Pneumocystis jirovecii pneumonia (PCP) is a life-threatening disease in allogeneic hematopoietic cell transplantation (HCT) recipients. Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred prophylaxis but has significant toxicity. We assessed 139 consecutive HCT patients for PCP prophylaxis in our center. According to our procedures, TMP-SMX should be given as first-line prophylaxis from engraftment. In case of intolerance, atovaquone (ATO) or aerosolized pentamidine may be given. Thirteen (9.3%) patients did not receive prophylaxis because they early died. Of the 126 prophylaxed patients, 113 (90%) received TMP-SMX and 13 (10%) received ATO as first-line regimen. However, only 51/113 (45%) patients received TMP-SMX as the sole prophylaxis: 60 patients were switched to ATO because of side effect. There were 18 PCP cases: 3 occurred before engraftment, 7 occurred under ATO, 3 occurred while prophylaxis was pending the resolution of side effects, and 5 occurred after stopping prophylaxis. No cases occurred under TMP-SMX while 7 (9.6%) cases occurred under first-(n = 13) or second (n = 60)-line ATO. There are many concerns about PCP prophylaxis after HCT: patients may develop PCP before engraftment or several months after stopping immunosuppressors, and half of them do not receive TMP-SMX all along the at-risk periods. New prophylactic drugs and strategies should be evaluated.

Canine theileriosis is a notorious tick borne piroplasmid infection of wild and domestic canines. The causative agent has not yet been accurately classified. PCR studies revealed that causative agent resembles to Theileria genus and thus provisionally named as Theileria annae. The other Theileria species reported in canines is Theileria annulata, Theileria equi and unnamed Theileria specie. This emergent canine infection is considered to be endemic in most of the European countries. However in Asia this disease has not been reported till date. The vectors responsible for transmission of this disease have not been determined. It has been suggested that DNA of Theileria annae has been detected in hard tick Ixodes hexagonus in Northwestern Spain and several other tick species. Clinically canine theileriosis is characterized by severe weakness, fever, hemoglobinuria and anemia. Recently atovaquone or buparvaquone plus azithromycin therapy showed better clinical efficacy. This comprehensive review is intended to summarize the current knowledge on prevalence and epidemiology of canine theileriosis in different countries of the world and associated tick vectors.

Heme is a key metabolic factor in all life. Malaria parasite has de novo heme-biosynthetic pathway, however the growth and development of parasite depend on the hemoglobin-derived heme metabolism process during the intraerythrocytic stages, such as the ingestion and degradation of hemoglobin in the food vacuole. The hemoglobin metabolism in the food vesicles mainly includes four aspects: hemoglobin transport and intake, hemoglobin enzymolysis to produce heme, heme polymerization into malarial pigment, and heme transport via the food vacuole. The potential mechanisms of antimalarial drugs,such as chloroquine, artemisinin and atovaquone may be related to this process. The main four aspects of this metabolic process, key metabolic enzymes, effects of antimalarial drugs on the process and their potential mechanism of action would be summarized in this paper, providing ideas for rational use and mechanism exploration of similar drugs.

Malaria is one of the most challenging human infectious diseases and both prevention and control have been hindered by the development of Plasmodium falciparum resistance to existing therapies. Several new compounds with novel mechanisms are in clinical development for the treatment of malaria including DSM265, an inhibitor of Plasmodium dihydroorotate dehydrogenase. In order to explore the mechanisms by which resistance might develop to DSM265 in the field, we selected for DSM265-resistant P. falciparum parasites in vitro. Any of five different amino acid changes led to reduced efficacy on the parasite and to decreased DSM265 binding to P. falciparum DHODH. The DSM265-resistant parasites retained full sensitivity to atovaquone. All but one of the observed mutations were in the DSM265 binding site, and the remaining C276F was in the adjacent flavin cofactor site. The C276F mutation was previously identified in a recrudescent parasite during a Phase IIa clinical study. We confirmed that this mutation (and the related C276Y) accounted for the full level of observed DSM265 resistance by re-generating the mutation using CRISPR/Cas9 genome editing. X-ray structure analysis of the C276F mutant enzyme showed that conformational changes of nearby residues were required to accommodate the larger F276 residue, which in turn led to a restriction in the size of the DSM265 binding pocket. These findings underscore the importance of developing DSM265 as part of a combination therapy with other agents for successful use against malaria.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and is the third most frequent cause of cancer-related deaths worldwide. The development of safe new anti-tumor agents has become increasingly important due to the steady rise in drug-resistant tumors. After assessing the efficacy of several candidate compounds that could inhibit hepatocellular carcinoma, we focused on atovaquone, an FDA-approved anti-malarial drug. In the present study, we found that atovaquone significantly inhibited hepatoma cell proliferation via S phase cell cycle arrest and both extrinsic and intrinsic apoptotic pathway induction associated with upregulation of p53 and p21. Molecular investigations demonstrated that atovaquone inhibits hepatoma cell proliferation by inducing double-stranded DNA breaks, leading to sustained activation of ataxia-telangiectasia mutated (ATM) and its downstream molecules such as cell cycle checkpoint kinase-2 (CHK2) and H2AX. In addition, we found that atovaquone also induced apoptosis, inhibited both cell proliferation and angiogenesis in vivo, and prolonged the survival time of tumor-bearing mice, without any obvious side effects. In conclusion, our data indicate that atovaquone is a safe and effective candidate drug that could be rapidly repurposed for HCC treatment.

Babesiosis caused by Babesia gibsoni is recognized throughout the world and can be difficult to treat. Resistance to atovaquone is associated with mutations in the B. gibsoni mitochondrial genome, specifically the M128 position of cytochrome b (cytb). The prevalence of cytb mutations in North America has not been reported.

Aerobic glycolysis is an important metabolic adaptation of cancer cells. There is growing evidence that oxidative phosphorylation is also an active metabolic pathway in many tumors, including in high grade serous ovarian cancer. Metastasized ovarian tumors use fatty acids for their energy needs. There is also evidence of ovarian cancer stem cells privileging oxidative phosphorylation (OXPHOS) for their metabolic needs. Metformin and thiazolidinediones such as rosiglitazone restrict tumor growth by inhibiting specific steps in the mitochondrial electron transport chain. These observations suggest that strategies to interfere with oxidative phosphorylation should be considered for the treatment of ovarian tumors. Here, we review the literature that supports this hypothesis and describe potential agents and critical control points in the oxidative phosphorylation pathway that can be targeted using small molecule agents. In this review, we also discuss potential barriers that can reduce the efficacy of the inhibitors of oxidative phosphorylation.

SUMMARYPrimary Toxoplasma gondii infection is usually subclinical, but cervical lymphadenopathy or ocular disease can be present in some patients. Active infection is characterized by tachyzoites, while tissue cysts characterize latent disease. Infection in the fetus and in immunocompromised patients can cause devastating disease. The combination of pyrimethamine and sulfadiazine (pyr-sulf), targeting the active stage of the infection, is the current gold standard for treating toxoplasmosis, but failure rates remain significant. Although other regimens are available, including pyrimethamine in combination with clindamycin, atovaquone, clarithromycin, or azithromycin or monotherapy with trimethoprim-sulfamethoxazole (TMP-SMX) or atovaquone, none have been found to be superior to pyr-sulf, and no regimen is active against the latent stage of the infection. Furthermore, the efficacy of these regimens against ocular disease remains uncertain. In multiple studies, systematic screening for Toxoplasma infection during gestation, followed by treatment with spiramycin for acute maternal infections and with pyr-sulf for those with established fetal infection, has been shown to be effective at preventing vertical transmission and minimizing the severity of congenital toxoplasmosis (CT). Despite significant progress in treating human disease, there is a strong impetus to develop novel therapeutics for both the acute and latent forms of the infection. Here we present an overview of toxoplasmosis treatment in humans and in animal models. Additional research is needed to identify novel drugs by use of innovative high-throughput screening technologies and to improve experimental models to reflect human disease. Such advances will pave the way for lead candidates to be tested in thoroughly designed clinical trials in defined patient populations.

Pneumomediastinum is a rare, potentially life-threatening complication of PCP that occurs in HIV-positive and HIV-negative patients. We are presenting a rare case pneumomediastinum caused by pneumocystis Jirovecii pneumonia in a HIV-negative patient with history of diffuse B-cell lymphoma on R CHOP chemotherapy. What is unique about our case is that the patient developed pneumomediastinum while in the hospital, on atovaquone that improved when switched to clindamycin and primaquine with improvement in her respiratory status. Another interesting point is that diagnosis was entertained due to the characteristic CT scan finding of ground glass opacities with cystic lung lesions and pneumomediastinum in an immunocompromised patient who was started on empirical treatment for PCP. The diagnosis was eventually confirmed with PCP PCR.