Drug resistance in protozoan parasites

Abstract

As with all other anti-infectives (antibiotics, anti-viral drugs, and anthelminthics), the limited arsenal of anti-protozoal drugs is being depleted by a combination of two factors: increasing drug resistance and the failure to replace old and often shamefully inadequate drugs, including those compromised by (cross)-resistance, through the development of new anti-parasitics. Both factors are equally to blame: a leaking bathtub may have plenty of water if the tap is left open; if not, it will soon be empty. Here, I will reflect on the factors that contribute to the drug resistance emergency that is unfolding around us, specifically resistance in protozoan parasites.Infections with protozoan pathogens will be with us for the foreseeable future. There is still no effective malaria vaccine despite enormous investment in money and effort over many years. Leishmaniasis is still spreading, including in Southern Europe. At least 100 million women worldwide suffer infection with the sexually transmitted Trichomonas vaginalis. Chagas Disease (American trypanosomiasis) affects communities from Texas to Argentina. Sleeping sickness (human African trypanosomiasis) remains a scourge in sub-Saharan Africa. Billions of people are infected with Toxoplasma gondii. Then, there are Cryptosporidium spp., Entamoeba histolytica, and Giardia spp. -but you get the idea.In almost all cases, we rely on treatment (no vaccines) with a few old drugs that would never pass safety evaluation if entered into trials now. Despite the clear clinical need, there is in fact very little serious new drug development going on for these protozoan infections, and what little there is, is driven by private organisations including the Medicines for Malaria Venture (MMV), the Drugs for Neglected Diseases initiative (DNDi), the Wellcome Trust (in part through its support of the Drug Development Unit at the University of Dundee), the Bill and Melinda Gates Foundation [in part through the Consortium for Parasitic Drug Development (CPDD)], and the Institute for OneWorld Health rather than governments or the private sector. These organisations do phenomenally good work with limited resources and have taken multiple new drugs or formulations into clinical use or trials. However, their budgets clearly fall far short of the level of effort that is needed to tackle all these neglected protozoan diseases. The investment discrepancy with welfare diseases such as obesity, atherosclerosis, diabetes, and some forms of cancer does not need further elaboration.Moreover, while malaria and the kinetoplastid diseases have a champion in MMV and DNDi, respectively, there is no such champion for trichomoniasis, cryptosporidiosis, giardiasis, toxoplasmosis, etc. And that is not mentioning important protozoan animal infections such as nagana (e.g. cattle; Trypanosoma congolense, T. brucei, and T. vivax), surra (e.g. camels, buffalo; T. evansi), babesiosis (cattle, dogs; Babesia bovis, B. canis), dourine (horses; T. equiperdum), theileriosis (cattle, sheep, goats; Theileria annulata...

Anti-parasitic activity of polyether ionophores

“…Another problem is that currently used anti-parasitic drugs have a number of limitations; they are difficult to administer, toxic, expensive and predominantly limited in scope, efficacy and/or availability [24][25][26]. Moreover, the phenomenon of drug resistance is spreading rapidly and many promising vaccines have not met expectations [27][28][29].…”

The Strong Anti-Kinetoplastid Properties of Bee Propolis: Composition and Identification of the Active Agents and Their Biochemical Targets

“…Thus, propolis is a source of natural compounds, preselected by evolution, against important neglected diseases such as leishmaniasis, sleeping sickness, and Chagas disease. The broad anti-kinetoplastid activity of propolis components reviewed here, together with the generally low toxicity to macrophages and experimental animals, beneficial immunomodulation, and our recent findings that the main bioactive metabolites (flavonoids) present in propolis are well absorbed and tolerated by the human body [154], gives ample scope for further investigations toward the rational development of anti-kinetoplastid drugs that will replace the existing ones, which have many undesirable side effects and often suffer from drug resistance after decades of use [155]. However, questions remain with regard to the efficacy of propolis components (such as flavonoids) in vivo since, although these compounds are often well absorbed, they are also rapidly metabolized particularly to glucuronides and sulfates.…”

The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History

“…It is a dogma in the pharmacology of infectious diseases that resistance will (eventually) occur for any drug. Certainly, the infectious agents have many tricks up their proverbial sleeves, often not anticipated [185]. Yet, there is no proof of suramin resistance in African trypanosomes, despite approximately 100 years of usage in East Africa.…”