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The Journal of Infectious Diseases Jan 2024Human babesiosis is a potentially fatal tick-borne disease caused by intraerythrocytic Babesia parasites. The emergence of resistance to recommended therapies highlights...
Human babesiosis is a potentially fatal tick-borne disease caused by intraerythrocytic Babesia parasites. The emergence of resistance to recommended therapies highlights the need for new and more effective treatments. Here we demonstrate that the 8-aminoquinoline antimalarial drug tafenoquine inhibits the growth of different Babesia species in vitro, is highly effective against Babesia microti and Babesia duncani in mice and protects animals from lethal infection caused by atovaquone-sensitive and -resistant B. duncani strains. We further show that a combination of tafenoquine and atovaquone achieves cure with no recrudescence in both models of human babesiosis. Interestingly, elimination of B. duncani infection in animals following drug treatment also confers immunity to subsequent challenge. Altogether, the data demonstrate superior efficacy of tafenoquine plus atovaquone combination over current therapies for the treatment of human babesiosis and highlight its potential in providing protective immunity against Babesia following parasite clearance.
Topics: Humans; Animals; Mice; Babesiosis; Atovaquone; Babesia; Models, Theoretical; Aminoquinolines
PubMed: 38169301
DOI: 10.1093/infdis/jiad315 -
Viruses Aug 2023The emergence of SARS-CoV-1 in 2003 followed by MERS-CoV and now SARS-CoV-2 has proven the latent threat these viruses pose to humanity. While the SARS-CoV-2 pandemic...
The emergence of SARS-CoV-1 in 2003 followed by MERS-CoV and now SARS-CoV-2 has proven the latent threat these viruses pose to humanity. While the SARS-CoV-2 pandemic has shifted to a stage of endemicity, the threat of new coronaviruses emerging from animal reservoirs remains. To address this issue, the global community must develop small molecule drugs targeting highly conserved structures in the coronavirus proteome. Here, we characterized existing drugs for their ability to inhibit the endoribonuclease activity of the SARS-CoV-2 non-structural protein 15 (nsp15) via in silico, in vitro, and in vivo techniques. We have identified nsp15 inhibition by the drugs pibrentasvir and atovaquone which effectively inhibit SARS-CoV-2 and HCoV-OC43 at low micromolar concentrations in cell cultures. Furthermore, atovaquone, but not pibrentasvir, is observed to modulate HCoV-OC43 dsRNA and infection in a manner consistent with nsp15 inhibition. Although neither pibrentasvir nor atovaquone translate to clinical efficacy in a murine prophylaxis model of SARS-CoV-2 infection, atovaquone may serve as a basis for the design of future nsp15 inhibitors.
Topics: Animals; Mice; SARS-CoV-2; COVID-19; Atovaquone; Endoribonucleases; Coronavirus OC43, Human
PubMed: 37766247
DOI: 10.3390/v15091841 -
Confining Prepared Ultrasmall Nanozymes Loading ATO for Lung Cancer Catalytic Therapy/Immunotherapy.Advanced Materials (Deerfield Beach,... Nov 2023Nanozymes with inherent enzyme-mimicking catalytic properties combat malignant tumor progression via catalytic therapy, while the therapeutic efficacy still needs to be...
Nanozymes with inherent enzyme-mimicking catalytic properties combat malignant tumor progression via catalytic therapy, while the therapeutic efficacy still needs to be improved. In this work, ultrasmall platinum nanozymes (nPt) in a confined domain of a wormlike pore channel in gold nanobipyramidal-mesoporous silica dioxide nanocomposites, producing nanozyme carriers AP-mSi with photoenhanced peroxidase ability, are innovatively synthesized. Afterward, based on the prepared AP-mSi, a lung-cancer nanozymes probe (AP-HAI) is ingeniously produced by removing the SiO template, modifying human serum albumin, and loading atovaquone molecules (ATO) as well as IR780. Under NIR light irradiation, inner AuP and IR780 collaborate for photothermal process, thus facilitating the peroxidase-like catalytic process of H O . Additionally, loaded ATO, a cell respiration inhibitor, can impair tumor respiration metabolism and cause oxygen retention, hence enhancing IR780's photodynamic therapy (PDT) effectiveness. As a result, IR780's PDT and nPt nanozymes' photoenhanced peroxidase-like ability endow probes a high ROS productivity, eliciting antitumor immune responses to destroy tumor tissue. Systematic studies reveal that the obvious reactive oxygen species (ROS) generation is obtained by the strategy of using nPt nanozymes and reducing oxygen consumption by ATO, which in turn enables lung-cancer synergetic catalytic therapy/immunogenic-cell-death-based immunotherapy. The results of this work would provide theoretical justification for the practical use of photoenhanced nanozyme probes.
Topics: Humans; Lung Neoplasms; Reactive Oxygen Species; Silicon Dioxide; Neoplasms; Immunotherapy; Lung; Peroxidases; Cell Line, Tumor
PubMed: 37748441
DOI: 10.1002/adma.202303722 -
MBio Oct 2023parasites rely on a functional electron transport chain (ETC) within their mitochondrion for proliferation, and compounds targeting mitochondrial functions are...
parasites rely on a functional electron transport chain (ETC) within their mitochondrion for proliferation, and compounds targeting mitochondrial functions are validated antimalarials. Here, we localize patatin-like phospholipase 2 (PNPLA2, PF3D7_1358000) to the mitochondrion and reveal that disruption of the PNPLA2 gene impairs asexual replication. PNPLA2-null parasites are hypersensitive to proguanil and inhibitors of the mitochondrial ETC, including atovaquone. In addition, PNPLA2-deficient parasites show reduced mitochondrial respiration and reduced mitochondrial membrane potential, indicating that disruption of PNPLA2 leads to a defect in the parasite ETC. Lipidomic analysis of the mitochondrial phospholipid cardiolipin (CL) reveals that loss of PNPLA2 is associated with a moderate shift toward shorter-chained and more saturated CL species, implying a contribution of PNPLA2 to CL remodeling. PNPLA2-deficient parasites display profound defects in gametocytogenesis, underlining the importance of a functional mitochondrial ETC during both the asexual and sexual development of the parasite. IMPORTANCE For their proliferation within red blood cells, malaria parasites depend on a functional electron transport chain (ETC) within their mitochondrion, which is the target of several antimalarial drugs. Here, we have used gene disruption to identify a patatin-like phospholipase, PNPLA2, as important for parasite replication and mitochondrial function in . Parasites lacking PNPLA2 show defects in their ETC and become hypersensitive to mitochondrion-targeting drugs. Furthermore, PNPLA2-deficient parasites show differences in the composition of their cardiolipins, a unique class of phospholipids with key roles in mitochondrial functions. Finally, we demonstrate that parasites devoid of PNPLA2 have a defect in gametocyte maturation, underlining the importance of a functional ETC for parasite transmission to the mosquito vector.
PubMed: 37882543
DOI: 10.1128/mbio.01718-23 -
Ticks and Tick-borne Diseases Jul 2023In the present study, the effect of a combination therapy consisting of diminazene aceturate (DA) and imidocarb dipropionate (ID) on the in vitro growth of several...
In the present study, the effect of a combination therapy consisting of diminazene aceturate (DA) and imidocarb dipropionate (ID) on the in vitro growth of several parasitic piroplasmids, and on Babesia microti in BALB/c mice was evaluated using a fluorescence-based SYBR Green I test. We evaluated the structural similarities between the regularly used antibabesial medications, DA and ID, and the recently found antibabesial drugs, pyronaridine tetraphosphate, atovaquone, and clofazimine, using atom pair fingerprints (APfp). The Chou-Talalay approach was used to determine the interactions between the two drugs. A Celltac MEK-6450 computerized hematology analyzer was used to detect hemolytic anemia every 96 hours in mice infected with B. microti and in those treated with either mono- or combination therapy. According to the APfp results, DA and ID have the most structural similarities (MSS). DA and ID had synergistic and additive interactions against the in vitro growth of Babesia bigemina and Babesia bovis, respectively. Low dosages of DA (6.25 mg kg) and ID (8.5 mg kg) in conjunction with each other inhibited B. microti growth by 16.5 %, 32 %, and 4.5 % more than 25 mg kg DA, 6.25 mg kg DA, and 8.5 mg kg ID monotherapies, respectively. In the blood, kidney, heart, and lung tissues of mice treated with DA/ID, the B. microti small subunit rRNA gene was not detected. The obtained findings suggest that DA/ID could be a promising combination therapy for treating bovine babesiosis. Also, such combination may overcome the potential problems of Babesia resistance and host toxicity induced by utilizing full doses of DA and ID.
Topics: Animals; Mice; Babesiosis; Theileria; Babesia; Imidocarb
PubMed: 37011497
DOI: 10.1016/j.ttbdis.2023.102145 -
PloS One 2023Antimalarial drugs that can block the transmission of Plasmodium gametocytes to mosquito vectors would be highly beneficial for malaria elimination efforts. Identifying...
Assessment of the transmission blocking activity of antimalarial compounds by membrane feeding assays using natural Plasmodium falciparum gametocyte isolates from West-Africa.
Antimalarial drugs that can block the transmission of Plasmodium gametocytes to mosquito vectors would be highly beneficial for malaria elimination efforts. Identifying transmission-blocking drugs currently relies on evaluation of their activity against gametocyte-producing laboratory parasite strains and would benefit from a testing pipeline with genetically diverse field isolates. The aims of this study were to develop a pipeline to test drugs against P. falciparum gametocyte field isolates and to evaluate the transmission-blocking activity of a set of novel compounds. Two assays were designed so they could identify both the overall transmission-blocking activity of a number of marketed and experimental drugs by direct membrane feeding assays (DMFA), and then also discriminate between those that are active against the gametocytes (gametocyte killing or sterilizing) or those that block development in the mosquito (sporontocidal). These DMFA assays used venous blood samples from naturally infected Plasmodium falciparum gametocyte carriers and locally reared Anopheles gambiae s.s. mosquitoes. Overall transmission-blocking activity was assessed following a 24 hour incubation of compound with gametocyte infected blood (TB-DMFA). Sporontocidal activity was evaluated following addition of compound directly prior to feeding, without incubation (SPORO-DMFA); Gametocyte viability was retained during 24-hour incubation at 37°C when gametocyte infected red blood cells were reconstituted in RPMI/serum. Methylene-blue, MMV693183, DDD107498, atovaquone and P218 showed potent transmission-blocking activity in the TB-DMFA, and both atovaquone and the novel antifolate P218 were potent inhibitors of sporogonic development in the SPORO-DMA. This work establishes a pipeline for the integral use of field isolates to assess the transmission-blocking capacity of antimalarial drugs to block transmission that should be validated in future studies.
Topics: Animals; Humans; Plasmodium falciparum; Antimalarials; Atovaquone; Folic Acid Antagonists; Malaria, Falciparum; Africa, Western
PubMed: 37494413
DOI: 10.1371/journal.pone.0284751 -
Antimicrobial Agents and Chemotherapy Jul 2023Ivermectin is an endectocide used widely to treat a variety of internal and external parasites. Field trials of ivermectin mass drug administration for malaria...
Ivermectin is an endectocide used widely to treat a variety of internal and external parasites. Field trials of ivermectin mass drug administration for malaria transmission control have demonstrated a reduction of mosquito survival and human malaria incidence. Ivermectin will mostly be deployed together with artemisinin-based combination therapies (ACT), the first-line treatment of falciparum malaria. It has not been well established if ivermectin has activity against asexual stage Plasmodium falciparum or if it interacts with the parasiticidal activity of other antimalarial drugs. This study evaluated antimalarial activity of ivermectin and its metabolites in artemisinin-sensitive and artemisinin-resistant P. falciparum isolates and assessed drug-drug interaction with artemisinins and its partner drugs. The concentration of ivermectin causing half of the maximum inhibitory activity (IC) on parasite survival was 0.81 μM with no significant difference between artemisinin-sensitive and artemisinin-resistant isolates ( = 0.574). The ivermectin metabolites were 2-fold to 4-fold less active than the ivermectin parent compound ( < 0.001). Potential pharmacodynamic drug-drug interactions of ivermectin with artemisinins, ACT-partner drugs, and atovaquone were studied using mixture assays providing isobolograms and derived fractional inhibitory concentrations. There were no synergistic or antagonistic pharmacodynamic interactions when combining ivermectin and antimalarial drugs. In conclusion, ivermectin does not have clinically relevant activity against the asexual blood stages of P. falciparum. It also does not affect the antimalarial activity of artemisinins or ACT-partner drugs against asexual blood stages of P. falciparum.
Topics: Animals; Humans; Antimalarials; Plasmodium falciparum; Ivermectin; Artemisinins; Malaria, Falciparum; Malaria; Drug Combinations; Drug Resistance
PubMed: 37338381
DOI: 10.1128/aac.01730-22 -
Travel Medicine and Infectious Disease 2023Hair analysis to identify substance use is an established methodology. This could also be a method to monitor adherence to antimalarial drugs. We aimed to establish a...
BACKGROUND
Hair analysis to identify substance use is an established methodology. This could also be a method to monitor adherence to antimalarial drugs. We aimed to establish a methodology to determine hair concentrations of atovaquone, proguanil and mefloquine in travellers using chemoprophylaxis.
METHODS
A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous analysis of the antimalarial drugs -atovaquone (ATQ), proguanil (PRO) and mefloquine (MQ), in human hair. The hair samples from five volunteers were used for this proof-of-concept analysis. Three volunteers were taking daily atovaquone/proguanil (ATQ/PRO) chemoprophylaxis and two volunteers were using weekly mefloquine (MQ) chemoprophylaxis.
RESULTS
With this proof-of-principle analysis, we could show that ATQ/PRO and MQ are integrated into the hair matrix. Chemoprophylaxis could be quantified with the established method. In hair segments, maximal concentrations of 3.0 ng/mL/20 mg hair proguanil, 1.3 ng/mL/20 mg hair atovaquone and 78.3 ng/mL/20 mg hair mefloquine were measured. Moreover, malaria drug concentration changes correlated with the time interval since finishing the chemoprophylaxis regimen.
CONCLUSIONS
The validated method was used successfully for the analysis of antimalarial-drug positive hair samples containing atovaquone, proguanil or mefloquine. This research shows that hair can be used for adherence monitoring of chemoprophylaxis and paves the way for larger studies and optimized procedures.
Topics: Humans; Antimalarials; Proguanil; Atovaquone; Mefloquine; Chromatography, Liquid; Drug Therapy, Combination; Travel; Tandem Mass Spectrometry; Drug Combinations
PubMed: 37209974
DOI: 10.1016/j.tmaid.2023.102590 -
Case Reports in Infectious Diseases 2024We report a challenging case of persistent relapsing babesiosis in an immunocompromised host that was successfully managed with atovaquone-proguanil (Malarone)....
We report a challenging case of persistent relapsing babesiosis in an immunocompromised host that was successfully managed with atovaquone-proguanil (Malarone). Malignant B-cell transformation and immunosuppressants, such as rituximab, deplete normal B-cells which normally produce antibodies to combat Babesia infection. Treatment can be prolonged and challenging in immunocompromised hosts. Atovaquone-proguanil (Malarone) is a novel therapy that can be used as part of a salvage regimen in case antimicrobial resistance or failure exists. Weighing the risks and benefits of continuing cancer therapy treatment or reducing the level of immunosuppression may aid in treatment. These are just as important as the choice of antimicrobial therapy for effective treatment and eradication of Babesia infection, especially in immunocompromised hosts.
PubMed: 38774593
DOI: 10.1155/2024/7168928 -
Chemical Science Oct 2023Photodynamic therapy (PDT) has emerged as an invasive and promising antitumour treatment, however, the hypoxia in deep tumour tissues and the poor water-solubility of...
Photodynamic therapy (PDT) has emerged as an invasive and promising antitumour treatment, however, the hypoxia in deep tumour tissues and the poor water-solubility of photosensitizers as bottlenecks greatly hinder PDT efficiency. Herein, a tumour microenvironment (TME) activated supramolecular nanoplatform consisting of the pillar[5]arene-based amphiphilic polymer POPD, the phototherapeutic agent Cy7-CN, respiratory medication atovaquone (ATO) and chemotherapeutic drug pyridinyl camptothecin (CPT-Py) was constructed for imaging-guided hypoxia-ameliorated phototherapies. Owing to host-guest interaction, the photochemical and photophysical properties of cyanine were improved exceedingly due to the suppression of π-π stacking. Triggered by the acidic microenvironment in tumour sites, the supramolecular nanoplatform would dissociate and release CPT-Py and ATO which inhibits mitochondria-associated oxidative phosphorylation (OXPHOS) and encourages more oxygen to be used in enhanced PDT. and studies verified that the rational combination of ATO-enhanced PDT and PTT overcame the disadvantages of single phototherapy and formed mutual promotion, and simultaneously sensitized chemotherapeutic drugs, which resulted in high tumour inhibition. It is hoped that the supramolecular nanoplatform could shed light on the development of phototherapeutic agents.
PubMed: 37886080
DOI: 10.1039/d3sc03797e