Membrane active chelators as novel anti-African trypanosome and anti-malarial drugs

AbstractMalaria (Plasmodium spp.) and human African trypanosomiasis (Trypanosoma brucei spp.) are vector borne, deadly parasitic diseases. While chemotherapeutic agents for both diseases are available, difficulty in disease eradication and development of drug resistance require that new therapies targeting unexplored pathways or exploiting novel modes of action be developed. Intracellular Plasmodium and extracellular Trypanosoma brucei may have unique and essential requirements for divalent metal ions, beyond that deemed physiological for the host. Membrane Active Chelators (MACs), biologically active only in a hydrophobic lipid environment, are able to bind metal ions at elevated non-physiological concentrations in the vicinity of cell membranes. A dose–response relationship study using validated viability assays revealed that two MAC drugs, DP-b99 and DP-460, were cytotoxic for these parasites in vitro. The 50% effective concentration (EC50) values for DP-b99 and DP-460 were 87μM and 39μM for Trypanosoma brucei brucei and 21μM and 28μM for erythrocytic Plasmodium falciparum, respectively. Furthermore, drug potency was maintained for at least 24h in serum containing medium at 37°C. While the exact mechanism of action of MACs against intracellular malaria and extracellular African trypanosome parasites has yet to be determined, their potential as antiparasitic agents warrants further investigation

Broadening Participation in Biology Education Research: Engaging Community College Students and Faculty

Nearly half of all undergraduates are enrolled at community colleges (CCs), including the majority of U.S. students who represent groups underserved in the sciences. Yet only a small minority of studies published in discipline-based education research journals address CC biology students, faculty, courses, or authors. This marked underrepresentation of CC biology education research (BER) limits the availability of evidence that could be used to increase CC student success in biology programs. To address this issue, a diverse group of stakeholders convened at the Building Capacity for Biology Education Research at Community Colleges meeting to discuss how to increase the prevalence of CC BER and foster participation of CC faculty as BER collaborators and authors. The group identified characteristics of CCs that make them excellent environments for studying biology teaching and learning, including student diversity and institutional cultures that prioritize teaching, learning, and assessment. The group also identified constraints likely to impede BER at CCs: limited time, resources, support, and incentives, as well as misalignment between doing research and CC faculty identities as teachers. The meeting culminated with proposing strategies for faculty, administrators, journal editors, scientific societies, and funding agencies to better support CC BER

Clinically relevant atovaquone-resistant human malaria parasites fail to transmit by mosquito.

Long-acting injectable medications, such as atovaquone, offer the prospect of a "chemical vaccine" for malaria, combining drug efficacy with vaccine durability. However, selection and transmission of drug-resistant parasites is of concern. Laboratory studies have indicated that atovaquone resistance disadvantages parasites in mosquitoes, but lack of data on clinically relevant Plasmodium falciparum has hampered integration of these variable findings into drug development decisions. Here we generate atovaquone-resistant parasites that differ from wild type parent by only a Y268S mutation in cytochrome b, a modification associated with atovaquone treatment failure in humans. Relative to wild type, Y268S parasites evidence multiple defects, most marked in their development in mosquitoes, whether from Southeast Asia (Anopheles stephensi) or Africa (An. gambiae). Growth of asexual Y268S P. falciparum in human red cells is impaired, but parasite loss in the mosquito is progressive, from reduced gametocyte exflagellation, to smaller number and size of oocysts, and finally to absence of sporozoites. The Y268S mutant fails to transmit from mosquitoes to mice engrafted with human liver cells and erythrocytes. The severe-to-lethal fitness cost of clinically relevant atovaquone resistance to P. falciparum in the mosquito substantially lessens the likelihood of its transmission in the field

Novel antitrypanosomal agents

Trypanosomes are the causative agents of Chagas' disease in Central and South America and sleeping sickness in sub-Saharan Africa. The current chemotherapy of the human trypanosomiases relies on only six drugs, five of which were developed > 30 years ago. In addition, these drugs display undesirable toxic side effects and the emergence of drug-resistant trypanosomes has been reported. Therefore, the development of new drugs in the treatment of Chagas' disease and sleeping sickness is urgently required. This article summarises the recent progress in identifying novel lead compounds for antitrypanosomal chemotherapy. Particular emphasis is placed on those agents showing promising, selective antitrypanosomal activity

Malaria-Infected Mice Are Completely Cured by One 6 mg/kg Oral Dose of a New Monomeric Trioxane Sulfide Combined with Mefloquine

Sixteen new anilide derivatives of the natural trioxane artemisinin were prepared and evaluated for antimalarial efficacy in <i>Plasmodium berghei</i> infected mice. Of these 16 new anilides administered orally as one 6 mg/kg dose combined with 18 mg/kg mefloquine hydrochloride, only sulfide 3-arteSanilide <b>12d</b> was completely curative: on day 30 after infection, all mice in this group had no detectable parasitemia, gained as much weight as the uninfected control mice, and behaved normally

Synthesis and structure-activity relationships of new quinolone-type molecules against Trypanosoma brucei

Human African trypanosomiasis (HAT) or sleeping sickness is caused by two subspecies of Trypanosoma brucei , Trypanosoma brucei gambiense , and Trypanosoma brucei rhodesiense and is one of Africa's old plagues. It causes a huge number of infections and cases of death per year because, apart from limited access to health services, only inefficient chemotherapy is available. Since it was reported that quinolones such as ciprofloxacin show antitrypanosomal activity, a novel quinolone-type library was synthesized and tested. The biological evaluation illustrated that 4-quinolones with a benzylamide function in position 3 and cyclic or acyclic amines in position 7 exhibit high antitrypanosomal activity. Structure-activity relationships (SAR) are established to identify essential structural elements. This analysis led to lead structure 29, which exhibits promising in vitro activity against T. b. brucei (IC(50) = 47 nM) and T. b. rhodesiense (IC(50) = 9 nM) combined with low cytotoxicity against macrophages J774.1. Screening for morphological changes of trypanosomes treated with compounds 19 and 29 suggested differences in the morphology of mitochondria of treated cells compared to those of untreated cells. Segregation of the kinetoplast is hampered in trypanosomes treated with these compounds; however, topoisomerase II is probably not the main drug targe