The rapid development of drug-resistance by Trypanosoma evansi in immunosuppressed mice

Osman, Abdullahi S.; Jennings, F. W.; Holmes, P.H.

doi:10.1016/0001-706x(92)90081-8

Cited by 38 publications

(25 citation statements)

References 26 publications

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“…Similar results have been obtained by other groups working on induction of trypanosome resistance to arsenicals (Frommel and Balber 1987;Osman et al 1992;Zhang et al 1993). Since Berenil-resistant field isolates of T. evansi have been shown to be sensitive to Cymelarsan, it will be interesting to observe whether this cross-resistance is also found in Cymelarsan-resistant field isolates that may be collected in the future.…”

Section: Discussionsupporting

confidence: 89%

“…This drug is a water-soluble, trivalent derivative of the arsenical drug Arsobal and has proved effective against T. evansi both in animal infections (Zweygarth et al 1992;Payne et al 1994) and in vitro (Zweygarth and Kaminsky 1990;Zhang et al 1992). Cymelarsan has been described as a curative agent only, but resistance to this drug has been induced readily in mice (Osman et al 1992) and in vitro (Zhang et al 1993).…”

Section: Introductionmentioning

confidence: 99%

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Alteration to one of three adenosine transporters is associated with resistance to Cymelarsan in Trypanosoma evansi

Ross¹,

Barns²

1996

Parasitology Research

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Continuous exposure of Trypanosoma evansi bloodstream forms to Cymelarsan in vitro resulted in the induction of resistance to the drug over a period of 4.5 months. Induction of resistance to Cymelarsan was accompanied by increased resistance to both Arsobal and Berenil, but Cymelarsan-resistant trypanosomes remained sensitive to Suramin and Antrycide. Since resistance to arsenical drugs in trypanosomes has been linked to changes in adenosine uptake, the adenosine metabolism in drug-sensitive and drug-resistant clones was measured. The initial rate of [3H]-adenosine uptake was much higher in sensitive trypanosomes than in drug-resistant parasites, but the amount of radiolabel accumulated by each population was similar. Both adenine and inosine inhibited incorporation of [3H]-adenosine in each population, but in quite different ways. Adenine inhibited more than 80% of adenosine incorporation in drug-sensitive trypanosomes but suppressed less than half of this process in the resistant population. In contrast, inosine inhibited only 10-15% of adenosine incorporation in the sensitive parasites but was inhibitory to a much greater extent in resistant trypanosomes. Lysis of drug-sensitive trypanosomes by 1 microM Cymelarsan was inhibited by adenosine, adenine and Berenil but not by inosine. Furthermore, in drug-sensitive trypanosomes, adenosine uptake could be reduced in three stages by the sequential addition of inosine, Berenil and adenine, whereas in drug-resistant parasites a reduction in adenosine uptake was caused only by the addition of inosine and adenine. These observations provide evidence that the acquisition of resistance to Cymelarsan is accompanied by the loss of one of three adenosine transporters in T. evansi. In drug-sensitive trypanosomes, this transporter mediates the entry of adenine and also of Cymelarsan and Berenil into the parasites.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Alteration to one of three adenosine transporters is associated with resistance to Cymelarsan in Trypanosoma evansi

Ross¹,

Barns²

1996

Parasitology Research

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“…By frequent passage in immunosuppressed mice given subcurative drug treatments, T. evansi was demonstrated to rapidly develop high levels of resistance to diminazene aceturate and isometamidium chloride, which did not happen in immunocompetent mice. Immunosuppression of animals by a heavy parasite burden or stressful conditions in conjunction with underdosing may therefore play an important role in the development of drug resistance under field conditions [195, 196]. Moreover, the quick degradation of the effectiveness of the host immune system induced by T. evansi may explain the deadlock in developing an efficient anti-trypanosome vaccine, despite the identification of several nonvariant surface-exposed trypanosome immunogens.…”

Section: Immunosuppressive Effectsmentioning

confidence: 99%

Trypanosoma evansiand Surra: A Review and Perspectives on Origin, History, Distribution, Taxonomy, Morphology, Hosts, and Pathogenic Effects

Desquesnes

Holzmüller

Lai

et al. 2013

BioMed Research International

348

327

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Trypanosoma evansi, the agent of “surra,” is a salivarian trypanosome, originating from Africa. It is thought to derive from Trypanosoma brucei by deletion of the maxicircle kinetoplastic DNA (genetic material required for cyclical development in tsetse flies). It is mostly mechanically transmitted by tabanids and stomoxes, initially to camels, in sub-Saharan area. The disease spread from North Africa towards the Middle East, Turkey, India, up to 53° North in Russia, across all South-East Asia, down to Indonesia and the Philippines, and it was also introduced by the conquistadores into Latin America. It can affect a very large range of domestic and wild hosts including camelids, equines, cattle, buffaloes, sheep, goats, pigs, dogs and other carnivores, deer, gazelles, and elephants. It found a new large range of wild and domestic hosts in Latin America, including reservoirs (capybaras) and biological vectors (vampire bats). Surra is a major disease in camels, equines, and dogs, in which it can often be fatal in the absence of treatment, and exhibits nonspecific clinical signs (anaemia, loss of weight, abortion, and death), which are variable from one host and one place to another; however, its immunosuppressive effects interfering with intercurrent diseases or vaccination campaigns might be its most significant and questionable aspect.

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“…S2). A medically relevant outcome of this analysis is that it provides a potential explanation for the prevalence of high-resistant infection in immunosuppressed patients [49], [50] (see Text S4 in File S1). …”

Section: Resultsmentioning

confidence: 99%

Resource Competition May Lead to Effective Treatment of Antibiotic Resistant Infections

Gomes

Segrè

2013

PLoS ONE

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Drug resistance is a common problem in the fight against infectious diseases. Recent studies have shown conditions (which we call antiR) that select against resistant strains. However, no specific drug administration strategies based on this property exist yet. Here, we mathematically compare growth of resistant versus sensitive strains under different treatments (no drugs, antibiotic, and antiR), and show how a precisely timed combination of treatments may help defeat resistant strains. Our analysis is based on a previously developed model of infection and immunity in which a costly plasmid confers antibiotic resistance. As expected, antibiotic treatment increases the frequency of the resistant strain, while the plasmid cost causes a reduction of resistance in the absence of antibiotic selection. Our analysis suggests that this reduction occurs under competition for limited resources. Based on this model, we estimate treatment schedules that would lead to a complete elimination of both sensitive and resistant strains. In particular, we derive an analytical expression for the rate of resistance loss, and hence for the time necessary to turn a resistant infection into sensitive (tclear). This time depends on the experimentally measurable rates of pathogen division, growth and plasmid loss. Finally, we estimated tclear for a specific case, using available empirical data, and found that resistance may be lost up to 15 times faster under antiR treatment when compared to a no treatment regime. This strategy may be particularly suitable to treat chronic infection. Finally, our analysis suggests that accounting explicitly for a resistance-decaying rate may drastically change predicted outcomes in host-population models.

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The rapid development of drug-resistance by Trypanosoma evansi in immunosuppressed mice

Cited by 38 publications

References 26 publications

Alteration to one of three adenosine transporters is associated with resistance to Cymelarsan in Trypanosoma evansi

Alteration to one of three adenosine transporters is associated with resistance to Cymelarsan in Trypanosoma evansi

Trypanosoma evansiand Surra: A Review and Perspectives on Origin, History, Distribution, Taxonomy, Morphology, Hosts, and Pathogenic Effects

Resource Competition May Lead to Effective Treatment of Antibiotic Resistant Infections

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