-
The Journal of Antimicrobial... Jul 2021Data on consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials were collected from 30 EU/European Economic Area (EEA) countries over two... (Review)
Review
OBJECTIVES
Data on consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials were collected from 30 EU/European Economic Area (EEA) countries over two decades. This article reviews temporal trends, seasonal variation, presence of change-points and changes in the composition of main subgroups of tetracyclines, sulphonamides and trimethoprim and other antibacterials.
METHODS
For the period 1997-2017, data on consumption of tetracyclines (ATC group J01A), sulphonamides and trimethoprim (ATC group J01E), and other antibacterials (ATC group J01X) in the community and aggregated at the level of the active substance, were collected using the WHO ATC/DDD methodology (ATC/DDD index 2019). Consumption was expressed in DDD per 1000 inhabitants per day and in packages per 1000 inhabitants per day. Consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials was analysed based on ATC-4 subgroups and presented as trends, seasonal variation, presence of change-points and compositional changes.
RESULTS
In 2017, consumption of tetracyclines, sulphonamides and trimethoprim, and other antibacterials in the community expressed in DDD per 1000 inhabitants per day varied considerably between countries. Between 1997 and 2017, consumption of tetracyclines did not change significantly, while its seasonal variation significantly decreased over time. Consumption of sulphonamides and trimethoprim significantly decreased until 2006, and its seasonal variation significantly decreased over time. The consumption of other antibacterials showed no significant change over time or in seasonal variation.
CONCLUSIONS
Consumption and composition of tetracyclines, sulphonamides and trimethoprim, and other antibacterials showed wide variations between EU/EEA countries and over time. This represents an opportunity to further reduce consumption of these groups in some countries and improve the quality of their prescription.
Topics: Anti-Bacterial Agents; Drug Utilization; European Union; Humans; Sulfonamides; Tetracyclines; Trimethoprim
PubMed: 34312660
DOI: 10.1093/jac/dkab177 -
British Journal of Pharmacology Jun 2022The zinc finger transcription factor Snail is aberrantly activated in many human cancers and strongly associated with poor prognosis. As a transcription factor, Snail...
BACKGROUND AND PURPOSE
The zinc finger transcription factor Snail is aberrantly activated in many human cancers and strongly associated with poor prognosis. As a transcription factor, Snail has been traditionally considered an 'undruggable' target. Here, we identified a potent small-molecule inhibitor of Snail, namely trimethoprim, and investigated its potential antitumour effects and the underlying mechanisms.
EXPERIMENTAL APPROACH
The inhibitory action of trimethoprim on Snail protein and the related molecular mechanisms were revealed by molecular docking, biolayer interferometry, immunoblotting, immunoprecipitation, qRT-PCR, pull-down and cycloheximide pulse-chase assays. The anti-proliferative and anti-metastatic effects of trimethoprim via targeting Snail were tested in multiple cell-based assays and animal models.
KEY RESULTS
This study identified trimethoprim, an antimicrobial drug, as a potent antitumour agent via targeting Snail. Molecular modelling analysis predicted that trimethoprim directly binds to the arginine-174 pocket of Snail protein. We further discovered that trimethoprim strongly interrupts the interaction of Snail with CREB-binding protein (CBP)/p300, which consequently suppresses Snail acetylation and promotes Snail degradation through the ubiquitin-proteasome pathway. Furthermore, trimethoprim sufficiently inhibited the proliferation, epithelial-mesenchymal transition (EMT) and migration of cancer cells in vitro via specifically targeting Snail. More importantly, trimethoprim effectively reduced Snail-driven tumour growth and metastasis to vital organs such as lung, bone and liver.
CONCLUSIONS AND IMPLICATIONS
These findings indicate, for the first time, that trimethoprim suppresses tumour growth and metastasis via targeting Snail. This study provides insights for a better understanding of the anticancer effects of trimethoprim and offers a potential anticancer therapeutic agent for clinical treatment.
Topics: Animals; Anti-Bacterial Agents; Cell Line, Tumor; Cell Movement; Molecular Docking Simulation; Neoplasm Metastasis; Snail Family Transcription Factors; Transcription Factors; Trimethoprim
PubMed: 34855201
DOI: 10.1111/bph.15763 -
International Journal of Environmental... Dec 2022Phytoremediation is an environmentally friendly and economical method for removing organic contaminants from water. The purpose of the present study was to use for the...
Phytoremediation is an environmentally friendly and economical method for removing organic contaminants from water. The purpose of the present study was to use for the phytoremediation of water from sulfamethoxazole (SMX) and trimethoprim (TRI) residues. The experiment was conducted for 14 days, in which the loss of the pharmaceuticals in water and their concentration in plant tissues was monitored. Determination of SMX and TRI was conducted using liquid chromatography coupled with tandem mass spectrometry. The results revealed that various factors affected the removal of the contaminants from water, and their bioaccumulation coefficients were obtained. Additionally, the transformation products of SMX and TRI were identified. The observed decrease in SMX and TRI content after 14 days was 96.0% and 75.4% in water, respectively. SMX removal mainly involved photolysis and hydrolysis processes, whereas TRI was mostly absorbed by the plant. Bioaccumulation coefficients of the freeze-dried plant were in the range of 0.043-0.147 for SMX and 2.369-2.588 for TRI. Nine and six transformation products related to SMX and TRI, respectively, were identified in water and plant tissues. The detected transformation products stemmed from metabolic transformations and photolysis of the parent compounds.
Topics: Sulfamethoxazole; Trimethoprim; Hydrocharitaceae; Water; Water Pollutants, Chemical
PubMed: 36554877
DOI: 10.3390/ijerph192416994 -
Veterinary Research 2001Sulfonamides and trimethoprim have been used for many decades as efficient and inexpensive antibacterial agents for animals and man. Resistance to both has, however,... (Review)
Review
Sulfonamides and trimethoprim have been used for many decades as efficient and inexpensive antibacterial agents for animals and man. Resistance to both has, however, spread extensively and rapidly. This is mainly due to the horizontal spread of resistance genes, expressing drug-insensitive variants of the target enzymes dihydropteroate synthase and dihydrofolate reductase, for sulfonamide and trimethoprim, respectively. Two genes, sul1 and sul2, mediated by transposons and plasmids, and expressing dihydropteroate synthases highly resistant to sulfonamide, have been found. For trimethoprim, almost twenty phylogenetically different resistance genes, expressing druginsensitive dihydrofolate reductases have been characterized. They are efficiently spread as cassettes in integrons, and on transposons and plasmids. One particular gene, dfr9, seems to have originally been selected in the intestine of swine, where it was found in Escherichia coli, on large plasmids in a disabled transposon, Tn5393, originally found in the plant pathogen Erwinia amylovora. There are also many examples of chromosomal resistance to sulfonamides and trimethoprim, with different degrees of complexity, from simple base changes in the target genes to transformational and recombinational exchanges of whole genes or parts of genes, forming mosaic gene patterns. Furthermore, the trade-off, seen in laboratory experiments selecting resistance mutants, showing drug-resistant but also less efficient (increased Kms) target enzymes, seems to be adjusted for by compensatory mutations in clinically isolated drug-resistant pathogens. This means that susceptibility will not return after suspending the use of sulfonamide and trimethoprim.
Topics: Animals; Chromosomes; Drug Resistance, Microbial; Gene Transfer, Horizontal; Humans; Models, Chemical; Plasmids; Restriction Mapping; Sulfonamides; Trimethoprim; Trimethoprim Resistance
PubMed: 11432417
DOI: 10.1051/vetres:2001123 -
Environmental Research Nov 2022The presence of emerging pollutants, and specifically antibiotics, in agricultural soils has increased notably in recent decades, causing growing concern as regards...
The presence of emerging pollutants, and specifically antibiotics, in agricultural soils has increased notably in recent decades, causing growing concern as regards potential environmental and health issues. With this in mind, the current study focuses on evaluating the toxicity exerted by three antibiotics (amoxicillin, trimethoprim, and ciprofloxacin) on the growth of soil bacterial communities, when these pollutants are present at different doses, and considered in the short, medium, and long terms (1, 8 and 42 days of incubation). Specifically, the research was carried out in 12 agricultural soils having different physicochemical characteristics and was performed by means of the leucine (H) incorporation method. In addition, changes in the structure of soil microbial communities at 8 and 42 days were studied in four of these soils, using the phospholipids of fatty acids method for this. The main results indicate that the most toxic antibiotic was amoxicillin, followed by trimethoprim and ciprofloxacin. The results also show that the toxicity of amoxicillin decreases with time, with values of Log IC ranging from 0.07 ± 0.05 to 3.43 ± 0.08 for day 1, from 0.95 ± 0.07 to 3.97 ± 0.15 for day 8, and from 2.05 ± 0.03 to 3.18 ± 0.04 for day 42, during the incubation period. Regarding trimethoprim, 3 different behaviors were observed: for some soils the growth of soil bacterial communities was not affected, for a second group of soils trimethoprim toxicity showed dose-response effects that remained persistent over time, and, finally, for a third group of soils the toxicity of trimethoprim increased over time, being greater for longer incubation times (42 days). As regards ciprofloxacin, this antibiotic did not show a toxicity effect on the growth of soil bacterial communities for any of the soils or incubation times studied. Furthermore, the principal component analysis performed with the phospholipids of fatty acids results demonstrated that the microbial community structure of these agricultural soils, which persisted after 42 days of incubation, depended mainly on soil characteristics and, to a lesser extent, on the dose and type of antibiotic (amoxicillin, trimethoprim or ciprofloxacin). In addition, it was found that, in this research, the application of the three antibiotics to soils usually favored the presence of fungi and Gram-positive bacteria.
Topics: Amoxicillin; Anti-Bacterial Agents; Bacteria; Ciprofloxacin; Environmental Pollutants; Fatty Acids; Phospholipids; Soil; Soil Microbiology; Soil Pollutants; Trimethoprim
PubMed: 35872321
DOI: 10.1016/j.envres.2022.113916 -
Clinical Microbiology and Infection :... Jan 2012In the late 1960s, the combination of trimethoprim and sulphamethoxazole (co-trimoxazole) was introduced into clinical practice and used to treat many infectious... (Review)
Review
In the late 1960s, the combination of trimethoprim and sulphamethoxazole (co-trimoxazole) was introduced into clinical practice and used to treat many infectious diseases, such as urinary tract infections, respiratory infections, sexually transmitted diseases, Gram-negative sepsis, enteric infections and typhoid fever. Subsequently, co-trimoxazole was reported to be effective against numerous bacterial, fungal and protozoal pathogens, including Nocardia, Listeria monocytogenes, Brucella, Stenotrophomonas maltophilia, Burkholderia, Coxiella burnetii, Tropheryma whipplei, atypical mycobacteria, and Pneumocystis jirovecii. Among protozoal infections, in addition to toxoplasmosis, co-trimoxazole has been used to treat susceptible Plasmodium falciparum, Cyclospora and Isospora infections. Several retrospective and prospective studies have demonstrated good clinical outcome with co-trimoxazole in treating invasive methicillin-resistant Staphylococcus aureus infections. We summarize herein the accumulated evidence in the literature on the new, 'unconventional' clinical use of co-trimoxazole during the last three decades. In the era of widespread antibiotic resistance and shortage of new antibiotic options, large-scale, well-designed studies are needed to explore the tremendous potential concealed in this well-established drug.
Topics: Animals; Anti-Infective Agents; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Parasites; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 21851485
DOI: 10.1111/j.1469-0691.2011.03613.x -
Journal of Visualized Experiments : JoVE Apr 2021Chromatin-associated condensates are implicated in many nuclear processes, but the underlying mechanisms remain elusive. This protocol describes a chemically-induced...
Chromatin-associated condensates are implicated in many nuclear processes, but the underlying mechanisms remain elusive. This protocol describes a chemically-induced protein dimerization system to create condensates on telomeres. The chemical dimerizer consists of two linked ligands that can each bind to a protein: Halo ligand to Halo-enzyme and trimethoprim (TMP) to E. coli dihydrofolate reductase (eDHFR), respectively. Fusion of Halo enzyme to a telomere protein anchors dimerizers to telomeres through covalent Halo ligand-enzyme binding. Binding of TMP to eDHFR recruits eDHFR-fused phase separating proteins to telomeres and induces condensate formation. Because TMP-eDHFR interaction is non-covalent, condensation can be reversed by using excess free TMP to compete with the dimerizer for eDHFR binding. An example of inducing promyelocytic leukemia (PML) nuclear body formation on telomeres and determining condensate growth, dissolution, localization and composition is shown. This method can be easily adapted to induce condensates at other genomic locations by fusing Halo to a protein that directly binds to the local chromatin or to dCas9 that is targeted to the genomic locus with a guide RNA. By offering the temporal resolution required for single cell live imaging while maintaining phase separation in a population of cells for biochemical assays, this method is suitable for probing both the formation and function of chromatin-associated condensates.
Topics: Escherichia coli; Escherichia coli Proteins; Humans; Ligands; Protein Binding; Protein Multimerization; Telomere; Tetrahydrofolate Dehydrogenase; Trimethoprim
PubMed: 33900288
DOI: 10.3791/62173 -
Operative Neurosurgery (Hagerstown, Md.) Mar 2021
Topics: Drug Combinations; Humans; Sulfanilamides; Trimethoprim
PubMed: 33718955
DOI: 10.1093/ons/opab017 -
The Journal of Clinical Investigation Sep 2022BACKGROUNDSeveral molecular imaging strategies can identify bacterial infections in humans. PET affords the potential for sensitive infection detection deep within the...
BACKGROUNDSeveral molecular imaging strategies can identify bacterial infections in humans. PET affords the potential for sensitive infection detection deep within the body. Among PET-based approaches, antibiotic-based radiotracers, which often target key bacterial-specific enzymes, have considerable promise. One question for antibiotic radiotracers is whether antimicrobial resistance (AMR) reduces specific accumulation within bacteria, diminishing the predictive value of the diagnostic test.METHODSUsing a PET radiotracer based on the antibiotic trimethoprim (TMP), [11C]-TMP, we performed in vitro uptake studies in susceptible and drug-resistant bacterial strains and whole-genome sequencing (WGS) in selected strains to identify TMP resistance mechanisms. Next, we queried the NCBI database of annotated bacterial genomes for WT and resistant dihydrofolate reductase (DHFR) genes. Finally, we initiated a first-in-human protocol of [11C]-TMP in patients infected with both TMP-sensitive and TMP-resistant organisms to demonstrate the clinical feasibility of the tool.RESULTSWe observed robust [11C]-TMP uptake in our panel of TMP-sensitive and -resistant bacteria, noting relatively variable and decreased uptake in a few strains of P. aeruginosa and E. coli. WGS showed that the vast majority of clinically relevant bacteria harbor a WT copy of DHFR, targetable by [11C]-TMP, and that despite the AMR, these strains should be "imageable." Clinical imaging of patients with [11C]-TMP demonstrated focal radiotracer uptake in areas of infectious lesions.CONCLUSIONThis work highlights an approach to imaging bacterial infection in patients, which could affect our understanding of bacterial pathogenesis as well as our ability to better diagnose infections and monitor response to therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT03424525.FUNDINGInstitute for Translational Medicine and Therapeutics, Burroughs Wellcome Fund, NIH Office of the Director Early Independence Award (DP5-OD26386), and University of Pennsylvania NIH T32 Radiology Research Training Grant (5T32EB004311-12).
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Carbon Radioisotopes; Escherichia coli; Humans; Trimethoprim
PubMed: 36106638
DOI: 10.1172/JCI156679 -
Analytical and Bioanalytical Chemistry Apr 2022Antibiotics are some of the most widely used drugs. Their release in the environment is of great concern since their consumption is a major factor for antibiotic...
Antibiotics are some of the most widely used drugs. Their release in the environment is of great concern since their consumption is a major factor for antibiotic resistance, one of the most important threats to human health. Their occurrence and fate in agricultural systems have been extensively investigated in recent years. Yet whilst their biotic and abiotic degradation pathways have been thoroughly researched, their biotransformation pathways in plants are less understood, such as in case of trimethoprim. Although trimethoprim has been reported in the environment, its fate in higher plants still remains unknown. A bench-scale experiment was performed and 30 trimethoprim metabolites were identified in lettuce (Lactuca sativa L.), of which 5 belong to phase I and 25 to phase II. Data mining yielded a list of 1018 ions as possible metabolite candidates, which was filtered to a final list of 87 candidates. Molecular structures were assigned for 19 compounds, including 14 TMP metabolites reported for the first time. Alongside well-known biotransformation pathways in plants, additional novel pathways were suggested, namely, conjugation with sesquiterpene lactones, and abscisic acid as a part of phase II of plant metabolism. The results obtained offer insight into the variety of phase II conjugates and may serve as a guideline for studying the metabolization of other chemicals that share a similar molecular structure or functional groups with trimethoprim. Finally, the toxicity and potential contribution of the identified metabolites to the selective pressure on antibiotic resistance genes and bacterial communities via residual antimicrobial activity were evaluated.
Topics: Anti-Bacterial Agents; Biotransformation; Humans; Lactuca; Phytochemicals; Trimethoprim
PubMed: 35141763
DOI: 10.1007/s00216-022-03943-6