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ABSTRACT:
PROVIDER: PRJNA660858 | ENA |
REPOSITORIES: ENA
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Project description:Background: The rapid evolution and dissemination of mobilized colistin resistance gene (mcr) family has revealed as a severe threat to the global public health. Nevertheless, dramatic reduction in the prevalence of mcr-1, the major member of mcr family, was observed after the withdrawal of colistin in animal fodder in China since 2017, demonstrating that colistin acts as a selective stress to promote the dissemination of mcr-1. As the second largest lineage, mcr-3 was firstly discovered in 2017 and has been identified from numerous sources. However, whether the spreading of mcr-3 is driven by colistin remains unknown. Methods: To this end, we investigated the global prevalence of mcr-3 from 2005 to 2022 by an up-to-date systematic review, along with a nation-wide epidemiological study to establish the change of mcr-3 prevalence in China before and after 2017. To investigate the fitness cost imposed by MCR-3 upon bacterial host, in vitro and in vivo competitive assays were employed, along with morphological study and fluorescent observation. Moreover, by replacing non-optimal codons with optimal codons, synonymous mutations were introduced into the 5’-coding region of mcr-3 to study mechanisms accounting for the distinct fitness cost conferred by MCR-1 and MCR-3. Furthermore, by combining AlphaFold and molecular dynamics (MD) simulation, we provided a complete characterization on the putative lipid A binding pocket localized at the linker domain of MCR-3. Crucially, inhibitors targeting at the putative binding pocket of MCR-1 or MCR-3 were identified from small molecules library using the pipeline of virtual screening. Findings: The global prevalence of mcr-3 increased continuously from 2005 to 2022. The average prevalence was 0.18% during 2005-2014 and rapidly increased to 3.41% during 2020-2022. The prevalence of mcr-3 in China increased from 0.79% in 2016 to 5.87% in 2019. We found that the fitness of mcr-3-bearing E. coli and empty plasmid control was comparable but higher than that of mcr-1-positive strain. Although the putative lipid A binding pocket of MCR-3 was similar to that of in MCR-1, mcr-3 occupies remarkable codon bias at the 5’-end of coding region that disrupted the stability of mRNA, further reduced its protein expression in E. coli, resulting in the low fitness burden of bacterial host. Moreover, the 5’-end codon usage frequency appeared as a critical factor related with the evolution of mcr family. Furthermore, based on the similar lipid A binding pocket among MCR family protein, we identified three novel MCR inhibitors targeting at such pocket by screening from small-molecule library, which effectively restored the colistin susceptibility of mcr-bearing E. coli. Interpretation: For the first time, we found that the prevalence of mcr-3 increased continuously during 2016-2019 in China, demonstrating that the withdrawal of colistin in husbandry failed to prevent the dissemination of mcr-3. Our study evidenced that the 5’-end codon bias appeared as a crucial regulator upon the fitness cost conferred by horizontally transferred genes. Most importantly, the putative lipid A binding pocket verified from current study was a promising target site for designing inhibitors against mcr-positive strains.
2025-06-29 | GSE300593 | GEO
Project description:16 mcr-1-positive ST34 Salmonella strains
| PRJEB58788 | ENA
Project description:mcr-positive Salmonella enterica isolates collected from clinical patients. Genome sequencing and assembly
| PRJNA855361 | ENA
Project description:MCR-1 POSITIVE SALMONELLA ENTERICA ISOLATED FROM FOOD IN BRAZIL
| PRJNA508957 | ENA
Project description:To study the role of miRNAs in the transition from latent to active TB and to discover candidate biomarkers that may help predict TB progression, we have employed miRNA microarray expression profiling as a discovery platform to probe the transcriptome of peripheral blood mononuclear cells (PBMCs) with active TB, latent TB infection (LTBI), and healthy donors.Patients were recruited at the Shanghai Public Health Clinical Centre (Shanghai, China) from December, 2008 to May, 2009. The diagnosis of active TB was based on clinical presentation, chest radiography, and acid-fast stain of sputum smear.All the patients were HIV negative, as diagnosed by the Livzon Anti-HIV1/2 EIA Kit (Livzon Pharmaceutical Group Inc., Guangdong, China). Additional tests were also performed to detect hepatitis B virus (HBV) and hepatitis C virus (HCV) by using the Abbott AxSYM anti-HBsAg and HCV 3.0 antibody assay kit (Abbott Laboratories, Illinois) to exclude HBV- and HCV-positive patients (these 2 diseases are highly prevalent in China). Patients with a diabetes history were also excluded because diabetes could increase the risk of TB. Peripheral venous blood was drawn before treatment. Subjects with LTBI and healthy donors both without a history of clinical TB or other infectious diseases were recruited from the staff at the Shanghai Public Health Clinical Centre. TST and IGRA (T-SPOT®.TB, Oxford Immunuotec, Oxfordshire, U.K) results were used to distinguish the two groups. The LTBI group was TST-positive (TST>10 mm) and IGRA-positive while the healthy donors were TST-negative (TST<5 mm) and IGRA-negative.
2011-05-10 | GSE29190 | GEO