New Approaches to Overcome Transport Related Drug Resistance in Trypanosomatid Parasites

Abstract

Leishmania and Trypanosoma are members of the Trypanosomatidae family that cause severe human infections such as leishmaniasis, Chagas disease, and sleeping sickness affecting millions of people worldwide. Despite efforts to eradicate them, migrations are expanding these infections to developing countries. There are no vaccines available and current treatments depend only on chemotherapy. Drug resistance is a major obstacle for the treatment of these diseases given that existing drugs are old and limited, with some having severe side effects. Most resistance mechanisms developed by these parasites are related with a decreased uptake or increased efflux of the drug due to mutations or altered expression of membrane transporters. Different new approaches have been elaborated that can overcome these mechanisms of resistance including the use of inhibitors of efflux pumps and drug carriers for both active and passive targeting. Here we review new formulations that have been successfully applied to circumvent resistance related to drug transporters, opening alternative ways to solve drug resistance in protozoan parasitic diseases.

Babesia microti Aldo-keto Reductase-Like Protein Involved in Antioxidant and Anti-parasite Response

“…In Schistosoma japonicum , a lead compound, which inhibited enzymatic activity of recombinant S. japonicum AKR but showed relatively low cytotoxicity against host cells, and it suggested that it may be potentially used in the treatment of Schistosomiasis ( Liu et al, 2013 ). A recent study identified variants in cytb and rpl4 that were associate with relapsing babesiosis ( Lemieux et al, 2016 ), but parasites often utilize various mechanisms for drug resistance ( Garcia-Salcedo et al, 2016 ; White, 2017 ). Therefore, to understand the role of BmAKR in the mechanism of action of anti- Babesia drugs and to improve chemotherapy of babesiosis, we studied Bmakr expression when B. microti is exposed to atovaquone, robenidine, quinine, and artemisinin.…”

Histone Deacetylases As Targets for Antitrypanosomal Drugs

“…Some genes responsible for drug resistance have already been identified and their detailing can contribute towards progress against treatment failure [ 102 ]. Moreover, compounds that are able to inhibit ABC transporters and drug delivery systems (such as nanoparticles, which increases efficacy) have been used as an alternative to reverse resistance [ 105 ].…”

Adaptation and Therapeutic Exploitation of the Plasma Membrane of African Trypanosomes

“…Moreover, a plethora of drugs have been developed through target-based strategies, and which fail against intact cells, likely due to difficulty in crossing biological membranes. In this regard, the development of nanobodies (Nbs), small (~15 kDa) antibody fragments derived from camelid heavy chains, has recently proved to provide an unparalleled opportunity to test this concept [99,100].…”

“…An improved formulation reduced by ~100-fold the curative dose required when compare to free pentamidine in a murine model [102]. In this scenario, the pentamidine-loaded nanoparticle coated with the anti-VSG Nb specifically targets variable regions of the VSG coat in the surface and is further internalized by a clathrin-dependent mechanism and the rapid surface proteome turnover, potentially overcoming resistance associated to mutations in AQP2 [12,99,100]. Although promising, several aspects need to be considered carefully before these findings can be effectively translated into clinical trials, as well as consideration of alternative Nb targets and means for production; such studies are currently in progress in our laboratory and elsewhere.…”