TY - JOUR
T1 - An update on African trypanocide pharmaceutics and resistance
AU - Kasozi, Keneth
AU - MacLeod, Ewan T
AU - Ntulume, Ibrahim
AU - Fyfe, Jenna
AU - Welburn, Susan C
N1 - Funding Information:
This research was supported by the National Institute for Health Research (NIHR) Global Health Research Programme (16/136/33) using UK aid from the UK government. This work was also supported by Zhejiang University Education Foundation Emergency Research Fund, Global Challenges Research Fund, and the University of Edinburgh (SW and KK). The work was also funded by the Commonwealth Scholarship Commission (grant ID number: UGCS-2021-447) in the UK (KK).
Funding Information:
To preserve the efficacy of presently utilized drugs, it is critical to justify drug dose regimens based on whether the trypanosome species found in a specific region are phenotypically susceptible to trypanocide. Amid the continuing effort to develop new therapeutic and prophylactic trypanocidal drugs through Global Alliance for Livestock Veterinary Medicines (GALVmed), a public–private partnership with financial support from the Bill and Melinda Gates Foundation and the UK Department for International Development ( http://www.galvmed.org/en/ ), no novel authorized drug has been developed for the last 50 years, necessitating the urgency to focus on innovative drug discoveries. Notwithstanding this need, a majority of the pharmaceutical industries have been discouraged to further invest drug discoveries due to the elevated expenses required in medicine development and the poor projected return on chemotherapy sales in developing countries ().
Publisher Copyright:
Copyright © 2022 Kasozi, MacLeod, Ntulume and Welburn.
PY - 2022/3/7
Y1 - 2022/3/7
N2 - African trypanosomiasis is associated with
Trypanosoma evansi, T. vivax, T. congolense, and
T. brucei pathogens in African animal trypanosomiasis (AAT) while
T. b gambiense and
T. b rhodesiense are responsible for chronic and acute human African trypanosomiasis (HAT), respectively. Suramin sodium suppresses ATP generation during the glycolytic pathway and is ineffective against
T. vivax and
T. congolense infections. Resistance to suramin is associated with pathogen altered transport proteins. Melarsoprol binds irreversibly with pyruvate kinase protein sulfhydryl groups and neutralizes enzymes which interrupts the trypanosome ATP generation. Melarsoprol resistance is associated with the adenine-adenosine transporter, P2, due to point mutations within this transporter. Eflornithine is used in combination with nifurtimox. Resistance to eflornithine is caused by the deletion or mutation of TbAAT6 gene which encodes the transmembrane amino acid transporter that delivers eflornithine into the cell, thus loss of transporter protein results in eflornithine resistance. Nifurtimox alone is regarded as a poor trypanocide, however, it is effective in melarsoprol-resistant gHAT patients. Resistance is associated with loss of a single copy of the genes encoding for nitroreductase enzymes. Fexinidazole is recommended for first-stage and non-severe second-stage illnesses in gHAT and resistance is associated with trypanosome bacterial nitroreductases which reduce fexinidazole. In AAT, quinapyramine sulfate interferes with DNA synthesis and suppression of cytoplasmic ribosomal activity in the mitochondria. Quinapyramine sulfate resistance is due to variations in the potential of the parasite's mitochondrial membrane. Pentamidines create cross-links between two adenines at 4-5 pairs apart in adenine-thymine-rich portions of
Trypanosoma DNA. It also suppresses type II topoisomerase in the mitochondria of
Trypanosoma parasites. Pentamidine resistance is due to loss of mitochondria transport proteins P2 and HAPT1. Diamidines are most effective against
Trypanosome brucei group and act
via the P2/TbAT1 transporters. Diminazene aceturate resistance is due to mutations that alter the activity of P2, TeDR40 (
T. b. evansi). Isometamidium chloride is primarily employed in the early stages of trypanosomiasis and resistance is associated with diminazene resistance. Phenanthridine (homidium bromide, also known as ethidium bromide) acts by a breakdown of the kinetoplast network and homidium resistance is comparable to isometamidium. In humans, the development of resistance and adverse side effects against monotherapies has led to the adoption of nifurtimox-eflornithine combination therapy. Current efforts to develop new prodrug combinations of nifurtimox and eflornithine and nitroimidazole fexinidazole as well as benzoxaborole SCYX-7158 (AN5568) for HAT are in progress while little comparable progress has been done for the development of novel therapies to address trypanocide resistance in AAT.
AB - African trypanosomiasis is associated with
Trypanosoma evansi, T. vivax, T. congolense, and
T. brucei pathogens in African animal trypanosomiasis (AAT) while
T. b gambiense and
T. b rhodesiense are responsible for chronic and acute human African trypanosomiasis (HAT), respectively. Suramin sodium suppresses ATP generation during the glycolytic pathway and is ineffective against
T. vivax and
T. congolense infections. Resistance to suramin is associated with pathogen altered transport proteins. Melarsoprol binds irreversibly with pyruvate kinase protein sulfhydryl groups and neutralizes enzymes which interrupts the trypanosome ATP generation. Melarsoprol resistance is associated with the adenine-adenosine transporter, P2, due to point mutations within this transporter. Eflornithine is used in combination with nifurtimox. Resistance to eflornithine is caused by the deletion or mutation of TbAAT6 gene which encodes the transmembrane amino acid transporter that delivers eflornithine into the cell, thus loss of transporter protein results in eflornithine resistance. Nifurtimox alone is regarded as a poor trypanocide, however, it is effective in melarsoprol-resistant gHAT patients. Resistance is associated with loss of a single copy of the genes encoding for nitroreductase enzymes. Fexinidazole is recommended for first-stage and non-severe second-stage illnesses in gHAT and resistance is associated with trypanosome bacterial nitroreductases which reduce fexinidazole. In AAT, quinapyramine sulfate interferes with DNA synthesis and suppression of cytoplasmic ribosomal activity in the mitochondria. Quinapyramine sulfate resistance is due to variations in the potential of the parasite's mitochondrial membrane. Pentamidines create cross-links between two adenines at 4-5 pairs apart in adenine-thymine-rich portions of
Trypanosoma DNA. It also suppresses type II topoisomerase in the mitochondria of
Trypanosoma parasites. Pentamidine resistance is due to loss of mitochondria transport proteins P2 and HAPT1. Diamidines are most effective against
Trypanosome brucei group and act
via the P2/TbAT1 transporters. Diminazene aceturate resistance is due to mutations that alter the activity of P2, TeDR40 (
T. b. evansi). Isometamidium chloride is primarily employed in the early stages of trypanosomiasis and resistance is associated with diminazene resistance. Phenanthridine (homidium bromide, also known as ethidium bromide) acts by a breakdown of the kinetoplast network and homidium resistance is comparable to isometamidium. In humans, the development of resistance and adverse side effects against monotherapies has led to the adoption of nifurtimox-eflornithine combination therapy. Current efforts to develop new prodrug combinations of nifurtimox and eflornithine and nitroimidazole fexinidazole as well as benzoxaborole SCYX-7158 (AN5568) for HAT are in progress while little comparable progress has been done for the development of novel therapies to address trypanocide resistance in AAT.
U2 - 10.3389/fvets.2022.828111
DO - 10.3389/fvets.2022.828111
M3 - Article
C2 - 35356785
SN - 2297-1769
VL - 9
JO - Frontiers in Veterinary Science
JF - Frontiers in Veterinary Science
M1 - 828111
ER -