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Revue Medicale Suisse May 2024Multi-resistant Enterobacterales (MRE) are on the increase worldwide, with the main mechanism of resistance acquisition being horizontal transfer of plasmids coding for...
Multi-resistant Enterobacterales (MRE) are on the increase worldwide, with the main mechanism of resistance acquisition being horizontal transfer of plasmids coding for extended-spectrum betalactamase and/or carbapenemase. Low- and middle-income countries are the most affected, but surveillance in low-endemicity countries, such as Switzerland, is essential. International travel is one of the sources of MRE dissemination in the community, with the main risk factors for acquiring MRE being a stay in South or Southeast Asia and the use of antibiotics during travel. Other factors, notably animal and environmental, also explain this increase. Measures encompassing a One Health approach are therefore needed to address this issue.
Topics: Humans; Travel; Enterobacteriaceae Infections; Enterobacteriaceae; Drug Resistance, Multiple, Bacterial; Anti-Bacterial Agents; Risk Factors; Animals; One Health; Plasmids; beta-Lactamases
PubMed: 38693798
DOI: 10.53738/REVMED.2024.20.872.866 -
Structure (London, England : 1993) Nov 2023Multidrug resistance-associated protein 4 (MRP4) is an ATP-binding cassette (ABC) transporter expressed at multiple tissue barriers where it actively extrudes a wide...
Multidrug resistance-associated protein 4 (MRP4) is an ATP-binding cassette (ABC) transporter expressed at multiple tissue barriers where it actively extrudes a wide variety of drug compounds. Overexpression of MRP4 provides resistance to clinically used antineoplastic agents, making it a highly attractive therapeutic target for countering multidrug resistance. Here, we report cryo-EM structures of multiple physiologically relevant states of lipid bilayer-embedded human MRP4, including complexes between MRP4 and two widely used chemotherapeutic agents and a complex between MRP4 and its native substrate. The structures display clear similarities and distinct differences in the coordination of these chemically diverse substrates and, in combination with functional and mutational analysis, reveal molecular details of the transport mechanism. Our study provides key insights into the unusually broad substrate specificity of MRP4 and constitutes an important contribution toward a general understanding of multidrug transporters.
Topics: Humans; Antineoplastic Agents; ATP-Binding Cassette Transporters; Drug Resistance, Multiple; Membrane Transport Proteins; Multidrug Resistance-Associated Proteins
PubMed: 37683641
DOI: 10.1016/j.str.2023.08.014 -
Microbial Genomics Aug 2023Tuberculosis is a global pandemic disease with a rising burden of antimicrobial resistance. As a result, the World Health Organization (WHO) has a goal of enabling...
Tuberculosis is a global pandemic disease with a rising burden of antimicrobial resistance. As a result, the World Health Organization (WHO) has a goal of enabling universal access to drug susceptibility testing (DST). Given the slowness of and infrastructure requirements for phenotypic DST, whole-genome sequencing, followed by genotype-based prediction of DST, now provides a route to achieving this. Since a central component of genotypic DST is to detect the presence of any known resistance-causing mutations, a natural approach is to use a reference graph that allows encoding of known variation. We have developed DrPRG (Drug resistance Prediction with Reference Graphs) using the bacterial reference graph method Pandora. First, we outline the construction of a drug resistance reference graph. The graph is built from a global dataset of isolates with varying drug susceptibility profiles, thus capturing common and rare resistance- and susceptible-associated haplotypes. We benchmark DrPRG against the existing graph-based tool Mykrobe and the haplotype-based approach of TBProfiler using 44 709 and 138 publicly available Illumina and Nanopore samples with associated phenotypes. We find that DrPRG has significantly improved sensitivity and specificity for some drugs compared to these tools, with no significant decreases. It uses significantly less computational memory than both tools, and provides significantly faster runtimes, except when runtime is compared to Mykrobe with Nanopore data. We discover and discuss novel insights into resistance-conferring variation for - including deletion of genes and - and suggest mutations that may warrant reclassification as associated with resistance.
Topics: Humans; Mycobacterium tuberculosis; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial; Tuberculosis
PubMed: 37552534
DOI: 10.1099/mgen.0.001081 -
International Journal of Food... Oct 2023Salmonella enterica serovar Infantis is an emergent foodborne and zoonotic Salmonella serovar with critical implications for global health. In recent years, the... (Review)
Review
Salmonella enterica serovar Infantis is an emergent foodborne and zoonotic Salmonella serovar with critical implications for global health. In recent years, the prevalence of S. Infantis infections has increased in the United States, Europe, and Latin America, due to contaminated chicken and other foods. An essential trait of S. Infantis is its resistance to multiple antibiotics, including the critically important third-generation cephalosporins and quinolones, undermining effective medical treatment, particularly in low-resource settings. We describe the emergence of multidrug-resistant (MDR) S. Infantis, focusing on humans, animals, the environment, and food. We conducted a systematic review (1979-2021), selected 183 studies, and analyzed the origin, source, antimicrobial resistance, and presence of a conjugative plasmid of emerging S. Infantis (pESI) in reported isolates. S. Infantis has been detected worldwide, with a substantial increase since 2011. We found the highest number of isolations in the Americas (42.9 %), Europe (29.8 %), Western Pacific (17.2 %), Eastern Mediterranean (6.6 %), Africa (3.4 %), and South-East Asia (0.1 %). S. Infantis showed MDR patterns and numerous resistant genes in all sources. The primary source of MDR S. Infantis is broiler and their meat; however, this emerging pathogen is also present in other reservoirs such as food, wildlife, and the environment. Clinical cases of MDR S. Infantis have been reported in children and adults. The global emergence of S. Infantis is related to a plasmid (pESI) with antibiotic and arsenic- and mercury-resistance genes. Additionally, a new megaplasmid (pESI-like), carrying bla and antibiotic-resistant genes reported in an ancestral version, was detected in the broiler, human, and chicken meat isolates. Strains harboring pESI-like were primarily observed in the Americas and Europe. MDR S. Infantis has spread globally, potentially becoming a major public health threat, particularly in low- and middle-income countries.
Topics: Child; Animals; Humans; Salmonella enterica; Serogroup; Chickens; Drug Resistance, Multiple, Bacterial; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 37406596
DOI: 10.1016/j.ijfoodmicro.2023.110297 -
Drug Resistance Updates : Reviews and... Mar 2024Multidrug resistance protein 7 (MRP7), also known as ATP-binding cassette (ABC) transporter subfamily C10 (ABCC10), is an ABC transporter that was first identified in... (Review)
Review
Multidrug resistance protein 7 (MRP7), also known as ATP-binding cassette (ABC) transporter subfamily C10 (ABCC10), is an ABC transporter that was first identified in 2001. ABCC10/MRP7 is a 171 kDa protein located on the basolateral membrane of cells. ABCC10/MRP7 consists of three transmembrane domains and two nucleotide binding domains. It mediates multidrug resistance of tumor cells to a variety of anticancer drugs by increasing drug efflux and results in reducing intracellular drug accumulation. The transport substrates of ABCC10/MRP7 include antineoplastic drugs such as taxanes, vinca alkaloids, and epothilone B, as well as endobiotics such as leukotriene C4 (LTC) and estradiol 17 β-D-glucuronide. A variety of ABCC10/MRP7 inhibitors, including cepharanthine, imatinib, erlotinib, tariquidar, and sildenafil, can reverse ABCC10/MRP7-mediated MDR. Additionally, the presence or absence of ABCC10/MRP7 is also closely related to renal tubular dysfunction, obesity, and other diseases. In this review, we discuss: 1) Structure and functions of ABCC10/MRP7; 2) Known substrates and inhibitors of ABCC10/MRP7 and their potential therapeutic applications in cancer; and 3) Role of ABCC10/MRP7 in non-cancerous diseases.
Topics: Humans; Multidrug Resistance-Associated Proteins; Antineoplastic Agents; Drug Resistance, Neoplasm; Drug Resistance, Multiple; Imatinib Mesylate; Neoplasms
PubMed: 38330827
DOI: 10.1016/j.drup.2024.101062 -
Scientific Reports Oct 2023Tuberculosis disease (TB), caused by Mycobacterium tuberculosis, is a major global public health problem, resulting in more than 1 million deaths each year. Drug...
Tuberculosis disease (TB), caused by Mycobacterium tuberculosis, is a major global public health problem, resulting in more than 1 million deaths each year. Drug resistance (DR), including multi-drug (MDR-TB), is making TB control difficult and accounts for 16% of new and 48% of previously treated cases. To further complicate treatment decision-making, many clinical studies have reported patients harbouring multiple distinct strains of M. tuberculosis across the main lineages (L1 to L4). The extent to which drug-resistant strains can be deconvoluted within mixed strain infection samples is understudied. Here, we analysed M. tuberculosis isolates with whole genome sequencing data (n = 50,723), which covered the main lineages (L1 9.1%, L2 27.6%, L3 11.8%, L4 48.3%), with genotypic resistance to isoniazid (HR-TB; n = 9546 (29.2%)), rifampicin (RR-TB; n = 7974 (24.4%)), and at least MDR-TB (n = 5385 (16.5%)). TB-Profiler software revealed 531 (1.0%) isolates with potential mixed sub-lineage infections, including some with DR mutations (RR-TB 21/531; HR-TB 59/531; at least MDR-TB 173/531). To assist with the deconvolution of such mixtures, we adopted and evaluated a statistical Gaussian Mixture model (GMM) approach. By simulating 240 artificial mixtures of different ratios from empirical data across L1 to L4, a GMM approach was able to accurately estimate the DR profile of each lineage, with a low error rate for the estimated mixing proportions (mean squared error 0.012) and high accuracy for the DR predictions (93.5%). Application of the GMM model to the clinical mixtures (n = 531), found that 33.3% (188/531) of samples consisted of DR and sensitive lineages, 20.2% (114/531) consisted of lineages with only DR mutations, and 40.6% (229/531) consisted of lineages with genotypic pan-susceptibility. Overall, our work demonstrates the utility of combined whole genome sequencing data and GMM statistical analysis approaches for providing insights into mono and mixed M. tuberculosis infections, thereby potentially assisting diagnosis, treatment decision-making, drug resistance and transmission mapping for infection control.
Topics: Humans; Mycobacterium tuberculosis; Antitubercular Agents; Coinfection; Tuberculosis, Multidrug-Resistant; Tuberculosis; Mutation; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial
PubMed: 37816829
DOI: 10.1038/s41598-023-44341-x -
Studies in Health Technology and... Nov 2023Salmonella is a food-borne pathogen that can cause zoonoses. The emergence of drug-resistant strains of Salmonella is of great concern. It is necessary to understand the...
Salmonella is a food-borne pathogen that can cause zoonoses. The emergence of drug-resistant strains of Salmonella is of great concern. It is necessary to understand the prevalence of antibiotic resistance, antibiotic resistance genes and virulence genes in human Salmonella. In this study, drug susceptibility test was used to detect and analyze the drug resistance of 24 Salmonella strains collected from human. A multi-drug resistant strain QLUF123 was selected for whole genome sequencing, and its drug resistance genes and virulence genes were analyzed. The results showed that 24 Salmonella strains were resistant to the tested antibiotics, 87.50% of the strains had multi-drug resistance, the resistance rate to ceftazidime, sulfamethoxazole and tilmicosin reached more than 80%. The alignment results based on the whole genome sequence showed that there were multiple types of drug-resistant genes in QLUF123, among which efflux pump system genes were the most abundant, including sdiA, mdtK, baeR and other multidrug-resistant efflux pump system genes. QLUF123 carried 46 kinds of virulence factors and 249 related virulence genes, among which the three functions of secretory system, adhesion and motility accounted for the most virulence genes, accounting for 93.57%. In this study, antibiotic resistance of human Salmonella was detected by drug sensitivity test, and drug resistance and virulence genes in Salmonella were analyzed by whole genome sequencing technology, which is of great significance for scientific treatment and rational drug use of related diseases caused by Salmonella infection.
Topics: Animals; Humans; Virulence; Drug Resistance, Multiple, Bacterial; Salmonella; Virulence Factors; Anti-Bacterial Agents
PubMed: 38007764
DOI: 10.3233/SHTI230864 -
Current Microbiology Aug 2023Salmonella enterica is one of the foodborne pathogens that can infect humans, spreading from one person to another by contaminated food and water. To identify the...
Salmonella enterica is one of the foodborne pathogens that can infect humans, spreading from one person to another by contaminated food and water. To identify the pathogenic S. enterica from the contaminated food product, culture-based and molecular identifications, drug resistance profiling, virulence and genetic traits of the strains have been used. Herein, different animal products was subjected to screen for S. enterica prevalence, pathogenic characterization and compared with clinical Salmonella isolates (human). A total of 173 isolates from animal products and 51 isolates from clinical samples were collected. S. Typhi, S. Agona and S. Ohio were predominant serovars in blood, stool and different animal products. Both, clinical [37% (n = 19/51)] and animal product-associated isolates [21% (n = 37/173)] expressed their highest resistance to nalidixic acid. Thirty-one percentage of (n = 16/51) clinical isolates and 12% (n = 21/173) animal food-associated isolates were resistant to multiple classes of antibiotics. Class 1 integrons encoded by S. Typhi, S. Infantis and S. Emek were screened for sequence analysis, the result revealed that the cassettes encoded-aminoglycoside acetyltransferase and dihydrofolate reductase enzymes. Salmonella pathogenicity island-1 encoded-hilA gene was detected most frequently in all the isolates. PFGE profile revealed the genetic traits of the isolates which were closely linked with antibiotic-resistant properties and virulent characteristics. Only S. Enteritidis, collected from different samples had clonal similarities. In summary, drug-resistant pathogenic Salmonella prevalence was observed in the animal product that could be an important alarm to consumers with the risk of enteric fever and it causes the potential risk to public health.
Topics: Animals; Humans; Salmonella enterica; Phylogeny; Drug Resistance, Multiple, Bacterial; Salmonella; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 37544954
DOI: 10.1007/s00284-023-03343-8 -
European Journal of Clinical... Dec 2023In recent years, multidrug-resistant Acinetobacter baumannii has emerged globally as a major threat to the healthcare system. It is now listed by the World Health... (Review)
Review
In recent years, multidrug-resistant Acinetobacter baumannii has emerged globally as a major threat to the healthcare system. It is now listed by the World Health Organization as a priority one for the need of new therapeutic agents. A. baumannii has the capacity to develop robust biofilms on biotic and abiotic surfaces. Biofilm development allows these bacteria to resist various environmental stressors, including antibiotics and lack of nutrients or water, which in turn allows the persistence of A. baumannii in the hospital environment and further outbreaks. Investigation into therapeutic alternatives that will act on both biofilm formation and antimicrobial resistance (AMR) is sorely needed. The aim of the present review is to critically discuss the various mechanisms by which AMR and biofilm formation may be co-regulated in A. baumannii in an attempt to shed light on paths towards novel therapeutic opportunities. After discussing the clinical importance of A. baumannii, this critical review highlights biofilm-formation genes that may be associated with the co-regulation of AMR. Particularly worthy of consideration are genes regulating the quorum sensing system AbaI/AbaR, AbOmpA (OmpA protein), Bap (biofilm-associated protein), the two-component regulatory system BfmRS, the PER-1 β-lactamase, EpsA, and PTK. Finally, this review discusses ongoing experimental therapeutic strategies to fight A. baumannii infections, namely vaccine development, quorum sensing interference, nanoparticles, metal ions, natural products, antimicrobial peptides, and phage therapy. A better understanding of the mechanisms that co-regulate biofilm formation and AMR will help identify new therapeutic targets, as combined approaches may confer synergistic benefits for effective and safer treatments.
Topics: Humans; Anti-Bacterial Agents; Acinetobacter baumannii; Drug Resistance, Bacterial; Biofilms; Quorum Sensing; Drug Resistance, Multiple, Bacterial
PubMed: 37897520
DOI: 10.1007/s10096-023-04677-8 -
American Journal of Ophthalmology Sep 2023
Topics: Humans; Lubricant Eye Drops; Pseudomonas aeruginosa; Public Health; Anti-Bacterial Agents; Pseudomonas Infections; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial
PubMed: 37336385
DOI: 10.1016/j.ajo.2023.06.011