Signatures of Selection at Drug Resistance Loci in Mycobacterium tuberculosis

Mortimer, Tatum D; Weber, Alexandra M.; Pepperell, Caitlin S.

doi:10.1128/msystems.00108-17

Cited by 38 publications

(52 citation statements)

References 65 publications

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“…We did not detect an effect of purifying selection on inference of migration in our three population simulation analyses (Appendix S2, Figures S13 and S14), but differences in the strength of purifying selection could contribute to the lineage-specific differences we observed in the size of inferred population expansions: i.e., genome-wide patterns of purifying selection could differ among lineages. Previous evidence has suggested that the fitness trade-offs of drug resistance mutations vary among lineages (Mortimer, Weber, & Pepperell, 2018), making this intriguing possibility potentially feasible.…”

Section: Lineage and Region Specific Patterns Of Migrationmentioning

confidence: 99%

Lineage specific histories of Mycobacterium tuberculosis dispersal in Africa and Eurasia

et al. 2019

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Mycobacterium tuberculosis ( M.tb ) is a globally distributed, obligate pathogen of humans that can be divided into seven clearly defined lineages. An emerging consensus places the origin and global dispersal of M.tb within the past 6,000 years: identifying how the ancestral clone of M.tb spread and differentiated within this timeframe is important for identifying the ecological drivers of the current pandemic. We used Bayesian phylogeographic inference to reconstruct the migratory history of M.tb in Africa and Eurasia and to investigate lineage specific patterns of spread from a geographically diverse sample of 552 M.tb genomes. Applying evolutionary rates inferred with ancient M.tb genome calibration, we estimated the timing of major events in the migratory history of the pathogen. Inferred timings contextualize M.tb dispersal within historical phenomena that altered patterns of connectivity throughout Africa and Eurasia: trans‐Indian Ocean trade in spices and other goods, the Silk Road and its predecessors, the expansion of the Roman Empire, and the European Age of Exploration. We found that Eastern Africa and Southeast Asia have been critical in the dispersal of M.tb . Our results further reveal that M.tb populations have grown through range expansion, as well as in situ, and delineate the independent evolutionary trajectories of bacterial subpopulations underlying the current pandemic.

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Section: Lineage and Region Specific Patterns Of Migrationmentioning

confidence: 99%

Lineage specific histories of Mycobacterium tuberculosis dispersal in Africa and Eurasia

et al. 2019

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“…The use of genomic data to detect homoplasy events is not an uncommon scientific technique [52][53][54]. In Mycobacterium tuberculosis, it is a well-known method to identify advantageous mutations, as they are likely to be associated with phenotypes such as drug resistance, heightened transmissibility, or host adaptation [12][13][14][15]. A similar approach was taken recently by Benjak et al to screen for highly polymorphic genes and genomic regions of Mycobacterium leprae [55].…”

Section: Discussionmentioning

confidence: 99%

“…One can use the Consistency Index to recognize genomic locations subjected to homoplasy, and relate the single-nucleotide polymorphism (SNP) positions that are inconsistent with the phylogeny to antibiotic resistance, as has e.g. been done in multiple studies on Mycobacteria spp [12][13][14][15].…”

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confidence: 99%

Genome-wide analysis inEscherichia coliunravels an unprecedented level of genetic homoplasy associated with cefotaxime resistance

Coolen¹,

Drijver

Verweij

et al. 2020

Preprint

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ABSTRACTCefotaxime (CTX) is a commonly used third-generation cephalosporin (3GC) to treat infections caused by Escherichia coli. Two genetic mechanisms have been associated with 3GC resistance in E. coli. The first is the conjugative transfer of a plasmid harboring antibiotic resistance genes. The second is the introduction of mutations in the promoter region of the ampC β-lactamase gene that cause chromosomal-encoded β-lactamase hyperproduction. A wide variety of promoter mutations related to AmpC hyperproduction have been described. However, their link to a specific 3GC such as CTX resistance has not been reported. Here, we measured CTX MICs in 172 cefoxitin resistant E. coli isolates and performed genome-wide analysis of homoplastic mutations associated with CTX resistance by comparing Illumina whole-genome sequencing data of all isolates to a PacBio tailored-made reference chromosome. We mapped the mutations on the reference chromosome and determined their occurrence in the phylogeny, revealing extreme homoplasy at the −42 position of the ampC promoter. The 24 occurrences of a “T” at the −42 position rather than the wild type “C”, resulted from 18 independent C>T mutations in 5 phylogroups. The −42 C>T mutation was only observed in E. coli lacking a plasmid-encoded ampC gene. The association of the −42 C>T mutation with CTX resistance was confirmed to be significant (FDR < 0.05). To conclude, genome-wide analysis of homoplasy in combination with CTX resistance identifies the −42 C>T mutation of the ampC promotor as significantly associated with CTX resistance and underline the role of recurrent mutations in the spread of antibiotics resistance.Impact StatementIn the past decades, the worldwide spread of extended spectrum beta-lactamases (ESBLs) has led to a substantial increase in the prevalence of resistant common pathogens, thereby restricting available treatment options. Although acquired resistance genes, e.g. ESBLs, get most attention, chromosome-encoded resistance mechanisms may play an important role as well. In E. coli chromosome-encoded β-lactam resistance can be caused by alterations in the promoter region of the ampC gene. To improve our understanding of how frequently these alterations occur, a comprehensive interpretation of the evolution of these mutations is essential. This study is the first to apply genome-wide homoplasy analysis to better perceive adaptation of the E. coli genome to antibiotics. Thereby, this study grants insights into how chromosomal-encoded antibiotic resistance evolves and, by combining genome-wide association studies with homoplasy analyses, provides potential strategies for future association studies into the causes of antibiotics resistance.Data summaryAll data is available under BioProject: PRJNA592140. Raw Illumina sequencing data and metadata of all 171 E. coli isolates used in this study is available from the Sequence Read Archive database under accession no. SAMN15052485 to SAMN15052655. Full reference chromosome of ampC_0069 is available via GenBank accession no. CP046396.1 and NCBI Reference Sequence: NZ_CP046396.1.

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“…Sulfamethoxazole has been the first-line antibiotic agent against Stenotrophomonas for decades and is widely use in agriculture. The usage of specific antibiotic agent has been shown to result in purifying selection in certain genes of resistant strains ( Mortimer et al, 2018 ), because purifying selection on a subset of genes can be intensified in the setting of resistance. After sufficiently long-term usage of the same antibiotic agent, resistance may even reach a point of stabilizing evolution, completely reducing or invaliding the efficiency of the drug ( Cornick et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Genome Sequencing and Comparative Analysis of Stenotrophomonas acidaminiphila Reveal Evolutionary Insights Into Sulfamethoxazole Resistance

Huang

Chen

et al. 2018

Front. Microbiol.

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Stenotrophomonas acidaminiphila is an aerobic, glucose non-fermentative, Gram-negative bacterium that been isolated from various environmental sources, particularly aquatic ecosystems. Although resistance to multiple antimicrobial agents has been reported in S. acidaminiphila, the mechanisms are largely unknown. Here, for the first time, we report the complete genome and antimicrobial resistome analysis of a clinical isolate S. acidaminiphila SUNEO which is resistant to sulfamethoxazole. Comparative analysis among closely related strains identified common and strain-specific genes. In particular, comparison with a sulfamethoxazole-sensitive strain identified a mutation within the sulfonamide-binding site of folP in SUNEO, which may reduce the binding affinity of sulfamethoxazole. Selection pressure analysis indicated folP in SUNEO is under purifying selection, which may be owing to long-term administration of sulfonamide against Stenotrophomonas.

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Signatures of Selection at Drug Resistance Loci in Mycobacterium tuberculosis

Cited by 38 publications

References 65 publications

Lineage specific histories of Mycobacterium tuberculosis dispersal in Africa and Eurasia

Lineage specific histories of Mycobacterium tuberculosis dispersal in Africa and Eurasia

Genome-wide analysis inEscherichia coliunravels an unprecedented level of genetic homoplasy associated with cefotaxime resistance

Genome Sequencing and Comparative Analysis of Stenotrophomonas acidaminiphila Reveal Evolutionary Insights Into Sulfamethoxazole Resistance

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