Mapping and sequencing of mutations in the Escherichia colirpoB gene that lead to rifampicin resistance

Jin, Ding Jun; Gross, Carol A.

doi:10.1016/0022-2836(88)90517-7

Cited by 630 publications

(569 citation statements)

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“…39 A caracterização do gene rpoB em Echerichia coli demonstrou que a rifampicina interage especificamente com a subunidade β da RNA polimerase e que mutações no locus rpoB conferem trocas conformacionais, impedindo uma ligação eficiente do fármaco e, conseqüentemente, a resistência. 16,41 Essas informações auxiliaram na compreensão das bases de resistência à RMP em M. tuberculosis. (Figura 1).…”

Section: Resistência à Rifampicinaunclassified

Tuberculose resistente: revisão molecular

et al. 2002

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ResumoO progresso na compreensão dos mecanismos de resistência aos fármacos usados no tratamento da tuberculose tem permitido o desenvolvimento de novos métodos para a detecção da tuberculose resistente. A resistente aos fármacos representa uma ameaça para os programas de controle da tuberculose. Para tanto, é necessário conhecer o padrão de sensibilidade das linhagens para fornecer o tratamento adequado. Os estudos moleculares dos mecanismos de ação dos fármacos antituberculose têm elucidado as bases genéticas da resistência aos fármacos em Mycobacterium tuberculosis. Os mecanismos de resistência aos fármacos na tuberculose são causados por mutações cromossomais em diferentes genes da bactéria. Durante a exposição aos fármacos, há uma pressão seletiva favorecendo o desenvolvimento de linhagens resistentes. A tuberculose multirresistente é um problema nacional e internacional que traz sérias dificuldades para o controle global da doença. Realizou-se uma revisão sobre os mecanismos moleculares associados à resistência aos fármacos com ênfase nas novas perspectivas para detectar os isolados resistentes. AbstractProgress to understanding the basis of resistance to antituberculous drugs has allowed molecular tests for detection of drug-resistant tuberculosis to be developed. Drug-resistant tuberculosis poses a threat to tuberculosis control programs. It is necessary thus to know drug susceptibilities of individual patient's strain to provide the appropriate drug combinations. Molecular studies on the mechanism of action of antituberculous drugs have elucidated the genetic basis of drug resistance in M. tuberculosis. The mechanisms of drug resistance in tuberculosis are a result of chromosomal mutations in different genes of the bacteria. Upon drug exposure there is a selective pressure for such resistant mutants. Multidrug-resistant tuberculosis is a health problem of increasing significance for the whole global community. This paper reviews the molecular mechanisms associated with drugresistance as well the new perspectives for detecting resistant isolates. Current Comments Atualização

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Section: Resistência à Rifampicinaunclassified

Tuberculose resistente: revisão molecular

et al. 2002

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“…The target of Rif is the ␤-subunit of RNA pol, so that mutations that confer Rif R localize to the rpoB gene (10). In particular, Rif R mutations typically fall in one of three clusters of rpoB.…”

Section: Resultsmentioning

confidence: 99%

“…In particular, Rif R mutations typically fall in one of three clusters of rpoB. These regions have been extensively sequenced and characterized in earlier work (10)(11)(12). To examine the mutations in detail, 48 clonal DNA isolates were sequenced for each genotype (wild-type and ileS Ala ) after each time period (1 and 7 days).…”

Section: Resultsmentioning

confidence: 99%

An editing-defective aminoacyl-tRNA synthetase is mutagenic in aging bacteria via the SOS response

Bacher

Schimmel

2007

Proc. Natl. Acad. Sci. U.S.A.

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Mistranslation in bacterial and mammalian cells leads to production of statistical proteins that are, in turn, associated with specific cell or animal pathologies, including death of bacterial cells, apoptosis of mammalian cells in culture, and neurodegeneration in the mouse. A major source of mistranslation comes from heritable defects in the editing activities of aminoacyl-tRNA synthetases. These activities clear errors of aminoacylation by deacylation of mischarged tRNAs. We hypothesized that, in addition to previously reported phenotypes in bacterial and mammalian systems, errors of aminoacylation could be mutagenic and lead to disease. As a first step in testing this hypothesis, the effect of an editing defect in a single tRNA synthetase on the accumulation of mutations in aging bacteria was investigated. A striking, statistically significant, enhancement of the mutation rate in aging bacteria was found. This enhancement comes from an increase in error-prone DNA repair through induction of the bacterial SOS response. Thus, mistranslation, as caused by an editing-defective tRNA synthetase, can lead to heritable genetic changes that could, in principle, be linked to disease.aminoacylation errors ͉ error-prone DNA polymerases ͉ amino acid misincorporation ͉ genetic code ambiguity A s organisms age, mutations accumulate over time owing to direct environmental insults that are incompletely or inaccurately repaired. Recent work directed our attention to the possibility that mistranslation could play a role in producing mutations in aging populations. In particular, mistranslation can arise from editing defects in aminoacyl-tRNA synthetases. These enzymes catalyze the first step of protein synthesis, where each amino acid is linked to its cognate tRNA bearing the anticodon triplet associated with the amino acid. Because of inherent physiochemical limitations of some enzymes to discriminate between structurally similar amino acids, mischarged tRNAs, such as Val-tRNA Ile or Ser-tRNA Ala , are produced. Normally, these mischarged tRNAs are cleared by hydrolytic editing, which occurs at a distinct active site within the synthetase. But even a small defect, caused by a mutation in the editing center, can lead to extreme cell pathologies and disease.For example, mice that carry a mild mutation in the editing domain of alanyl-tRNA synthetase suffer from ataxia (1). The mutant alanyl-tRNA synthetase mischarges tRNA Ala with serine and, as a consequence, mistranslation occurs that leads to induction of the unfolded protein response. That, in turn, leads to the degeneration of Purkinje cells in the cerebellum, beginning within 3 weeks of age. Similarly, in human cell culture, an inducible, editing-defective valyl-tRNA synthetase caused cellular degradation and apoptosis (2).With these recent results in mind, we were motivated to investigate the possibility that mistranslation could also lead to heritable genetic changes. Previously, we generated a knock-in mutant allele of ileS that encodes no functional editing domain (3)....

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“…A portion of the rpoB gene (expected approximate size 708 bp [22]) encompassing three clusters (I, II and III) which relate to rifampicin resistance [15] was also amplified using primers, SALRPOF3…”

Section: Genotypic Characterisationmentioning

confidence: 99%

A new concept to stimulate mucosal as well as systemic immunity by parenteral vaccination as applied to the development of a live attenuatedSalmonella entericaserovar Dublin vaccine

2007

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-A new concept of slow "drip feeding" that enables activation of mucosal as well as systemic immunity following parenteral vaccination was demonstrated using Salmonella Dublin in a mouse model. The live vaccine candidate, N-RM25, generated from a wild S. Dublin strain utilising metabolic-drift (spontaneous chromosomal) mutations had a unique sensitivity to bile and restricted growth in the presence of a very low concentration of bile salts No. 3 (0.075% (w/v)) but also had the ability to survive in a high concentration (19.2%) of the substance. Following intraperitoneal administration with 10 7 cfu, N-RM25 colonised and survived (10 1 -10 3 cfu/g) in the liver and spleen of mice for over 24 days without causing disease. A small number of the mutant organisms also penetrated the gall bladder and gut, most likely via the enterohepatic circulation. N-RM25 induced significant levels of serum IgG, IgA and intestinal secretory IgA. A second metabolic-drift mutant (R-NM29) that was rapidly eliminated from the liver and spleen and highly unlikely to penetrate the gall bladder and gut, stimulated some systemic immunity, but induced no mucosal immunity because it did not reach the immune stimulation sites within the gut. In vaccine trials, N-RM25 was significantly more effective in eliminating the homologous challenge bacteria (S. Dublin wild strain FD436) from the internal organs and intestinal lumen when compared to R-NM29 and the negative control. N-RM25 prevented the development of systemic infection and produced 100% protection.Salmonella Dublin / bile / live attenuated vaccine / parenteral vaccination / mucosal immunity

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Mapping and sequencing of mutations in the Escherichia colirpoB gene that lead to rifampicin resistance

Cited by 630 publications

References 50 publications

Tuberculose resistente: revisão molecular

Tuberculose resistente: revisão molecular

An editing-defective aminoacyl-tRNA synthetase is mutagenic in aging bacteria via the SOS response

A new concept to stimulate mucosal as well as systemic immunity by parenteral vaccination as applied to the development of a live attenuatedSalmonella entericaserovar Dublin vaccine

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