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A novel resistance mechanism against beta-lactams in Streptococcus pneumoniae involves CpoA, a putative glycosyltransferase.

ABSTRACT: Piperacillin resistance in Streptococcus pneumoniae was mediated by mutations in a novel gene, cpoA, that also confer transformation deficiency and a decrease in penicillin-binding protein la. cpoA is part of an operon located downstream of the primary sigma factor of S. pneumoniae. The deduced protein, CpoA, and the peptide encoded by the adjacent 3' open reading frame contained domains homologous to glycosyltransferases of procaryotes and eucaryotes that act on membrane-associated substrates, such as enzymes functioning in lipopolysaccharide core biosynthesis of gram-negative bacteria, RodD of Bacillus subtilis, which is involved in teichoic acid biosynthesis, and the human PIG-A protein, which is required for early steps of glycosylphosphatidylinositol anchor biosynthesis. This suggests that the cpo operon has a similar function related to cell surface components.

SUBMITTER: Grebe T

PROVIDER: S-EPMC179116 | biostudies-other | 1997 May

REPOSITORIES: biostudies-other

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A novel resistance mechanism against beta-lactams in Streptococcus pneumoniae involves CpoA, a putative glycosyltransferase.

Grebe T T Paik J J Hakenbeck R R

Journal of bacteriology 19970501 10

Piperacillin resistance in Streptococcus pneumoniae was mediated by mutations in a novel gene, cpoA, that also confer transformation deficiency and a decrease in penicillin-binding protein la. cpoA is part of an operon located downstream of the primary sigma factor of S. pneumoniae. The deduced protein, CpoA, and the peptide encoded by the adjacent 3' open reading frame contained domains homologous to glycosyltransferases of procaryotes and eucaryotes that act on membrane-associated substrates, ...[more]

PMID: 9150233

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Project description:Streptococcus pneumoniae is a major pathogen in the community and presents high rates of resistance to the available antibiotics. To prevent antibiotic treatment failure caused by highly resistant bacteria, increasing the prescribed antibiotic dose has recently been suggested. The aim of the present study was to assess the influence of beta-lactam prescribed doses on the emergence of resistance and selection in the community. A mathematical model was constructed by combining S. pneumoniae pharmacodynamic and population-dynamic approaches. The received-dose heterogeneity in the population was specifically modeled. Simulations over a 50-year period were run to test the effects of dose distribution and antibiotic exposure frequency changes on community resistance patterns, as well as the accuracy of the defined daily dose as a predictor of resistance. When the frequency of antibiotic exposure per year was kept constant, dose levels had a strong impact on the levels of resistance after a 50-year simulation. The lowest doses resulted in a high prevalence of nonsusceptible strains (> or =70%) with MICs that were still low (1 mg/liter), whereas high doses resulted in a lower prevalence of nonsusceptible strains (<40%) and higher MICs (2 mg/liter). Furthermore, by keeping the volume of antibiotics constant in the population, different patterns of use (low antibiotic dose and high antibiotic exposure frequency versus high dose and low frequency) could lead to markedly different rates of resistance distribution and prevalence (from 10 to 100%). Our results suggest that pneumococcal resistance patterns in the community are strongly related to the individual beta-lactam doses received: limiting beta-lactam use while increasing the doses could help reduce the prevalence of resistance, although it should select for higher levels of resistance. Surveillance networks are therefore encouraged to collect both daily antibiotic exposure frequencies and individual prescribed doses.

Project description:Antimicrobial resistance is mostly studied by means of phenotypic growth inhibition determinations, in combination with PCR confirmations or further characterization by means of whole genome sequencing (WGS). However, the actual proteins that cause resistance such as enzymes and a lack of porins cannot be detected by these methods. Improvements in liquid chromatography (LC) and mass spectrometry (MS) enabled easier and more comprehensive proteome analysis. In the current study, susceptibility testing, WGS and MS are combined into a multi-omics approach to analyze resistance against frequently used antibiotics within the beta-lactam, aminoglycoside and fluoroquinolone group in E. coli and K. pneumoniae. Our aim was to study which currently known mechanisms of resistance can be detected at the protein level using liquid chromatography-mass spectrometry (LC-MS/MS) and to assess whether these could explain beta-lactam, aminoglycoside, and fluoroquinolone resistance in the studied isolates. Furthermore, we aimed to identify significant protein to resistance correlations which have not yet been described before and to correlate the abundance of different porins in relation to resistance to different classes of antibiotics. Whole genome sequencing, high-resolution LC-MS/MS and antimicrobial susceptibility testing by broth microdilution were performed for 187 clinical E. coli and K. pneumoniae isolates. Resistance genes and proteins were identified using the Comprehensive Antibiotic Resistance Database (CARD). All proteins were annotated using the NCBI RefSeq database and Prokka. Proteins of small spectrum beta-lactamases, extended spectrum beta-lactamases, AmpC beta-lactamases, carbapenemases, and proteins of 16S ribosomal RNA methyltransferases and aminoglycoside acetyltransferases can be detected in E. coli and K. pneumoniae by LC-MS/MS. The detected mechanisms matched with the phenotype in the majority of isolates. Differences in the abundance and the primary structure of other proteins such as porins also correlated with resistance. LC-MS/MS is a different and complementary method which can be used to characterize antimicrobial resistance in detail as not only the primary resistance causing mechanisms are detected, but also secondary enhancing resistance mechanisms.

Dataset Information

A novel resistance mechanism against beta-lactams in Streptococcus pneumoniae involves CpoA, a putative glycosyltransferase.

Publications

A novel resistance mechanism against beta-lactams in Streptococcus pneumoniae involves CpoA, a putative glycosyltransferase.

Similar Datasets

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