Genetic features of persistently antimicrobial drug-susceptible extraintestinal pathogenic Escherichia coli pandemic sequence type 95

Extraintestinal pathogenic Escherichia coli (ExPEC) belonging to multilocus sequence type 95 (ST95) is one of the most widespread ExPEC lineages associated with bloodstream infections (BSI) and urinary tract infections (UTI). In contrast to other widespread ExPEC sequence types, a large proportion ST95 strains remains susceptible to all antimicrobial agents used to treat BSI or UTI. We aimed to identify genomic features of ST95 associated with persistent drug susceptibility. We conducted a genome-wide association study of 80 ExPEC ST95 isolates from patients with BSI or UTI in Northern California, and 1669 ST95 isolates deposited in the Enterobase database. Of the total of 1749 ST95 isolates, we compared whole-genome sequences of 887 drug-susceptible strains and 862 strains resistant to one or more drugs (defined genotypically as strains harboring drug-resistance genes annotated in the ResFinder database) to identify genetic features associated with strains devoid of drug-resistance genes. By a genome-wide association study of 553 UTI and BSI ST95 isolates, we found 44 accessory genes significantly associated with drug susceptibility, six of which encoded hypothetical proteins. Fifteen of these were not found in any of the WGSs of ST131 ExPEC strains, which are frequently multidrug-resistant, and eight of these genes were annotated to encode transporter or transfer systems. These findings highlight the potential mechanisms by which ST95 strains may resist the acquisition of mobile DNA elements carrying drug-resistance genes.

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A Genome-Wide Association Study Identifies Two Novel Promising Candidate Genes Affecting Escherichia coli F4ab/F4ac Susceptibility in Swine

PLoS ONE ◽

10.1371/journal.pone.0032127 ◽

2012 ◽

Vol 7 (3) ◽

pp. e32127 ◽

Cited By ~ 24

Author(s):

Wei-Xuan Fu ◽

Yang Liu ◽

Xin Lu ◽

Xiao-Yan Niu ◽

Xiang-Dong Ding ◽

...

Keyword(s):

Escherichia Coli ◽

Association Study ◽

Candidate Genes ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Promising Candidate ◽

Genome Wide ◽

A Genome

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Mutations in dnaA and a cryptic interaction site increase drug resistance in Mycobacterium tuberculosis

PLoS Pathogens ◽

10.1371/journal.ppat.1009063 ◽

2020 ◽

Vol 16 (11) ◽

pp. e1009063

Author(s):

Nathan D. Hicks ◽

Samantha R. Giffen ◽

Peter H. Culviner ◽

Michael C. Chao ◽

Charles L. Dulberger ◽

...

Keyword(s):

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Genome Wide Association Study ◽

Critical Concentration ◽

Drug Susceptibility ◽

Interaction Site ◽

Clinical Strains ◽

Synonymous Mutations ◽

Genome Wide ◽

A Genome

Genomic dissection of antibiotic resistance in bacterial pathogens has largely focused on genetic changes conferring growth above a single critical concentration of drug. However, reduced susceptibility to antibiotics—even below this breakpoint—is associated with poor treatment outcomes in the clinic, including in tuberculosis. Clinical strains of Mycobacterium tuberculosis exhibit extensive quantitative variation in antibiotic susceptibility but the genetic basis behind this spectrum of drug susceptibility remains ill-defined. Through a genome wide association study, we show that non-synonymous mutations in dnaA, which encodes an essential and highly conserved regulator of DNA replication, are associated with drug resistance in clinical M. tuberculosis strains. We demonstrate that these dnaA mutations specifically enhance M. tuberculosis survival during isoniazid treatment via reduced expression of katG, the activator of isoniazid. To identify DnaA interactors relevant to this phenotype, we perform the first genome-wide biochemical mapping of DnaA binding sites in mycobacteria which reveals a DnaA interaction site that is the target of recurrent mutation in clinical strains. Reconstructing clinically prevalent mutations in this DnaA interaction site reproduces the phenotypes of dnaA mutants, suggesting that clinical strains of M. tuberculosis have evolved mutations in a previously uncharacterized DnaA pathway that quantitatively increases resistance to the key first-line antibiotic isoniazid. Discovering genetic mechanisms that reduce drug susceptibility and support the evolution of high-level drug resistance will guide development of biomarkers capable of prospectively identifying patients at risk of treatment failure in the clinic.

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A Genome-Wide Association Study of Resistance to Stripe Rust (Puccinia striiformis f. sp. tritici) in a Worldwide Collection of Hexaploid Spring Wheat (Triticum aestivum L.)

G3 Genes|Genome|Genetics ◽

10.1534/g3.114.014563 ◽

2015 ◽

Vol 5 (3) ◽

pp. 449-465 ◽

Cited By ~ 118

Author(s):

Marco Maccaferri ◽

Junli Zhang ◽

Peter Bulli ◽

Zewdie Abate ◽

Shiaoman Chao ◽

...

Keyword(s):

Association Study ◽

Stripe Rust ◽

Spring Wheat ◽

Resistance Genes ◽

Genome Wide Association Study ◽

Puccinia Striiformis ◽

Infection Type ◽

Genome Wide Association ◽

Genome Wide ◽

A Genome

Abstract New races of Puccinia striiformis f. sp. tritici (Pst), the causal pathogen of wheat stripe rust, show high virulence to previously deployed resistance genes and are responsible for large yield losses worldwide. To identify new sources of resistance we performed a genome-wide association study (GWAS) using a worldwide collection of 1000 spring wheat accessions. Adult plants were evaluated under field conditions in six environments in the western United States, and seedlings were tested with four Pst races. A single-nucleotide polymorphism (SNP) Infinium 9K-assay provided 4585 SNPs suitable for GWAS. High correlations among environments and high heritabilities were observed for stripe rust infection type and severity. Greater levels of Pst resistance were observed in a subpopulation from Southern Asia than in other groups. GWAS identified 97 loci that were significant for at least three environments, including 10 with an experiment-wise adjusted Bonferroni probability < 0.10. These 10 quantitative trait loci (QTL) explained 15% of the phenotypic variation in infection type, a percentage that increased to 45% when all QTL were considered. Three of these 10 QTL were mapped far from previously identified Pst resistance genes and QTL, and likely represent new resistance loci. The other seven QTL mapped close to known resistance genes and allelism tests will be required to test their relationships. In summary, this study provides an integrated view of stripe rust resistance resources in spring wheat and identifies new resistance loci that will be useful to diversify the current set of resistance genes deployed to control this devastating disease.

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