Perspectives From Systems Biology to Improve Knowledge of Leishmania Drug Resistance

Abstract

Neglected Tropical Diseases include a broad range of pathogens, hosts, and vectors, which represent evolving complex systems. Leishmaniasis, caused by different Leishmania species and transmitted to humans by sandflies, are among such diseases. Leishmania and other Trypanosomatidae display some peculiar features, which make them a complex system to study. Leishmaniasis chemotherapy is limited due to high toxicity of available drugs, long-term treatment protocols, and occurrence of drug resistant parasite strains. Systems biology studies the interactions and behavior of complex biological processes and may improve knowledge of Leishmania drug resistance. System-level studies to understand Leishmania biology have been challenging mainly because of its unusual molecular features. Networks integrating the biochemical and biological pathways involved in drug resistance have been reported in literature. Antioxidant defense enzymes have been identified as potential drug targets against leishmaniasis. These and other biomarkers might be studied from the perspective of systems biology and systems parasitology opening new frontiers for drug development and treatment of leishmaniasis and other diseases. Our main goals include: 1) Summarize current advances in Leishmania research focused on chemotherapy and drug resistance. 2) Share our viewpoint on the application of systems biology to Leishmania studies. 3) Provide insights and directions for future investigation.

In silico screening, molecular dynamic simulations, and in vitro activity of selected natural compounds as an inhibitor of Leishmania donovani 3-mercaptopyruvate sulfurtransferase

“…The most common drugs used for treating leishmaniasis are pentavalent antimonial, amphotericin B, miltefosine, paromomycin, and pentamidine (Chakravarty and Sundar 2019 ; Singh and Kumar 2014 ). However, these drug treatments suffer from one or more limitations, such as treatment failure (Ponte-Sucre et al 2017 ), resistance (Horacio et al 2021 ), longer half-life (Reimao et al 2020 ), relapses after treatment (Araújo et al 2021 ), toxicity (Arenas et al 2017 ), or higher cost (Azim et al 2021 ). Considering the absence of a vaccine, a number of alternative strategies are being researched from a range of significant pathways to create a new drug for the disease (Ranjan et al 2020 ; Vijayakumar et al 2019 ; Vijayakumar and Das 2018 ).…”

Strategies in the drug discovery and development for leishmaniasis: immunomodulators, natural products, synthetic compounds, and drug repositioning

“…In addition to the differences in sensitivity naturally existing between the species of Leishmania to available drugs, there is also an increase in the reports of the emergence of resistance to these drugs Uliana et al, 2018). Leishmania resistance mechanisms to conventional treatments involve a number of factors, such as molecular modifications of the parasite such as ATP-binding cassette (ABC) and aquaporin (AQP) transporters, changes in the lipid membrane, and oxidative stress Horaćio et al, 2021). Leishmania Viannia braziliensis is the main etiological agent of American tegumentary leishmaniasis (ATL) and associated with the cutaneous (CL) and mucocutaneous (ML) forms, including in Brazil, with frequent reports of refractoriness to treatment (Amato et al, 2008;Rugani et al, 2018;Anversa et al, 2018).…”

Therapeutic effect of oral quercetin in hamsters infected with Leishmania Viannia braziliensis

“…In addition to the differences in sensitivity naturally existing between the species of Leishmania to available drugs, there is also an increase in the reports of the emergence of resistance to these drugs (Ponte-Sucre et al, 2017;Uliana et al, 2018). Leishmania resistance mechanisms to conventional treatments involve a number of factors, such as molecular modifications of the parasite such as ATP-binding cassette (ABC) and aquaporin (AQP) transporters, changes in the lipid membrane, and oxidative stress (Ponte-Sucre et al, 2017;Horaćio et al, 2021). Leishmania Viannia braziliensis is the main etiological agent of American tegumentary leishmaniasis (ATL) and associated with the cutaneous (CL) and mucocutaneous (ML) forms, including in Brazil, with frequent reports of refractoriness to treatment (Amato et al, 2008;Rugani et al, 2018;Anversa et al, 2018).…”