dependent promoters between four- and 26-fold, while variants from clinical strains were less effective, with a threefold activation at most. Accordingly, phenotypes associated with a hyperactive CiaRH system, β-lactam resistance, and prevention of competence development, were far more pronounced in the laboratory mutants. Amino acid changes affecting CiaH function were positioned throughout the protein. Five of the most activating changes are located close to the conserved histidine and one in the extracytoplasmic sensor domain. The characterization of new alleles of expands the spectrum of CiaH variants, which may help to elucidate signal transduction of this important regulatory system. Our study also demonstrates that alleles overstimulating CiaR regulon expression are present in clinical isolates of .

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2011-11-01
2019-10-17
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