Dataset Information

Global Burden of Colistin-Resistant Bacteria: Mobilized Colistin Resistance Genes Study (1980-2018).

ABSTRACT: Colistin is considered to be an antimicrobial of last-resort for the treatment of multidrug-resistant Gram-negative bacterial infections. The recent global dissemination of mobilized colistin resistance (mcr) genes is an urgent public health threat. An accurate estimate of the global prevalence of mcr genes, their reservoirs and the potential pathways for human transmission are required to implement control and prevention strategies, yet such data are lacking. Publications from four English (PubMed, Scopus, the Cochrane Database of Systematic Reviews and Web of Science) and two Chinese (CNKI and WANFANG) databases published between 18 November 2015 and 30 December 2018 were identified. In this systematic review and meta-analysis, the prevalence of mcr genes in bacteria isolated from humans, animals, the environment and food products were investigated. A total of 974 publications were identified. 202 observational studies were included in the systematic review and 71 in the meta-analysis. mcr genes were reported from 47 countries across six continents and the overall average prevalence was 4.7% (0.1-9.3%). China reported the highest number of mcr-positive strains. Pathogenic Escherichia coli (54%), isolated from animals (52%) and harboring an IncI2 plasmid (34%) were the bacteria with highest prevalence of mcr genes. The estimated prevalence of mcr-1 pathogenic E. coli was higher in food-animals than in humans and food products, which suggests a role for foodborne transmission. This study provides a comprehensive assessment of prevalence of the mcr gene by source, organism, genotype and type of plasmid.

SUBMITTER: Elbediwi M

PROVIDER: S-EPMC6843232 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Global Burden of Colistin-Resistant Bacteria: Mobilized Colistin Resistance Genes Study (1980-2018).

Elbediwi Mohammed M Li Yan Y Paudyal Narayan N Pan Hang H Li Xiaoliang X Xie Shaohua S Rajkovic Andreja A Feng Youjun Y Fang Weihuan W Rankin Shelley C SC Yue Min M

Microorganisms 20191016 10

Colistin is considered to be an antimicrobial of last-resort for the treatment of multidrug-resistant Gram-negative bacterial infections. The recent global dissemination of mobilized colistin resistance (<i>mcr</i>) genes is an urgent public health threat. An accurate estimate of the global prevalence of <i>mcr</i> genes, their reservoirs and the potential pathways for human transmission are required to implement control and prevention strategies, yet such data are lacking. Publications from fou ...[more]

PMID: 31623244

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Project description:BackgroundThe high incidence of bacterial genes that confer resistance to last-resort antibiotics, such as colistin, caused by mobilized colistin resistance (mcr) genes, poses an unprecedented threat to human health. Understanding the spread, evolution, and distribution of such genes among human populations will help in the development of strategies to diminish their occurrence. To tackle this problem, we investigated the distribution and prevalence of potential mcr genes in the human gut microbiome using a set of bioinformatics tools to screen the Unified Human Gastrointestinal Genome (UHGG) collection for the presence, synteny and phylogeny of putative mcr genes, and co-located antibiotic resistance genes.ResultsA total of 2079 antibiotic resistance genes (ARGs) were classified as mcr genes in 2046 metagenome assembled genomes (MAGs), distributed across 1596 individuals from 41 countries, of which 215 were identified in plasmidial contigs. The genera that presented the largest number of mcr-like genes were Suterella and Parasuterella. Other potential pathogens carrying mcr genes belonged to the genus Vibrio, Escherichia and Campylobacter. Finally, we identified a total of 22,746 ARGs belonging to 21 different classes in the same 2046 MAGs, suggesting multi-resistance potential in the corresponding bacterial strains, increasing the concern of ARGs impact in the clinical settings.ConclusionThis study uncovers the diversity of mcr-like genes in the human gut microbiome. We demonstrated the cosmopolitan distribution of these genes in individuals worldwide and the co-presence of other antibiotic resistance genes, including Extended-spectrum Beta-Lactamases (ESBL). Also, we described mcr-like genes fused to a PAP2-like domain in S. wadsworthensis. These novel sequences increase our knowledge about the diversity and evolution of mcr-like genes. Future research should focus on activity, genetic mobility and a potential colistin resistance in the corresponding strains to experimentally validate those findings.

Project description:Mobilized colistin resistance (mcr) genes are plasmid-borne genes that confer resistance to colistin, an antibiotic used to treat severe bacterial infections. To date, eight known mcr homologues have been described (mcr-1 to -8). Here, we describe mcr-9, a novel mcr homologue detected during routine in silico screening of sequenced Salmonella genomes for antimicrobial resistance genes. The amino acid sequence of mcr-9, detected in a multidrug-resistant (MDR) Salmonella enterica serotype Typhimurium (S Typhimurium) strain isolated from a human patient in Washington State in 2010, most closely resembled mcr-3, aligning with 64.5% amino acid identity and 99.5% coverage using Translated Nucleotide BLAST (tblastn). The S. Typhimurium strain was tested for phenotypic resistance to colistin and was found to be sensitive at the 2-mg/liter European Committee on Antimicrobial Susceptibility Testing breakpoint under the tested conditions. mcr-9 was cloned in colistin-susceptible Escherichia coli NEB5α under an IPTG (isopropyl-β-d-thiogalactopyranoside)-induced promoter to determine whether it was capable of conferring resistance to colistin when expressed in a heterologous host. Expression of mcr-9 conferred resistance to colistin in E. coli NEB5α at 1, 2, and 2.5 mg/liter colistin, albeit at a lower level than mcr-3 Pairwise comparisons of the predicted protein structures associated with all nine mcr homologues (Mcr-1 to -9) revealed that Mcr-9, Mcr-3, Mcr-4, and Mcr-7 share a high degree of similarity at the structural level. Our results indicate that mcr-9 is capable of conferring phenotypic resistance to colistin in Enterobacteriaceae and should be immediately considered when monitoring plasmid-mediated colistin resistance.IMPORTANCE Colistin is a last-resort antibiotic that is used to treat severe infections caused by MDR and extensively drug-resistant (XDR) bacteria. The World Health Organization (WHO) has designated colistin as a "highest priority critically important antimicrobial for human medicine" (WHO, Critically Important Antimicrobials for Human Medicine, 5th revision, 2017, https://www.who.int/foodsafety/publications/antimicrobials-fifth/en/), as it is often one of the only therapies available for treating serious bacterial infections in critically ill patients. Plasmid-borne mcr genes that confer resistance to colistin pose a threat to public health at an international scale, as they can be transmitted via horizontal gene transfer and have the potential to spread globally. Therefore, the establishment of a complete reference of mcr genes that can be used to screen for plasmid-mediated colistin resistance is essential for developing effective control strategies.

Project description:ImportanceGastric cancer is one of the most common cancers, with a high mortality-to-incidence ratio. It is uncertain whether developed nations may encounter an increasing burden of gastric cancer in young adults, as occurs for other cancers.ObjectivesTo evaluate the incidence and mortality of gastric cancer and compare the global incidence trends between younger (<40 years) and older (≥40 years) populations.Design, setting, and participantsThis population-based cohort study analyzed data from global and national cancer registries, including data from 1980 to 2018, with at least 15 calendar years of incidence and mortality data. Data on age-standardized incidence and mortality rates of gastric cancer among 48 countries were retrieved from the Surveillance, Epidemiology, and End Results Program, the National Cancer Institute, the Nordic Cancer Registries, and the World Health Organization Mortality Database. The 10-year incidence trend of gastric cancer was assessed by age and sex. The 2018 GLOBOCAN database was used for reporting the global incidence and mortality of gastric cancer, the most recent data available at the time of analysis. Analyses were performed between January 10, 2020, and March 20, 2020.Main outcomes and measuresThe average annual percent change (AAPC) of the incidence and mortality trends as evaluated by joinpoint regression analysis.ResultsA total of 1 033 701 new cases of gastric cancer and 782 685 related deaths were reported in 2018. Overall, the incidence of gastric cancer decreased in 29 countries, and mortality decreased in 41 countries. The age-standardized incidence of gastric cancer decreased from a range of 2.6 to 59.1 in 1980 to a range of 2.5 to 56.8 in 2018 per 100 000 persons. The overall age-standardized mortality rate changed from a range of 1.3 to 25.8 in 1980 to a range of 1.5 to 18.5 in 2018 per 100 000 persons, but increasing mortality was observed in Thailand (female: AAPC, 5.30; 95% CI, 4.38-6.23; P < .001; male: AAPC, 3.92; 95% CI, 2.14-5.74; P < .001). The incidence of gastric cancer decreased in most regions among individuals 40 years or older and increased in populations younger than 40 years in several countries, including Sweden (male: AAPC, 13.92; 95% CI, 7.16-21.11; P = .001), Ecuador (female: AAPC, 6.05; 95% CI, 1.40-10.92; P = .02), and the UK (male: AAPC, 4.27; 95% CI, 0.15-8.55; P = .04; female: AAPC, 3.60; 95% CI, 3.59-3.61; P < .001).Conclusions and relevanceIn this population-based cohort study, an increasing incidence of gastric cancer was observed in younger individuals in some countries, highlighting the need for more preventive strategies in younger populations. Future research should explore the reasons for these epidemiologic trends.

Project description:Mobilized colistin resistance genes (mcr) may confer resistance to the last-resort antimicrobial colistin and can often be transmitted horizontally. mcr encode phosphoethanolamine transferases (PET), which are closely related to chromosomally encoded, intrinsic lipid modification PET (i-PET; e.g., EptA, EptB, CptA). To gain insight into the evolution of mcr within the context of i-PET, we identified 69,814 MCR-like proteins present across 256 bacterial genera (obtained by querying known MCR family representatives against the National Center for Biotechnology Information [NCBI] non-redundant protein database via protein BLAST). We subsequently identified 125 putative novel mcr-like genes, which were located on the same contig as (i) ≥1 plasmid replicon and (ii) ≥1 additional antimicrobial resistance gene (obtained by querying the PlasmidFinder database and NCBI's National Database of Antibiotic Resistant Organisms, respectively, via nucleotide BLAST). At 80% amino acid identity, these putative novel MCR-like proteins formed 13 clusters, five of which represented putative novel MCR families. Sequence similarity and a maximum likelihood phylogeny of mcr, putative novel mcr-like, and ipet genes indicated that sequence similarity was insufficient to discriminate mcr from ipet genes. A mixed-effect model of evolution (MEME) indicated that site- and branch-specific positive selection played a role in the evolution of alleles within the mcr-2 and mcr-9 families. MEME suggested that positive selection played a role in the diversification of several residues in structurally important regions, including (i) a bridging region that connects the membrane-bound and catalytic periplasmic domains, and (ii) a periplasmic loop juxtaposing the substrate entry tunnel. Moreover, eptA and mcr were localized within different genomic contexts. Canonical eptA genes were typically chromosomally encoded in an operon with a two-component regulatory system or adjacent to a TetR-type regulator. Conversely, mcr were represented by single-gene operons or adjacent to pap2 and dgkA, which encode a PAP2 family lipid A phosphatase and diacylglycerol kinase, respectively. Our data suggest that eptA can give rise to "colistin resistance genes" through various mechanisms, including mobilization, selection, and diversification of genomic context and regulatory pathways. These mechanisms likely altered gene expression levels and enzyme activity, allowing bona fide eptA to evolve to function in colistin resistance.

Dataset Information

Global Burden of Colistin-Resistant Bacteria: Mobilized Colistin Resistance Genes Study (1980-2018).

Publications

Global Burden of Colistin-Resistant Bacteria: Mobilized Colistin Resistance Genes Study (1980-2018).

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