Recurrent Plasmodium falciparum Malaria in U.S. Travelers Treated with Artemether-Lumefantrine.

We report two cases of recurrent malaria in U.S. travelers returning from Africa (Ghana and Central African Republic) despite a full course of artemether-lumefantrine (AL).

Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance.

Artemisinins (ART) are critical anti-malarials and despite their use in combination therapy, ART-resistant Plasmodium falciparum is spreading globally. To counter ART resistance, we designed artezomibs (ATZs), molecules that link an ART with a proteasome inhibitor (PI) via a non-labile amide bond and hijack parasite's own ubiquitin-proteasome system to create novel anti-malarials in situ. Upon activation of the ART moiety, ATZs covalently attach to and damage multiple parasite proteins, marking them for proteasomal degradation.

Susceptibilities of Ugandan Plasmodium falciparum Isolates to Proteasome Inhibitors.

The proteasome is a promising target for antimalarial chemotherapy. We assessed susceptibilities of fresh Plasmodium falciparum isolates from eastern Uganda to seven proteasome inhibitors: two asparagine ethylenediamines, two macrocyclic peptides, and three peptide boronates; five had median IC values <100 nM. TDI8304, a macrocylic peptide lead compound with drug-like properties, had a median IC of 16 nM.

Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors.

With over 200 million cases and close to half a million deaths each year, malaria is a threat to global health, particularly in developing countries. , the parasite that causes the most severe form of the disease, has developed resistance to all antimalarial drugs. Resistance to the first-line antimalarial artemisinin and to artemisinin combination therapies is widespread in Southeast Asia and is emerging in sub-Saharan Africa.

Use of tafenoquine to treat a patient with relapsing babesiosis with clinical and molecular evidence of resistance to azithromycin and atovaquone.

Tafenoquine is a highly effective treatment for infections in animal models. An immunocompromised patient infected by a strain of that was at least partially resistant to both azithromycin and atovaquone was treated with tafenoquine. Systematic clinical studies using tafenoquine for treating other patients with babesiosis should be considered.

Can repurposing drugs play a role in malaria control?

Innovative drug treatments for malaria, optimally with novel targets, are needed to combat the threat of parasite drug resistance. As drug development efforts continue, there may be a role for a host-targeting, repurposed cancer drug administered together with an artemisinin combination therapy that was shown to improve the speed of recovery from a malaria infection.

Relapsed Infection Following Allogeneic Hematopoietic Cell Transplantation in a Patient With B-cell Acute Lymphoblastic Leukemia: Case Report and Review of the Literature.

A patient with relapsed/refractory B-cell acute lymphoblastic leukemia developed babesiosis before allogeneic hematopoietic cell transplantation while on atovaquone for pneumonia prophylaxis. Despite receiving a prolonged course of atovaquone and azithromycin until whole-blood DNA was no longer detected by polymerase chain reaction, her post-transplant course was complicated by relapsed babesiosis. We investigate the potential host and parasite characteristics causing relapsing/persistent infection.

Telomere length dynamics in response to DNA damage in malaria parasites.

Malaria remains a major cause of morbidity and mortality in the developing world. Recent work has implicated chromosome end stability and the repair of DNA breaks through telomere healing as potent drivers of variant antigen diversification, thus associating basic mechanisms for maintaining genome integrity with aspects of host-parasite interactions. Here we applied long-read sequencing technology to precisely examine the dynamics of telomere addition and chromosome end stabilization in response to double-strand breaks within subtelomeric regions.

Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages-erythrocytic, gametocyte, liver, and gamete activation stages-indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission-blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin-sensitive and artemisinin-resistant P.

The contribution of extrachromosomal DNA to genome plasticity in malaria parasites.

Malaria caused by the protozoan parasite Plasmodium falciparum continues to impose significant morbidity and mortality, despite substantial investment into drug and vaccine development and deployment. Underlying the resilience of this parasite is its remarkable ability to undergo genome modifications, thus, providing parasite populations with extensive genetic variability that accelerates selection of drug resistance and limits the efficacy of most vaccines. This genome plasticity is rooted in the mechanisms of DNA repair that parasites employ to maintain genome integrity, a process skewed toward homologous recombination through the evolutionary loss of classical nonhomologous end joining.

Vive la Différence: Exploiting the Differences between Rodent and Human Malarias.

Experimental research into malaria biology and pathogenesis has historically focused on two model systems, in vitro culture of the human parasite Plasmodium falciparum and in vivo infections of laboratory animals using rodent parasites. While there is clear value in having a manipulatable animal model for studying malaria, there have occasionally been controversies around how representative the rodent model is of the human disease, and therefore significant emphasis has been placed on the similarities between the two biological systems. By focusing on basic nuclear functions, we wish to highlight that identifying key differences in the parasites and their interactions with their mammalian hosts can be equally informative and provide remarkable insights into the biology and evolution of these important infectious organisms.

Case Report: Mucosal Leishmaniasis in New York City.

The six previously reported civilian cases of mucosal leishmaniasis (ML) diagnosed in the United States have all represented imported New World ML. We describe two new patients with ML diagnosed in New York City-a Syrian immigrant with a nasal mass (), the first report of Old World ML in the United States, and an American ecologist who worked in Bolivia and had been treated for cutaneous infection 23 years before developing lesions (. () ) initially of the uvula, soft palate, and posterior pharynx and subsequently the larynx.

Evolution of Host Specificity by Malaria Parasites through Altered Mechanisms Controlling Genome Maintenance.

The protozoan parasites that cause malaria infect a wide variety of vertebrate hosts, including birds, reptiles, and mammals, and the evolutionary pressures inherent to the host-parasite relationship have profoundly shaped the genomes of both host and parasite. Here, we report that these selective pressures have resulted in unexpected alterations to one of the most basic aspects of eukaryotic biology, the maintenance of genome integrity through DNA repair. Malaria parasites that infect humans continuously generate genetic diversity within their antigen-encoding gene families through frequent ectopic recombination between gene family members, a process that is a crucial feature of the persistence of malaria globally.

A Histone Methyltransferase Inhibitor Can Reverse Epigenetically Acquired Drug Resistance in the Malaria Parasite Plasmodium falciparum.

Malaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 () family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds, and parasites can acquire resistance by silencing gene expression, thereby reducing drug uptake.

Improvement of Asparagine Ethylenediamines as Anti-malarial -Selective Proteasome Inhibitors.

The proteasome (Pf20S) emerged as a target for antimalarials. Pf20S inhibitors are active at multiple stages of the parasite life cycle and synergize with artemisinins, suggesting that Pf20S inhibitors have potential to be prophylactic, therapeutic, and transmission blocking as well as are useful for combination therapy. We recently reported asparagine ethylenediamines (AsnEDAs) as immunoproteasome inhibitors and modified AsnEDAs as selective Pf20S inhibitors.

Rapid antigen diversification through mitotic recombination in the human malaria parasite Plasmodium falciparum.

Malaria parasites possess the remarkable ability to maintain chronic infections that fail to elicit a protective immune response, characteristics that have stymied vaccine development and cause people living in endemic regions to remain at risk of malaria despite previous exposure to the disease. These traits stem from the tremendous antigenic diversity displayed by parasites circulating in the field. For Plasmodium falciparum, the most virulent of the human malaria parasites, this diversity is exemplified by the variant gene family called var, which encodes the major surface antigen displayed on infected red blood cells (RBCs).

FIKK Kinase, a Ser/Thr Kinase Important to Malaria Parasites, Is Inhibited by Tyrosine Kinase Inhibitors.

A relatively high-affinity inhibitor of FIKK kinase from the malaria parasite was identified by in vitro assay of recombinant kinase. The FIKK kinase family is unique to parasitic organisms of the Apicomplexan order and has been shown to be critical in malaria parasites. The recombinant kinase domain was expressed and screened against a small molecule library, revealing a number of tyrosine kinase inhibitors that block FIKK kinase activity.

Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.

We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the proteasome (Pf20S) β5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against strains from patients in Africa. The β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and with artemisinin.

Pharmacological Disruption of Sea Urchin Tube Foot Motility and Behavior.

The understanding of the molecular basis of sea urchin behavior and sensory and motor systems lags far behind that of many other animal species. To investigate whole-animal behavior pharmacologically, we first demonstrated that immersion in drug solution is an effective drug administration route for sea urchins, whereas oral drug administration was found to be ineffective. Although intracoelomic injection was found to be effective at administering drugs, it was also found that injection itself can disrupt normal sea urchin behavior.

The anthraquinone emodin inhibits the non-exported FIKK kinase from Plasmodium falciparum.

The FIKK family of kinases is unique to parasites of the Apicomplexan order, which includes all malaria parasites. Plasmodium falciparum, the most virulent form of human malaria, has a family of 19 FIKK kinases, most of which are exported into the host red blood cell during malaria infection. Here, we confirm that FIKK 8 is a non-exported member of the FIKK kinase family.