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Journal of Cellular and Molecular... Oct 2023The widespread emergence of antimalarial drug resistance has created a major threat to public health. Malaria is a life-threatening infectious disease caused by...
The widespread emergence of antimalarial drug resistance has created a major threat to public health. Malaria is a life-threatening infectious disease caused by Plasmodium spp., which includes Apicoplast DNA polymerase and Plasmodium falciparum cysteine protease falcipain-2. These components play a critical role in their life cycle and metabolic pathway, and are involved in the breakdown of erythrocyte hemoglobin in the host, making them promising targets for anti-malarial drug design. Our current study has been designed to explore the potential inhibitors from haplopine derivatives against these two targets using an in silico approach. A total of nine haplopine derivatives were used to perform molecular docking, and the results revealed that Ligands 03 and 05 showed strong binding affinity compared to the control compound atovaquone. Furthermore, these ligand-protein complexes underwent molecular dynamics simulations, and the results demonstrated that the complexes maintained strong stability in terms of RMSD (root mean square deviation), RMSF (root mean square fluctuation), and Rg (radius of gyration) over a 100 ns simulation period. Additionally, PCA (principal component analysis) analysis and the dynamic cross-correlation matrix showed positive outcomes for the protein-ligand complexes. Moreover, the compounds exhibited no violations of the Lipinski rule, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions yielded positive results without indicating any toxicity. Finally, density functional theory (DFT) and molecular electrostatic potential calculations were conducted, revealing that the mentioned derivatives exhibited better stability and outstanding performance. Overall, this computational approach suggests that these haplopine derivatives could serve as a potential source for developing new, effective antimalarial drugs to combat malaria. However, further in vitro or in vivo studies might be conducted to determine their actual effectiveness.
PubMed: 37724615
DOI: 10.1111/jcmm.17940 -
Experimental Parasitology Nov 2023Conditional gene expression is a powerful tool to investigate putative vaccine and drug targets, especially in a haploid organism such as Plasmodium falciparum....
Conditional gene expression is a powerful tool to investigate putative vaccine and drug targets, especially in a haploid organism such as Plasmodium falciparum. Inducible systems based on regulation of either transcription, translation, protein or mRNA stability, among others, allow switching on an off the expression of any desired gene causing specific gain or loss of function phenotypes. However, those systems can be cumbersome involving the construction of large plasmids and generation of multiple transgenic parasite lines. In addition, the dynamic range of regulation achieved is not predictable for each individual gene and can be insufficient to generate detectable phenotypes when the genes of interest are silenced. Here, we combined up to three distinct inducible systems to regulate the expression of a single gene. Expression of the reporter NanoLuc luciferase was regulated over 40-fold, which correlates to the regulation achieved by each individual system multiplied by each other. We applied the conditionally expressed NanoLuc to evaluate the effect of fast-acting antimalarials such as chloroquine and artesunate as well as of slower-acting ones such as atovaquone. The conditionally expressed reporter allowed faster and more reliable detection of toxicity to the parasite, which correlated to the expected action of each compound. Bioluminescence achieved by the expression of this inducible highly sensitive reporter is therefore a promising tool to investigate the temporal effect of potential new antimalarials. This single plasmid combination system might also prove useful to achieve sufficient regulation of genes of interest to produce loss-of-function phenotypes.
PubMed: 37716462
DOI: 10.1016/j.exppara.2023.108620 -
Microbial Pathogenesis Nov 2023Despite recent advances for treating cerebral toxoplasmosis (CT), monitoring the parasite burden and treatment response is still challenging. miRNAs are small non-coding...
Assessment of tissue levels of miR-146a and proinflammatory cytokines in experimental cerebral toxoplasmosis following atovaquone and clindamycin treatment: An in vivo study.
BACKGROUND
Despite recent advances for treating cerebral toxoplasmosis (CT), monitoring the parasite burden and treatment response is still challenging. miRNAs are small non-coding RNAs with regulatory functions that can be used in diagnosis and treatment monitoring. We investigated the changes in miR-146a, BAG-1 gene, IL-6, and IL-10 tissue levels in the brain of BALB/c mice with chronic CT caused by the PRU strain of T. gondii following anti-parasitic and antibiotic treatment.
METHOD
Fifty-three 6-to 8-week-old BALB/c mice were infected using intraperitoneal inoculation of cerebral cysts of T. gondii PRU strain and then divided into five groups as follows: group 1 included mice treated with 100 mg/kg/d Atovaquone (AT), group 2 included mice treated with 400 mg/kg/d clindamycin (CL), group 3 included mice treated with combination therapy (AT + CL), group 4 included infected untreated mice as a positive control (PC), and; group 5 included uninfected untreated mice as negative control (NC). After the completion of the treatment course, tissue level of mir-146a, miR-155, BAG-1 gene, IL-6, and IL-10 was investigated with real-time polymerase chain reaction. The IL-6/IL-10 ratio was calculated as an indicator of immune response. Moreover, brain cyst numbers were counted on autopsy samples.
RESULTS
miR-146a, IL-6, IL-10, and BAG-1 genes were expressed in PC, but not in the NC group; miR-146a, IL-6, IL-10, and BAG-1 gene expression were significantly lower in AT, CL, and AT + CL compared with PC. MiR-146a and BAG-1 levels in AT and CL were not different statistically, however, they both had lower levels compared to AT + CL (P < 0.01). There was no difference in the expression of IL-6 and IL-10 between treatment groups. BAG-1 expression was significantly lower in AT, than in CL and AT + CL (P < 0.0089 and < 0.002, respectively). The PC group showed a higher ratio of IL-6/IL-10, although this increase was not statistically significant. It is noteworthy that the treatment with AT reduced this ratio; in the inter-group comparison, this ratio showed a decrease in the AT and AT + CL compared to the PC. The number of brain tissue cysts was significantly lower in AT, CL, and AT + CL, than in PC (p < 0.0001). AT had significantly lower brain cysts than CL and AT + CL (P < 0.0001).
CONCLUSION
It seems that the factors studied in the current research (microRNA and cytokines) are a suitable index for evaluating the response to antiparasitic and antibiotic treatment. However, more studies should be conducted in the future to confirm our findings.
Topics: Animals; Mice; Toxoplasmosis, Cerebral; Atovaquone; Cytokines; Clindamycin; Interleukin-10; Interleukin-6; Toxoplasma; MicroRNAs; Cysts; Anti-Bacterial Agents
PubMed: 37683834
DOI: 10.1016/j.micpath.2023.106340 -
Medical Mycology Sep 2023Pneumocystis jirovecii is a transmissible fungus responsible for severe pneumonia (Pneumocystis pneumonia [PCP]) in immunocompromised patients. Missense mutations due to... (Review)
Review
Pneumocystis jirovecii is a transmissible fungus responsible for severe pneumonia (Pneumocystis pneumonia [PCP]) in immunocompromised patients. Missense mutations due to atovaquone selective pressure have been identified on cytochrome b (CYB) gene of P. jirovecii. It was recently shown that atovaquone prophylaxis can lead to the selection of specific P. jirovecii CYB mutants potentially resistant to atovaquone among organ transplant recipients. In this context, our objectives were to provide data on P. jirovecii CYB mutants and the putative selective pressure exerted by atovaquone on P. jirovecii organisms in France. A total of 123 patients (124 P. jirovecii specimens) from four metropolitan hospitals and two overseas hospitals were retrospectively enrolled. Fourteen patients had prior exposure to atovaquone, whereas 109 patients did not at the time of P. jirovecii detection. A 638 base-pair fragment of the CYB gene of P. jirovecii was amplified and sequenced. A total of 10 single nucleotide polymorphisms (SNPs) were identified. Both missense mutations C431T (Ala144Val) and C823T (Leu275Phe), located at the Qo active site of the enzyme, were significantly associated with prior atovaquone exposure, these mutations being conversely incidental in the absence of prior atovaquone exposure (P < 0.001). Considering that the aforementioned hospitals may be representative of the national territory, these findings suggest that the overall presence of P. jirovecii CYB mutants remains low in France.
Topics: Animals; Pneumocystis carinii; Atovaquone; Cytochromes b; Retrospective Studies; Mutation
PubMed: 37656874
DOI: 10.1093/mmy/myad095 -
Arthritis Care & Research Feb 2024This manuscript assesses the incidence of Pneumocystis jiroveci pneumonia (PJP) among patients receiving contemporary treatment regimens for antineutrophil cytoplasmic...
OBJECTIVE
This manuscript assesses the incidence of Pneumocystis jiroveci pneumonia (PJP) among patients receiving contemporary treatment regimens for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and adverse events associated with PJP prophylaxis.
METHODS
Incident users of rituximab or cyclophosphamide for AAV were identified in the TriNetX electronic health records database from 2011 to 2022. The incidence rates (IRs) of PJP in the first 6 months of induction therapy with rituximab and/or cyclophosphamide and during postinduction maintenance therapy with rituximab were calculated. Cox proportional hazard models were used to estimate hazard ratios (HRs) and confidence intervals (CIs) for the risk of adverse events commonly associated with PJP prophylaxis.
RESULTS
We identified 1,461 AAV cases who received induction therapy with rituximab (69.7%), cyclophosphamide (18.9%), or both (11.4%). Prophylaxis prescribed within 30 days of induction included trimethoprim-sulfamethoxazole (30.7%), atovaquone (5.4%), dapsone (3.8%), and pentamidine (0.8%). During induction therapy, 10 cases of PJP were identified (IR 15.0 cases per 1,000 patient-years); no deaths occurred. In adjusted analyses, those who received prophylaxis had a higher risk of leukopenia (HR 3.1; 95% CI 1.1-8.6), rash (HR 1.9; 95% CI 1.0-3.6), and nephropathy (HR 2.6; 95% CI 1.3-5.1) than those who did not. During rituximab maintenance therapy (n = 709), five cases of PJP were identified (IR 2.1 cases per 1,000 person-years), one of whom died during the hospitalization associated with a PJP diagnosis.
CONCLUSION
Rates of PJP in patients with AAV were lower than previously observed, and few cases occurred during rituximab maintenance therapy. PJP prophylaxis was associated with adverse events.
Topics: Humans; Rituximab; Pneumocystis carinii; Incidence; Pneumonia, Pneumocystis; Cyclophosphamide; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
PubMed: 37643919
DOI: 10.1002/acr.25222 -
International Journal of Clinical... Nov 2023At our institution, patients with hematological disease who require pneumonia (PJP) prophylaxis were administered atovaquone at a low dose (750 mg/day). However, there...
OBJECTIVE
At our institution, patients with hematological disease who require pneumonia (PJP) prophylaxis were administered atovaquone at a low dose (750 mg/day). However, there have been few reports on the efficacy of low-dose atovaquone administration, and the purpose of this study is, therefore, to investigate its effectiveness.
MATERIALS AND METHODS
We investigated the expression of PJP in patients with hematological disease who received atovaquone administration. Atovaquone was administered at a low dose of 750 mg once daily, and the follow-up time was the period of PJP prophylaxis that included atovaquone administration.
RESULTS
85 patients were included in the study. The median age of the study population was 72 years (range: 33 - 97). The duration of atovaquone treatment and follow-up time were 150 days (22 - 1,018) and 258 days (22 - 1,457), respectively. In hematologic diseases, multiple myeloma was high in 31 patients and malignant lymphoma in 28 patients. No patients exhibited PJP during the observation period.
CONCLUSION
In hematological disease patients with relatively low risk of PJP, low-dose atovaquone may prevent the onset of PJP.
Topics: Humans; Adult; Middle Aged; Aged; Aged, 80 and over; Pneumonia, Pneumocystis; Atovaquone; Pneumocystis carinii; Trimethoprim, Sulfamethoxazole Drug Combination; Hematologic Diseases; Retrospective Studies
PubMed: 37622674
DOI: 10.5414/CP204368 -
The American Journal of Tropical... Oct 2023Antimalarial medications are recommended for chemoprevention as part of malaria control programs to decrease the morbidity and mortality related to more than 200 million...
Antimalarial medications are recommended for chemoprevention as part of malaria control programs to decrease the morbidity and mortality related to more than 200 million infections each year. We sought to evaluate patient and provider acceptability of malaria chemoprevention in a long-acting formulation. We administered questionnaires to patients and providers in malaria endemic districts in Kenya and Zambia. Questions explored preferences and concerns around long-acting antimalarial formulations compared with oral formulations. We recruited 202 patient respondents (Kenya, n = 102; Zambia, n = 100) and 215 provider respondents (Kenya, n = 105; Zambia, n = 110). Long-acting injection was preferred to oral pills, whereas oral pills were preferred to implant or transdermal administration by patient respondents. Of 202 patient respondents, 80% indicated that they 'definitely would try' malaria chemoprevention offered by injection instead of oral pills. Of parents or guardians, 84% of 113 responded that they 'definitely would' have their child age < 12 years and 90% of 88 'definitely would' have their child ≥12 years receive an injection for malaria prevention. Provider respondents indicated that they would be more likely to prescribe a long-acting injectable product compared with an oral product for malaria chemoprevention in adults (70%), adolescents ages 12 years and older (67%), and children <12 years (81%). Potential for prolonged adverse effects with long-acting products was the highest concern for patient respondents, while higher medication-related cost was cited as the most concerning barrier to implementation by providers. Overall, these findings indicate enthusiasm for the development of long-acting injectable antimalarials to provide individual delivery method options across age groups.
Topics: Child; Adult; Adolescent; Humans; Antimalarials; Malaria; Chemoprevention; Zambia; Injections
PubMed: 37604474
DOI: 10.4269/ajtmh.23-0245 -
Veterinary World Jun 2023New anticancer drugs are being developed to avoid the toxicity and chemoresistance of the currently available drugs. The Food and Drug Administration-approved...
BACKGROUND AND AIM
New anticancer drugs are being developed to avoid the toxicity and chemoresistance of the currently available drugs. The Food and Drug Administration-approved anti-malarial drug atovaquone is known to act as a selective oxidative phosphorylation inhibitor in the mitochondria by competing with CO Q10 (mitochondrial complex II and III). This study aimed to investigate the effect of atovaquone by examining the Na/K-ATPase (NKA) activity in various canine cell lines.
MATERIALS AND METHODS
Canine cell lines were treated with various concentrations (2.5, 5, 10, 15, and 20 μM) of atovaquone for 24, 48, and 72 h. Human cell lines were used as a control to validate the canine cancer cell lines. The activities of the drugs against the cancer cell lines were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromideassay. The cell metabolic activity was determined by measuring the activities of the nicotinamide adenine dinucleotide phosphate-dependent cellular oxidoreductase enzymes. The NKA activity was measured using the single-cell patch clamping assay.
RESULTS
Atovaquone-induced apoptosis by elevating the concentration of reactive oxygen species (ROS) in the tumor cells, leading to cell death. Treatment of canine cancer cells with N-acetylcysteine (ROS inhibitor) reduced the activity of the drug. Furthermore, atovaquone inhibited more than 45% of the NKA ion current.
CONCLUSION
This study demonstrated effects of atovaquone against canine cancer cell lines. The data may prove beneficial in repurposing the drug as a new anticancer agent in canine clinical trials, which might aid in fighting human cancer.
PubMed: 37577204
DOI: 10.14202/vetworld.2023.1185-1192 -
Antiviral Research Sep 2023The antimalarial drug atovaquone was recently reported to inhibit the in vitro replication of different arboviruses, including chikungunya virus (CHIKV) and Zika virus...
The antimalarial drug atovaquone was recently reported to inhibit the in vitro replication of different arboviruses, including chikungunya virus (CHIKV) and Zika virus (ZIKV). Furthermore, atovaquone was shown to block Plasmodium parasite transmission by Anopheles mosquitoes when the mosquitoes were exposed to low concentrations on treated surfaces (i.e. tarsal exposure). Therefore, we evaluated the anti-CHIKV and -ZIKV effects of atovaquone via tarsal exposure in Aedes aegypti mosquitoes. We first confirmed that atovaquone exerted a dose-dependent antiviral effect on CHIKV and ZIKV replication in mosquito-derived cells. The modest antiviral effect could be rescued by adding exogenous uridine. Next, we assessed the effect of tarsal exposure to atovaquone on the fitness of Ae. aegypti. Concentrations up to 100 μmol/m did not affect the fecundity and egg-hatching rate. No significant effect on mosquito survival was observed when mosquitoes were exposed to concentrations up to 25 μmol/m. To evaluate the antiviral effect of atovaquone against CHIKV, we exposed female mosquitoes to 100 μmol/m atovaquone for 1h, after which the mosquitoes were immediately infected with CHIKV or ZIKV via bloodmeal. Atovaquone did not significantly reduce ZIKV or CHIKV infection in Ae. aegypti, but successfully blocked the transmission of CHIKV in saliva. Tarsal exposure to antiviral drugs could therefore be a potential new strategy to reduce virus transmission by mosquitoes.
Topics: Animals; Female; Zika Virus; Chikungunya virus; Aedes; Zika Virus Infection; Atovaquone; Mosquito Vectors; Chikungunya Fever; Antiviral Agents
PubMed: 37532005
DOI: 10.1016/j.antiviral.2023.105694 -
Case Reports in Infectious Diseases 2023Babesiosis is a tick-borne condition that causes hemolytic anemia and manifests with flu-like symptoms such as fevers, chills, fatigue, and anorexia. Very few case...
Babesiosis is a tick-borne condition that causes hemolytic anemia and manifests with flu-like symptoms such as fevers, chills, fatigue, and anorexia. Very few case reports have documented babesiosis infection associated with a false-positive HIV test. In this case report, we add to the current literature by describing a patient admitted for treatment of babesiosis who had a preliminary positive HIV test on admission and a negative repeat HIV test after one week of treatment for babesiosis. A 60-year-old male with a past medical history of high cholesterol presented to the Emergency Department after having abnormal laboratory tests with his primary care doctor. He reported fever, fatigue, anorexia, and worsening jaundice for three weeks. He was hypotensive and febrile on admission. A blood smear showed Babesia species with 1-2% infected red blood cells. He was admitted to the intensive care unit and received treatment with plasmapheresis, atovaquone, and antibiotics. The fourth-generation HIV 1/2 antigen/antibody test was initially positive but after treatment, HIV testing was negative. A misdiagnosis of HIV can greatly impact a patient's quality of life as antiretroviral therapy has multiple deleterious side effects. Clinicians must consider further evaluation of patients with acute babesiosis who also test positive for HIV.
PubMed: 37528903
DOI: 10.1155/2023/6271710