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African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites Trypanosoma congolense and Trypanosoma vivax , is a major problem in cattle and other livestocks in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here, we report the repositioning of a compound series initially developed for the treatment of human African trypanosomiasis. A medicinal chemistry program, focused on deriving more soluble analogues, led to development of a lead compound capable of curing cattle infected with both T. congolense and T. vivax via intravenous dosing. Further optimization has the potential to yield a single-dose intramuscular treatment for this disease. Comprehensive mode of action studies revealed that the molecular target of this promising compound and related analogues is the cyclin-dependent kinase CRK12.

African Animal Trypanosomosis (AAT) is a major disease of cattle in Togo and its control is essentially based on chemotherapy. However, because of excessive use of trypanocides during the past decades, chemo-resistance in the parasites has developed. In order to assess the current situation of AAT and resistance to trypanocidal drugs in Northern Togo, a study was conducted on cattle from December 2012 to August 2013 in the regions of Kara and Savanes. An initial cross-sectional survey was carried out in 40 villages using the Haematocrit Centrifugation Technique (HCT). Out of these, 5 villages with a trypanosome prevalence of >10% were selected for a block treatment study (BT) with diminazene diaceturate (DA: 3.5mg/kg for a 14-day follow-up) and isometamidium chloride (ISM: 0.5mg/kg for a 28-day follow-up). Positive blood samples collected during the parasitological surveys and an equivalent number of negatives were further analyzed by PCR-RFLP for trypanosome species confirmation and molecular diagnosis of resistance to DA in Trypanosoma congolense. The results from 1883 bovine blood samples confirmed a high overall trypanosome prevalence of 10.8% in Northern Togo. PCR-RFLP revealed that T. congolense is the dominant pathogenic trypanosome species (50.5%) followed by T. vivax (27.3%), and T. brucei (16.2%). The BT showed varying levels of treatment failures ranging from 0 to 30% and from 0 to 50% for DA and for ISM respectively, suggesting the existence of resistant trypanosome populations in the study area. Our results show that AAT still represents a major obstacle to the development of cattle husbandry in Northern Togo. In areas of high AAT risk, a community-based integrated strategy combining vector control, rational use of trypanocidal drugs and improving the general condition of the animals is recommended to decision makers., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Trypanocidal drug resistance is unanimously recognized as a threat for livestock production in regions where the prevalence of trypanosomosis is high. To assess the impact of the disease and the effect of drug resistance on the health of small ruminants, twelve Trypanosoma vivax isolates collected in 6 villages in the vicinity of Bobo Dioulasso (Burkina Faso) were injected into 12 groups of 5 Sahelian goats, two being treated with 3.5mg/kg body weight diminazene aceturate (DA), two with 0.5mg/kg body weight isometamidium chloride (ISM) and one left untreated as control. A monitoring was performed every 5 days for 100 days to evaluate the parasitaemia by buffy coat examination, the hematocrit and the body weight. Among the 12 groups, 6 were additionally monitored using a trypanosome specific 18S-PCR-RFLP every 5 days from day 30 to day 100 to verify the complete clearance of the parasites from the blood of the hosts. In six groups of goats, trypanosomes disappeared completely after treatment, five groups showed relapses in at least one goat treated with ISM and one group showed relapses in one goat treated with DA and one with ISM. For the 6 groups that were screened both using microscopic examination and trypanosome specific 18S-PCR-RFLP, the following results were observed: for the groups treated with DA, no relapses by microscopic examination and 83.3% (10/12) using the 18S-PCR-RFLP. For the groups treated with ISM, 25% (3/12) relapses by microscopic examination and 83.3% with the 18S-PCR-RFLP (10/12). The evolution of the PCV and the weight during the observation period from relapsing (either by microscopical examination or by 18S-PCR-RFLP diagnosis) and non relapsing animals were compared. The relative average PCV in goats that relapsed microscopically, decreased significantly more than in non-relapsing goats. This difference was not significant when relapses were detected using the trypanosome specific 18S-PCR-RFLP. This indicates that only the animals with the highest parasitaemia suffered from the infection. Relapses after treatment where the host controls the parasitaemia to a level below the sensitivity of the microscopical examination do not affect body weight nor PCV., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Tsetse fly-transmitted African animal trypanosomosis causes annual losses that run into billions of dollars. The disease is assumed to cause hunger and poverty in most sub-Saharan countries since it represents a serious impediment to sustainable livestock production. Both a cross-sectional and a longitudinal study were carried out from November to December 2007 to evaluate trypanosomosis risk and susceptibility of trypanosomes to trypanocidal drug treatment in village cattle populations in south-east Mali., Methods: Eight purposively selected villages participated in the study. In each village, eight traps deployed along drainage lines over 24 hour duration were used to catch tsetse. One hundred systematically selected cattle in the study villages were examined for trypanosomes. All trypanosome-positive cattle were randomly allocated into two treatment groups: a group treated with 0.5 mg/kg bw. isometamidium chloride (ISMM) and a group treated with 3.5 mg/kg bw. diminazene aceturate (DIM). The cattle were monitored for trypanosomes at day 14 and 28 post-treatment., Results: Of the 796 cattle examined, 125 (15.7%) were trypanosome-positive. Village trypanosome prevalences ranged between 11% and 19%. There were no significant (p > 0.05) differences in the village trypanosome prevalences. Trypanosoma congolense was the dominant trypanosome species accounting for 73% (91/125) of the infections and T. vivax the remainder. Twenty (31.7%) of the 63 cattle on 0.5 mg/kg bw. ISMM treatment were still positive14 days post-treatment. Of the 43 aparasitaemic cattle monitored to day 28, 25.6% (11) became parasitaemic, resulting in a cumulative failure rate of 49.2% (31/63). Trypanosoma congolense accounted for 77.4% (24/31) of failed ISMM treatments. The 62 cattle treated with 3.5 mg/kg bw. DIM resulted in 30.6% (19/62) failed treatments. Although 42.2% (19/45) of T. congolense positive cattle did not respond to DIM treatment, all T. vivax positive cattle responded positively to DIM treatment., Conclusions: The overreliance on trypanocides in the control of trypanosomosis will ultimately lead to multiple drug-resistant trypanosome populations as detected in villages in south-east Mali rendering the use of drugs doubtful. Effective alternative methods for trypanosomosis control ought to substitute chemotherapy to ensure sustainable cattle production in these villages. Since there is no single strategy for containing trypanocidal drug resistance, promotion of an integrated approach combining proven trypanosomosis control approaches in high trypanosomosis risk areas is most desirous. The best-bet strategy this study recommended for areas with multiple drug resistance included area-wide community tsetse control, control of co-infections to exploit self-cure against resistant trypanosome populations and the rational use of trypanocidal drugs which should be urgently promoted at all levels as a way of containing or reversing resistance.

A longitudinal study assessed the chemoresistance to isometamidium chloride (ISM) and diminazene aceturate (DA) in the region of the Boucle du Mouhoun in Burkina Faso. A preliminary cross-sectional survey allowed the identification of the 10 villages with the highest parasitological prevalences (from 2.1% to 16.1%). In each of these 10 villages, two herds of approximately 50 bovines were selected, one being treated with ISM (1mg/kg b.w.) and the other remaining untreated as control group. All animals (treated and untreated herds) becoming infected were treated with DA (3.5mg/kg b.w.). In total, 978 head of cattle were followed up. Fortnightly controls of the parasitaemia and PCV were carried out during 8 weeks. The main trypanosome species was Trypanosoma vivax (83.6%) followed by Trypanosoma congolense (16.4%). In two villages, less than 25% of the control untreated cattle became positive indicating no need to use prophylactic treatment. These two villages were not further studied. Resistance to ISM was observed in 5 of the remaining 8 villages (Débé, Bendougou, Kangotenga, Mou and Laro) where the relative risk (control/treated hazard ratios) of becoming infected was lower than 2 i.e. between 0.89 (95% CI: 0.43-2.74) and 1.75 (95% CI: 0.57-5.37). In contrast, this study did not show evidence of resistance to DA in the surveyed villages with only 8.6% (n=93) of the cattle relapsing after treatment. Our results suggest that because of the low prevalence of multiple resistances in the area a meticulous use of the sanative pair system would constitute the best option to delay as much as possible the spread of chemoresistance till complete eradication of the disease by vector control operations., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Because of the development of resistance in trypanosomes to trypanocidal drugs, the livelihood of millions of livestock keepers in sub-Saharan Africa is threatened now more than ever. The existing compounds have become virtually useless and pharmaceutical companies are not keen on investing in the development of new trypanocides. We may have found a breakthrough in the treatment of resistant trypanosomal infections, through the combination of the trypanocide isometamidium chloride (ISM) with two affordable veterinary antibiotics., Methodology/principal Findings: In a first experiment, groups of mice were inoculated with Trypanosoma congolense strains resistant to ISM and either left untreated or treated with (i) tetracycline, (ii) ISM or (iii) the combination of the antibiotic and the trypanocide. Survival analysis showed that there was a significant effect of treatment and resistance to treatment on the survival time. The groups treated with ISM (with or without antibiotic) survived significantly longer than the groups that were not treated with ISM (P<0.01). The group treated with the combination trypanocide/antibiotic survived significantly longer than the group treated with ISM (P<0.01). In a second experiment, groups of cattle were inoculated with the same resistant trypanosome strain and treated with (i) ISM, (ii) ISM associated with oxytetracycline or (iii) ISM associated with enrofloxacine. All animals treated with ISM became parasitaemic. In the groups treated with ISM-oxytetracycline and ISM-enrofloxacine, 50% of the animals were cured. Animals from the groups treated with a combination trypanocide/antibiotic presented a significantly longer prepatent period than animals treated with ISM (p<0.001). The impact of the disease on the haematocrit was low in all ISM treated groups. Yet, it was lower in the groups treated with the combination trypanocide/antibiotic (p<0.01)., Conclusions/significance: After optimization of the administration protocol, this new therapeutic combination could constitute a promising treatment for livestock infected with drug resistant T. congolense.