Drug resistance in pathogenic African trypanosomes: what hopes for the future?
Introduction
Trypanosomosis is a complex debilitating and often fatal disease caused by infection with one or more of the pathogenic tsetse-transmitted protozoan parasites of the genus Trypanosoma. The most important species responsible for the disease complex, commonly known as nagana in livestock, include Trypanosoma brucei, T. congolense and T. vivax, and the suid parasite T. simae, which is responsible for acute trypanosomosis in pigs. In Africa, Asia, the middle east and south America, T. evansi, the causative agent of surra, is important especially in draft and transport animals, and is exclusively transmitted mechanically by biting flies such as Tabanus and Stomoxys spp. On the other hand, T. gambiense and T. rhodesiense are the most important human pathogens responsible for West and East African sleeping sickness, respectively. It has long been established that Nagana renders approximately a quarter of Africa’s arable land mass unsuitable for profitable livestock farming (Molyneux, 1997). Losses in meat production, milk yield, and tractive power are estimated to cost approximately US$ 500 million annually and, if lost potential in livestock and crop production are also considered, then trypanosomosis may be costing Africa an estimated US$ 5 billion per year (ILRAD, 1994).
There is no effective vaccine against trypanosomes and in the absence of coherent environmentally friendly and sustainable vector control strategies, the control of trypanosomosis continues to rely principally on chemotherapy and chemoprophylaxis using the salts of three compounds: diminazene, an aromatic diamidine; homidium, a phenanthridine; and isometamidium, a phenanthridine–aromatic amidine (Leach and Roberts, 1981, ILRAD, 1990; Fig. 1). In addition, quinapyramine, suramin and recently, melarsen oxide cysteamine (cymelarsan) are generally used for therapy and prophylaxis of T. evansi (Leach and Roberts, 1981, Raynaud et al., 1989, Zhang et al., 1991, Ndoutamia et al., 1993). Of the six trypanocides, diminazene aceturate is the most commonly used therapeutic agent while isometamidium chloride is most commonly used as a prophylactic agent. These drugs, with the exception of cymelarsan, have been in use for at least 30 years. For instance, suramin has been in use since the 1920s, diminazene aceturate, homidium and quinapyramine were all introduced for field use in the 1950s, while isometamidium chloride came into field use in 1961 (Kinabo, 1993). Thus, cymelarsan, the trivalent water soluble analogue of the arsenical melarsoprol, introduced in 1985 for the exclusive treatment of T. evansi and other brucei-group trypanosome infections, and d,l-α-difluoromethyl-ornithine (DFMO) dubbed the ‘resurrection drug’, are the only new trypanocides commercially available for veterinary and human use, respectively, in over 30 years (Kuzoe, 1991, Raynaud et al., 1989).
The therapeutic and prophylactic use of trypanocides is beset by numerous limitations, including toxicity and the development of resistance by the parasites. The emergence of drug-resistant trypanosome strains is considered a very serious problem in trypanosomosis control, particularly for the resource-poor, at-risk populations and farmers in Africa and in the context of sustainable parasite control. Trypanosome resistance to trypanocides increases cost, reduces the efficiency of production and depletes the stock farmer of effective control tools (Donald, 1994). This increases the risk of environmental contamination due to progressive increase in frequency of use and dose rate of drugs with declining or little beneficial effects. Moreover, there is increased risk of toxicity from the use of large doses (Donald, 1994). Thus, the urgency for development of new, effective drugs with fewer problems associated with currently used drugs, cannot be over emphasized. Considerable work has been conducted in the last 2 decades on drug resistance in trypanosomosis and the search for alternative safe and effective therapeutic agents continues to be a future goal. In this review paper, we have highlighted some of the current status of knowledge concerning aspects of drug resistance in pathogenic trypanosomes, including strategies adopted to minimise development of resistance, possible areas of future research in new drug targets and alternative control strategies in the struggle against the human and livestock diseases caused by pathogenic trypanosomes.
Section snippets
Trypanocidal drug resistance in the field
Resistance to each of the commonly used animal trypanocides has emerged and has continued to mar effective veterinary management of trypanosomosis in Africa and elsewhere (Bacchi, 1993, Peregrine, 1994). From a historical perspective, it may be pertinent to mention that relapses were reported immediately after the introduction of suramin, the preferred drug for the treatment of camel trypanosomosis (Knowles, 1927). Nevertheless, such relapses were occasional and since a better alternative did
Mechanisms of tryoanocidal drug resistance
An understanding of the mechanisms of drug resistance by trypanosomes, among others, is important as it can lead to the identification of potential and novel drug targets and provide direction to how new chemotherapeutic strategies can be used to reduce development of resistance. In the latter instance rationale for combinations of existing drugs to increase therapeutic activity, decrease clinical toxicity and potentially reducing the frequency of the emergence of drug resistance (Barrett and
Cross- and multiple drug-resistance
As earlier stated, the treatment and prophylaxis of livestock trypanosomosis in Africa have largely depended on the use of diminazene, homidium, and isometamidium while quinapyramine is recommended for use against cameline and equine T. evansi trypanosomosis (Leach and Roberts, 1981, Ndoutamia et al., 1993). Ever since they were introduced more than 30 years ago resistance by strains of trypanosomes to each of these compounds has been reported in the field across Africa (Leach and Roberts, 1981
Sanative pairs
These are pairs of curative drugs which are not susceptible to cross-resistance between each other and thus could be used alternately in the field when resistance to either of them has occurred. This concept of sanative pairs of trypanocides was originally proposed by Whiteside (1958) with diminazene and homidium, or diminazene and isometamidium usually used in the field as sanative combinations (Whiteside, 1958, Whiteside, 1960, Whiteside, 1962). These pairs when strategically employed can be
Which way forward?
Due to antigenic variation, there is little or no hope for the production of anti-trypanosome vaccine in the foreseeable future. This, coupled with the limitations of current treatment methods such as toxicity and multiple drug resistance, has initiated the urgent search for more effective and less toxic chemotherapeutic agents in the fight against the disease. In this respect, proteinases of various pathogens have received attention as potential targets for chemotherapeutic intervention (
Concluding remarks
Because few trypanocidal drugs (both old and new) exist, there is no doubt that the development of individual resistance by pathogenic trypanosomes in the field portends a great danger to the control and treatment of trypanosomosis. Therefore, the emergence of multidrug-resistant field strains of the parasite is a serious problem in the management of the disease and a grave threat to livestock development and productivity in areas where they occur. In this review, we have highlighted the mode
Acknowledgements
The excellent library facilities provided by the Miyazaki Medical College greatly facilitated this work. DNO is a Japan Society for the Promotion of Science (JSPS) Postdoctoral Research Fellow and part of the work was supported by the Monbusho’s Grant-in Aid for JSPS Fellows.
References (99)
- et al.
Trypanocidal resistance in Trypanosoma evansi in vitro: effects of verapamil, cyproheptadine, combination with trypanocides
Vet. Parasitol.
(1996) - et al.
Lysis of trypanosomes by peptidylfluoromethyl ketones
Biochem. Biophys. Res. Commun.
(1990) Resistance to clinical drugs in African trypanosomes
Parasitol. Today
(1993)- et al.
Novel combination chemotherapy of experimental trypanosomiasis by using bleomycin and d,l-α-difluoromethylornithine: reversal by polyamines
Biochem. Pharmacol.
(1982) - et al.
The biochemical basis of arsenical-diamidine cross-resistance in African trypanosomes
Parasitol. Today
(1999) - et al.
A diamidine-resistant Trypanosoma equiperdum clone contains a P2 purine transporter with reduced substrate affinity
Mol. Biochem. Parasitol.
(1995) - et al.
Uptake of diamidine drugs by the P2 nucleoside transporter in melarsen-sensitive and -resistant Trypanosoma brucei brucei
J. Biol. Chem.
(1995) - et al.
Therapeutic effect of Berenil and Samorin in mice with four Trypanosoma populations isolated from Zambian cattle
Vet. Parasitol.
(1991) - et al.
Trypanosoma congolense: manifestation of resistance to Berenil and Samorin in cloned trypanosomes isolated from Zambian cattle
Int. J. Med. Microbiol. Virol. Parasitol. Infect. Dis.
(1992) - et al.
Characterization of melarsen resistant Trypanosoma brucei brucei with respect to other drugs and trypanothione metabolism
Mol. Biochem. Parasitol.
(1992)
The therapeutic and prophylactic properties of antrycide in trypanosomiasis of cattle
Br. Vet. J.
Flow cytofluorimetric analysis of drug accumulation by multidrug-resistant Trypanosoma brucei brucei and T. b. rhodesiense
Mol. Biochem. Parasitol.
Characterization of different proteolytic activities in Trypanosoma brucei brucei
Biochim. Biophys. Acta
Future prospects for the chemotherapy of human trypanosomiasis. 2. Combination chemotherapy and African trypanosomiasis
Trans. R. Soc. Trop. Med. Hyg.
Treatment with suramin and 2-substituted 5-nitroimidazoles of chronic murine Trypanosoma brucei
Trans. R. Soc. Trop. Med. Hyg.
Pharmacology of existing drugs for animal trypanosomiasis
Acta Trop.
Present status of chemotherapy and chemoprophylaxis of animal trypanosomiasis in the eastern hemisphere
Pharm. Therapeu.
Expression of resistance to isometamidium and diminazene in Trypanosoma congolense in Boran cattle infected by Glossina morsitans centralis
Acta Trop.
Long-term occurrence of Trypanosoma congolense resistant to diminazene, isometamidium and homidium in cattle at G hibe, Ethiopia
Acta Trop.
Occurrence of berenil resistant strains of T. vivax
Trans. R. Soc. Trop. Med. Hyg.
Mechanisms of action of phenanthridines and aminoquinaldine trypanocides
Adv. Chemother.
The effects of hyperosmolar agents lithium chloride and sucrose on the brain concentration of diminazene aceturate in rats
Acta Trop.
The rapid development of drug resistance by Trypanosoma evansi in immunosuppressed mice
Acta Trop.
Chemotherapy and delivery systems: haemoparasites
Vet. Parasitol.
Pharmacology of diminazene: a review
Acta Trop.
Induction of resistance to melarsenoxide cysteamine (Mel Cy) in Trypanosoma brucei brucei
Acta Trop.
Trypanosoma brucei: killing of bloodstream forms in vitro and in vivo by the cysteine proteinase inhibitor Z-Phe-Ala-CHN2
Exp. Parasitol.
Cysteine proteinase inhibitors kill cultured bloodstream forms of Trypanosoma brucei brucei
Exp. Parasitol.
Treatment of Gambian sleeping sickness in the Sudan with oral DFMO (d,l-α-difluoromethylornithine), an inhibitor of ornithine decarboxylase; first field trial
Trans. R. Soc. Trop. Med. Hyg.
In vivo and in vitro sensitivity of Trypanosoma evansi and T. equiperdum to diminazene, suramin, Mel Cy, quinapyramine and isometamidium
Acta Trop.
Combination therapy of trypanosomiasis using diminazene and non-steroidal anti-inflammatory drug
J. Chemother.
Isolation of drug-resistant strain of Trypanosoma congolense from the lower Shambelle region of southern Somalia
Trop. Anim. Hlth. Prod.
Isometamidium dextran complex: therapeutic activity against Trypanosoma vivax infection in Zebu cattle
J. Vet. Pharm. Therap.
Diminazene/Berenil: bioavailability and disposition in dairy goats
Acta Vet. Scand.
Clinical deafness associated with relapsing Trypanosoma brucei infection in a dog: a case report
Zaria Vet.
Effects of DFMO alone and in combination with levamisole in the treatment of experimental Trypanosoma congolense infections of rats
Bull. Anim. Hlth. Prod. Afr.
Effect of stage of infection with Trypanosoma evansi on cymelarsan therapy
Trop. Anim. Hlth. Prod.
Characterization of Trypanosoma brucei brucei S-adenosyl-l-methionine decarboxylase and its inhibition by berenil, pentamidine and methylglyoxal bis (quanylthydrazene)
Biochem. J.
In vitro activity of the trypanocidal diamidine DAPI on animal-infective Trypanosoma brucei brucei
Acta Trop.
Arsenical resistant trypanosomes lack an unusual adenosine transporter
Nature
Relapse infection after chemotherapy in dogs experimentally infected with Trypanosoma brucei brucei
J. Sm. Anim. Prac.
Efficacy of DFMO+bleomycin in a mouse model of central nervous system African trypanosomiasis
Proc. Natl. Acad. Sci. USA
A new drug combination for experimental late stage African trypanosomiasis: DFMO with suramin
Am. J. Trop. Med. Hyg.
Development of multiple drug resistance of Trypanosoma congolense in Zebu cattle under high natural tsetse fly challenge in the pastoral zone of Samorogouan, Burkina Faso
Acta Trop.
Epidemiolgoy of bovine trypanosomiasis in the Ghibe valley, southwest Ethiopia. 3. Occurrence of populations of Trypanosoma congolense resistant to diminazene, isometamidium and homidium
Acta Trop.
Parasite proteinasaes and amino acid metabolism: possibilities for chemotherapeutic exploitation
Parasitology
Cited by (83)
The continental atlas of tsetse and African animal trypanosomosis in Nigeria
2020, Acta TropicaCitation Excerpt :However, a number of challenges beset AAT prevention and control. The most commonly used trypanocides [i.e. diminazene aceturate and isometamidium chloride (Anene et al., 2001)] are obsolete (Giordani et al., 2016) and expensive for farmers. Additionally, because of inadequate support from veterinary services, livestock keepers often treat their animals with less-than-recommended doses of trypanocides, counterfeited medicines or indigenous plants (Atawodi et al., 2002; Grace et al., 2009; Kingsley, 2015), which often results in antimicrobial resistance (Chitambo and Arakawa, 1991; Kalu, 1995).
Sleeping sickness
2020, Molecular Advancements in Tropical Diseases Drug DiscoveryAlkynamide phthalazinones as a new class of TbrPDEB1 inhibitors (Part 2)
2019, Bioorganic and Medicinal ChemistryCitation Excerpt :The drugs against HAT currently available on the market have major disadvantages, including limited clinical efficacy in certain disease stages, complex administration protocols and toxicity.1,3–5 Additionally, the small repertoire of available drugs against HAT suffers from emerging drug resistance.6–10 While the number of new HAT cases has dropped considerably in the last few years,11 there remains an interest in developing novel and non-toxic trypanocidal agents.6–10
Thiazole, thio and semicarbazone derivatives against tropical infective diseases: Chagas disease, human African trypanosomiasis (HAT), leishmaniasis, and malaria
2019, European Journal of Medicinal ChemistryCitation Excerpt :There are many problems with the available treatments for these diseases. Treatment for Nagana includes drugs for prophylaxis and therapeutics, such as isomethadium chloride, diminazene aceturate, homidium bromide, and chloride salts [65–67]. One of the main problems of this therapy is the mutagenic-induced effect.