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The Journal of Antimicrobial... Feb 2023In early 2016, in Preah Vihear, Northern Cambodia, artesunate/mefloquine was used to cope with dihydroartemisinin/piperaquine-resistant Plasmodium falciparum parasites....
BACKGROUND
In early 2016, in Preah Vihear, Northern Cambodia, artesunate/mefloquine was used to cope with dihydroartemisinin/piperaquine-resistant Plasmodium falciparum parasites. Following this policy, P. falciparum strains harbouring molecular markers associated with artemisinin, piperaquine and mefloquine resistance have emerged. However, the lack of a viable alternative led Cambodia to adopt artesunate/mefloquine countrywide, raising concerns about a surge of triple-resistant P. falciparum strains.
OBJECTIVES
To assess the prevalence of triple-resistant parasites after artesunate/mefloquine implementation countrywide in Cambodia and to characterize their phenotype.
METHODS
For this multicentric study, 846 samples were collected from 2016 to 2019. Genotyping of molecular markers associated with artemisinin, piperaquine and mefloquine resistance was coupled with phenotypic analyses.
RESULTS
Only four triple-resistant P. falciparum isolates (0.47%) were identified during the study period. These parasites combined the pfk13 polymorphism with pfmdr1 amplification, pfpm2 amplification and/or pfcrt mutations. They showed significantly higher tolerance to artemisinin, piperaquine and mefloquine and also to the mefloquine and piperaquine combination.
CONCLUSIONS
The use of artesunate/mefloquine countrywide in Cambodia has not led to a massive increase of triple-resistant P. falciparum parasites. However, these parasites circulate in the population, and exhibit clear resistance to piperaquine, mefloquine and their combination in vitro. This study demonstrates that P. falciparum can adapt to more complex drug associations, which should be considered in future therapeutic designs.
Topics: Humans; Mefloquine; Plasmodium falciparum; Antimalarials; Artesunate; Cambodia; Prevalence; Artemisinins; Quinolines; Malaria, Falciparum; Drug Resistance
PubMed: 36508338
DOI: 10.1093/jac/dkac403 -
EMBO Reports Oct 2023The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in the pathogenesis of a wide variety of human diseases. So far, drugs directly and...
The NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in the pathogenesis of a wide variety of human diseases. So far, drugs directly and specifically targeting the NLRP3 inflammasome are not available for clinical use since the safety and efficacy of new compounds are often unclear. A promising approach is thus to identify NLRP3 inhibitors from existing drugs that are already in clinical use. Here, we show that mefloquine, a well-known antimalarial drug, is a highly selective and potent NLRP3 inhibitor by screening a FDA-approved drug library. Mechanistically, mefloquine directly binds to the NLRP3 NACHT and LRR domains to prevent NLRP3 inflammasome activation. More importantly, mefloquine treatment attenuates the symptoms of lipopolysaccharide-induced systemic inflammation and Parkinson's disease-like neural damage in mice. Our findings identify mefloquine as a potential therapeutic agent for NLRP3-driven diseases and migth expand its clinical use considerably.
PubMed: 37621232
DOI: 10.15252/embr.202357101 -
The American Journal of Tropical... Apr 2022In malaria, rosetting is a phenomenon involving the cytoadherence of uninfected erythrocytes to infected erythrocytes (IRBC) harboring the late erythrocytic stage of...
In malaria, rosetting is a phenomenon involving the cytoadherence of uninfected erythrocytes to infected erythrocytes (IRBC) harboring the late erythrocytic stage of Plasmodium spp. Recently, artesunate-stimulated rosetting has been demonstrated to confer a survival advantage to P. falciparum late-stage IRBC. This study investigated the rosetting response of P. falciparum and P. vivax clinical isolates to ex vivo antimalarial treatments. Brief exposure of IRBC to chloroquine, mefloquine, amodiaquine, quinine, and lumefantrine increased the rosetting rates of P. falciparum and P. vivax. Furthermore, the ex vivo combination of artesunate with mefloquine and piperaquine also resulted in increased the rosetting rates. Drug-mediated rosette-stimulation has important implications for the therapeutic failure of rapidly cleared drugs such as artesunate. However, further work is needed to establish the ramifications of increased rosetting rates by drugs with longer half-lifves, such as chloroquine, mefloquine, and piperaquine.
PubMed: 35405642
DOI: 10.4269/ajtmh.21-1229 -
Frontiers in Cell and Developmental... 2022An exaggerated inflammatory response is the hallmark of a plethora of disorders. ATP is a central signaling molecule that orchestrates the initiation and resolution of... (Review)
Review
An exaggerated inflammatory response is the hallmark of a plethora of disorders. ATP is a central signaling molecule that orchestrates the initiation and resolution of the inflammatory response by enhancing activation of the inflammasome, leukocyte recruitment and activation of T cells. ATP can be released from cells through pannexin (Panx) channels, a family of glycoproteins consisting of three members, Panx1, Panx2, and Panx3. Panx1 is ubiquitously expressed and forms heptameric channels in the plasma membrane mediating paracrine and autocrine signaling. Besides their involvement in the inflammatory response, Panx1 channels have been shown to contribute to different modes of cell death (i.e., pyroptosis, necrosis and apoptosis). Both genetic ablation and pharmacological inhibition of Panx1 channels decrease inflammation and contribute to a better outcome in several animal models of inflammatory disease involving various organs, including the brain, lung, kidney and heart. Up to date, several molecules have been identified to inhibit Panx1 channels, for instance probenecid (Pbn), mefloquine (Mfq), flufenamic acid (FFA), carbenoxolone (Cbx) or mimetic peptides like Panx1. Unfortunately, the vast majority of these compounds lack specificity and/or serum stability, which limits their application. The recent availability of detailed structural information on the Panx1 channel from cryo-electron microscopy studies may open up innovative approaches to acquire new classes of synthetic Panx1 channel blockers with high target specificity. Selective inhibition of Panx1 channels may not only limit acute inflammatory responses but may also prove useful in chronic inflammatory diseases, thereby improving human health. Here, we reviewed the current knowledge on the role of Panx1 in the initiation and resolution of the inflammatory response, we summarized the effects of Panx1 inhibition in inflammatory pathologies and recapitulate current Panx1 channel pharmacology with an outlook towards future approaches.
PubMed: 36438559
DOI: 10.3389/fcell.2022.1020826 -
Infection and Drug Resistance 2023In recent years, carbapenem-resistant (CRPA) has spread around the world, leading to a high mortality and close attention of medical community. In this study, we aim to...
BACKGROUND
In recent years, carbapenem-resistant (CRPA) has spread around the world, leading to a high mortality and close attention of medical community. In this study, we aim to find a new strategy of treatment for CRPA infections.
METHODS
Eight strains of CRPA were collected, and PCR detected the multi-locus sequence typing (MLST). The antimicrobial susceptibility test was conducted using the VITEK@2 compact system. The minimum inhibitory concentration (MIC) for AS101 and mefloquine was determined using the broth dilution method. Antibacterial activity was tested in vitro and in vivo through the chessboard assay, time killing assay, and a mouse model. The mechanism of AS101 combined with mefloquine against CRPA was assessed through the biofilm formation inhibition assay, electron microscopy, and detection of reactive oxygen species (ROS).
RESULTS
The results demonstrated that all tested CRPA strains exhibited multidrug resistance. Moreover, our investigation revealed a substantial synergistic antibacterial effect of AS101-mefloquine in vitro. The assay for inhibiting biofilm formation indicated that AS101-mefloquine effectively suppressed the biofilm formation of CRPA-5 and CRPA-6. Furthermore, AS101-mefloquine were observed to disrupt the bacterial cell wall and enhance the permeability of the cell membrane. This effect was achieved by stimulating the production of ROS, which in turn hindered the growth of CRPA-3. To evaluate the therapeutic potential, a murine model of CRPA-3 peritoneal infection was established. Notably, AS101-mefloquine administration resulted in a significant reduction in bacterial load within the liver, kidney, and spleen of mice after 72 hours of treatment.
CONCLUSION
The present study showed that the combination of AS101 and mefloquine yielded a notable synergistic bacteriostatic effect both in vitro and in vivo, suggesting a potential clinical application of this combination in the treatment of CRPA.
PubMed: 38023412
DOI: 10.2147/IDR.S427232 -
Acta Pharmaceutica (Zagreb, Croatia) Dec 2023Here we present the synthesis and evaluation of the biological activity of new hybrid compounds, ureido-type (UT) harmiquins, based on chloroquine (CQ) or mefloquine...
Here we present the synthesis and evaluation of the biological activity of new hybrid compounds, ureido-type (UT) harmiquins, based on chloroquine (CQ) or mefloquine (MQ) scaffolds and β-carboline alkaloid harmine against cancer cell lines and . The hybrids were prepared from the corresponding amines by 1,1'-carbonyldiimidazole (CDI)-mediated synthesis. evaluation of the biological activity of the title compounds revealed two hit compounds. Testing of the antiproliferative activity of the new UT harmiquins, and previously prepared triazole-(TT) and amide-type (AT) CQ-based harmiquins, against a panel of human cell lines, revealed TT harmiquine as the most promising compound, as it showed pronounced and selective activity against the tumor cell line HepG2 ( = 5.48 ± 3.35 μmol L). Screening of the antiplasmodial activities of UT harmiquins against erythrocytic stages of the life cycle identified CQ-based UT harmiquine as a novel antiplasmodial hit because it displayed low values in the submicromolar range against CQ-sensitive and resistant strains ( 0.06 ± 0.01, and 0.19 ± 0.02 μmol L, respectively), and exhibited high selectivity against , compared to mammalian cells (SI = 92).
Topics: Humans; Antimalarials; Cell Line, Tumor; Chloroquine; Mefloquine; Parasitic Sensitivity Tests
PubMed: 38147482
DOI: 10.2478/acph-2023-0035 -
Nature Communications Jul 2023Increasing levels of artemisinin and partner drug resistance threaten malaria control and elimination globally. Triple artemisinin-based combination therapies (TACTs)...
Increasing levels of artemisinin and partner drug resistance threaten malaria control and elimination globally. Triple artemisinin-based combination therapies (TACTs) which combine artemisinin derivatives with two partner drugs are efficacious and well tolerated in clinical trials, including in areas of multidrug-resistant malaria. Whether early TACT adoption could delay the emergence and spread of antimalarial drug resistance is a question of vital importance. Using two independent individual-based models of Plasmodium falciparum epidemiology and evolution, we evaluated whether introduction of either artesunate-mefloquine-piperaquine or artemether-lumefantrine-amodiaquine resulted in lower long-term artemisinin-resistance levels and treatment failure rates compared with continued ACT use. We show that introduction of TACTs could significantly delay the emergence and spread of artemisinin resistance and treatment failure, extending the useful therapeutic life of current antimalarial drugs, and improving the chances of malaria elimination. We conclude that immediate introduction of TACTs should be considered by policy makers in areas of emerging artemisinin resistance.
Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Folic Acid Antagonists
PubMed: 37516752
DOI: 10.1038/s41467-023-39914-3 -
Journal For Immunotherapy of Cancer Mar 2024Ferroptosis plays an important role in enhancing the efficacy of anti-programmed cell death 1 (PD-1) immunotherapy; however, the molecular mechanisms by which tumor...
BACKGROUND
Ferroptosis plays an important role in enhancing the efficacy of anti-programmed cell death 1 (PD-1) immunotherapy; however, the molecular mechanisms by which tumor ferroptosis sensitizes melanoma and lung cancer to anti-PD-1 immunotherapy have not been elucidated.
METHODS
Cytotoxicity assays, colony formation assays, flow cytometry and animal experiments were used to evaluate the effects of mefloquine (Mef) on survival and ferroptosis in melanoma and lung cancer. RNA sequencing, Real-time quantitative PCR (qRT-PCR), western blotting, chromatin immunoprecipitation-qPCR and flow cytometry were used to determine the molecular mechanisms by which Mef regulates lysophosphatidylcholine acyltransferase 3 (LPCAT3). The relationship between LPCAT3 and the efficacy of anti-PD-1 immunotherapy was verified via a clinical database and single-cell RNA sequencing (ScRNA-Seq).
RESULTS
In this study, we discovered that Mef induces ferroptosis. Furthermore, treatment with Mef in combination with T-cell-derived interferon-γ (IFN-γ) enhanced tumor ferroptosis and sensitized melanoma and lung cancer cells to anti-PD-1 immunotherapy. Mechanistically, Mef upregulated the expression of LPCAT3, a key gene involved in lipid peroxidation, by activating IFN-γ-induced STAT1-IRF1 signaling, and knocking down LPCAT3 impaired the induction of ferroptosis by Mef+IFN-γ. Clinically, analysis of the transcriptome and single-cell sequencing results in patients with melanoma showed that LPCAT3 expression was significantly lower in patients with melanoma than in control individuals, and LPCAT3 expression was positively correlated with the efficacy of anti-PD-1 immunotherapy.
CONCLUSIONS
In conclusion, our study demonstrated a novel mechanism by which LPCAT3 is regulated, and demonstrated that Mef is a highly promising new target that can be utilized to enhance the efficacy of anti-PD-1 immunotherapy.
Topics: Animals; Humans; Melanoma; Mefloquine; Interferon-gamma; Ferroptosis; Cell Line, Tumor; Lung Neoplasms; Immunotherapy; STAT1 Transcription Factor; Interferon Regulatory Factor-1; 1-Acylglycerophosphocholine O-Acyltransferase
PubMed: 38471712
DOI: 10.1136/jitc-2023-008554 -
Molecules (Basel, Switzerland) Feb 2022Late-stage modification of drug molecules is a fast method to introduce diversity into the already biologically active scaffold. A notable number of analogs of... (Review)
Review
Late-stage modification of drug molecules is a fast method to introduce diversity into the already biologically active scaffold. A notable number of analogs of mefloquine, chloroquine, and hydroxychloroquine have been synthesized, starting from the readily available active pharmaceutical ingredient (API). In the current review, all the modifications sites and reactivity types are summarized and provide insight into the chemistry of these molecules. The approaches include the introduction of simple groups and functionalities. Coupling to other drugs, polymers, or carriers afforded hybrid compounds or conjugates with either easily hydrolyzable or more chemically inert bonds. The utility of some of the compounds was tested in antiprotozoal, antibacterial, and antiproliferative assays, as well as in enantiodifferentiation experiments.
Topics: Antimalarials; Chemistry Techniques, Synthetic; Humans; Hydroxychloroquine; Malaria; Mefloquine; Models, Molecular; Plasmodium; Quinolines
PubMed: 35164267
DOI: 10.3390/molecules27031003 -
The Medical Letter on Drugs and... Aug 2020
Review
Topics: Administration, Intravenous; Animals; Antimalarials; Artesunate; Clinical Trials as Topic; Humans; Malaria; Severity of Illness Index
PubMed: 32960866
DOI: No ID Found