Quantifying the Evolutionary Conservation of Genes Encoding Multidrug Efflux Pumps in the ESKAPE Pathogens To Identify Antimicrobial Drug Targets

Brooks, Lauren; Ul-Hasan, Sabah; Sistrom, Mark

doi:10.1128/msystems.00024-18

Cited by 23 publications

(15 citation statements)

References 41 publications

(40 reference statements)

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“…In this regard, the genus-level analysis and comparison of Enterobacter spp. versus K. pneumoniae indicates high genetic variation (average nucleotide diversity of 0.16 compared to 0.02) (314). This difference suggests that these individual species may have different mechanisms and evolutionary pressures that govern them.…”

Section: Discussionmentioning

confidence: 99%

Enterobacter spp.: Update on Taxonomy, Clinical Aspects, and Emerging Antimicrobial Resistance

2019

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SUMMARY The genus Enterobacter is a member of the ESKAPE group, which contains the major resistant bacterial pathogens. First described in 1960, this group member has proven to be more complex as a result of the exponential evolution of phenotypic and genotypic methods. Today, 22 species belong to the Enterobacter genus. These species are described in the environment and have been reported as opportunistic pathogens in plants, animals, and humans. The pathogenicity/virulence of this bacterium remains rather unclear due to the limited amount of work performed to date in this field. In contrast, its resistance against antibacterial agents has been extensively studied. In the face of antibiotic treatment, it is able to manage different mechanisms of resistance via various local and global regulator genes and the modulation of the expression of different proteins, including enzymes (β-lactamases, etc.) or membrane transporters, such as porins and efflux pumps. During various hospital outbreaks, the Enterobacter aerogenes and E. cloacae complex exhibited a multidrug-resistant phenotype, which has stimulated questions about the role of cascade regulation in the emergence of these well-adapted clones.

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Section: Discussionmentioning

confidence: 99%

Enterobacter spp.: Update on Taxonomy, Clinical Aspects, and Emerging Antimicrobial Resistance

2019

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“…Early studies have shown that genetic diversity of this gene can be captured by three alleles, differing up to 10% at the level of the nucleotide sequence and 5% in the polypeptide sequence; norAI (Yoshida et al, 1990), norAII (also described as norA23 ) (Noguchi et al, 2004) and norAIII (also described as norA1199 ) (Kaatz et al, 1993). The occurrence of norA variants is also strengthened by a recent study by Brooks et al (2018) that refers to the variability of this gene in a set of over 150 S. aureus strains. Although some studies have been conducted to ascertain the impact of this genetic diversity on the efflux activity of NorA (Schmitz et al, 1998; Sierra et al, 2000; Noguchi et al, 2004), this effect remains unclear.…”

Section: Introductionmentioning

confidence: 91%

Genetic Diversity of norA, Coding for a Main Efflux Pump of Staphylococcus aureus

et al. 2019

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NorA is the best studied efflux system of Staphylococcus aureus and therefore frequently used as a model for investigating efflux-mediated resistance in this pathogen. NorA activity is associated with resistance to fluoroquinolones, several antiseptics and disinfectants and several reports have pointed out the role of efflux systems, including NorA, as a first-line response to antimicrobials in S. aureus. Genetic diversity studies of the gene norA have described three alleles; norAI, norAII and norAIII. However, the epidemiology of these alleles and their impact on NorA activity remains unclear. Additionally, increasing studies do not account for norA variability when establishing relations between resistance phenotypes and norA presence or reported absence, which actually corresponds, as we now demonstrate, to different norA alleles. In the present study we assessed the variability of the norA gene present in the genome of over 1,000 S. aureus isolates, corresponding to 112 S. aureus strains with whole genome sequences publicly available; 917 MRSA strains sourced from a London-based study and nine MRSA isolates collected in a major Hospital in Lisbon, Portugal. Our analyses show that norA is part of the core genome of S. aureus. It also suggests that occurrence of norA variants reflects the population structure of this major pathogen. Overall, this work highlights the ubiquitous nature of norA in S. aureus which must be taken into account when studying the role played by this important determinant on S. aureus resistance to antimicrobials.

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“…Polymyxin E was discovered in the 1940s; yet, later on, it was abandoned in clinical practice due to its increased nephrotoxicity. However, due to the increase of multidrug resistance (MDR) in Gram-negative bacteria, especially in the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), colistin has been applied in clinical practice for the last few years as the last resort treatment option [2,3]. Currently, colistin resistance is considered a serious problem, due to a lack of alternative antibiotics [4,5].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of resazurin-based assay for rapid detection of polymyxin-resistant gram-negative bacteria

et al. 2020

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Background: Colistin resistance is considered a serious problem due to a lack of alternative antibiotics. The Rapid ResaPolymyxin Acinetobacter/Pseudomonas NP test is a resazurin reduction-based technique that relies on the visual detection of bacterial growth in the presence of a defined concentration of colistin. The aim of this study was to evaluate the performance of the Rapid ResaPolymyxin Acinetobacter/Pseudomonas NP test in the detection of colistin susceptibility in common clinical Gram-negative bacteria. Results: A total of 253 clinical isolates from a teaching hospital, including Acinetobacter baumanii (n = 58, 8 colistinresistant), Pseudomonas aeruginosa (n = 61, 11 colistin-resistant), Klebsiella pneumoniae (n = 70, 20 colistin-resistant) and Escherichia coli (n = 64, 14 colistin-resistant) were tested in this study. The sensitivity and specificity of the Rapid ResaPolymyxin Acinetobacter/Pseudomonas NP test compared to Broth microdilution method was 100 and 99%, respectively. Conclusions: Our results suggest that Rapid ResaPolymyxin Acinetobacter/Pseudomonas NP test could be used as an accurate detection method for colistin resistance.

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Quantifying the Evolutionary Conservation of Genes Encoding Multidrug Efflux Pumps in the ESKAPE Pathogens To Identify Antimicrobial Drug Targets

Cited by 23 publications

References 41 publications

Enterobacter spp.: Update on Taxonomy, Clinical Aspects, and Emerging Antimicrobial Resistance

Enterobacter spp.: Update on Taxonomy, Clinical Aspects, and Emerging Antimicrobial Resistance

Genetic Diversity of norA, Coding for a Main Efflux Pump of Staphylococcus aureus

Evaluation of resazurin-based assay for rapid detection of polymyxin-resistant gram-negative bacteria

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