Drug Resistance in Protozoa

Geary, Timothy G.; Edgar, S. A.; Jensen, James B.

doi:10.1007/978-1-4684-1233-8_10

Cited by 13 publications

(9 citation statements)

References 152 publications

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“…Regrettably, the existing collection of antileishmanial drugs is far from ideal, primarily due to their lack of selectivity toward the metabolic machinery of the parasite. Drug toxicity, as well as increased drug resistance (24,40), reinforces the need to develop new therapeutics and to identify and validate new drug targets.…”

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confidence: 99%

Spermidine Synthase Is Required for Virulence of Leishmania donovani

et al. 2011

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Genetic lesions in the polyamine biosynthetic pathway of Leishmania donovani, the causal agent of visceral leishmaniasis, are conditionally lethal mutations that render the insect vector form of the parasite auxotrophic for polyamines. Recently, we have demonstrated that a ⌬odc L. donovani null mutant lacking ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, was profoundly compromised in its ability to infect mice, indicating that ODC is essential for the infectious mammalian stage of the parasite and further validating the enzyme as a possible drug target. To assess whether other components of the polyamine biosynthetic pathway were also essential for parasite virulence, a cell line deficient in spermidine synthase (SPDSYN), the enzyme that converts putrescine to spermidine, was created by double-targeted gene replacement within a virulent L. donovani background. This ⌬spdsyn strain was auxotrophic for polyamines, required spermidine for growth in its insect vector form, and was adversely impacted in its ability to infect mice. These findings establish that SPDSYN, like ODC, is essential for maintaining a robust infection in mammals and indicate that pharmacologic inhibition of SPDSYN, and perhaps all components of the polyamine biosynthetic pathway, is a valid therapeutic strategy for the treatment of visceral and, potentially, other forms of leishmaniasis.

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confidence: 99%

Spermidine Synthase Is Required for Virulence of Leishmania donovani

et al. 2011

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“…There is no effective vaccine for leishmaniasis, and therefore, chemotherapy is the only means available to combat the disease. Unfortunately, the current arsenal of antileishmanial drugs is far from ideal, principally due to toxicity for the host, for which a lack of target specificity is the chief culprit, and to the acquisition of drug resistance (23,38). Thus, the identification and validation of new drug targets, particularly for treating visceral leishmaniasis, are imperative.…”

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confidence: 99%

Leishmania donovani Ornithine Decarboxylase Is Indispensable for Parasite Survival in the Mammalian Host

et al. 2009

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Mutations within the polyamine biosynthetic pathway of Leishmania donovani, the etiological agent of visceral leishmaniasis, confer polyamine auxotrophy to the insect vector or promastigote form of the parasite. However, whether the infectious or amastigote form of the parasite requires an intact polyamine pathway has remained an open question. To address this issue, conditionally lethal ⌬odc mutants lacking ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, were created by double targeted gene replacement within a virulent strain of L. donovani. ODC-deficient promastigotes and axenic amastigotes were auxotrophic for polyamines and capable of robust growth only when exogenous putrescine was supplied in the culture medium, confirming that polyamine biosynthesis is an essential nutritional pathway for L. donovani promastigotes. To assess whether the ⌬odc lesion also affected the ability of amastigotes to sustain a robust infection, macrophage and mouse infectivity experiments were performed. Parasite loads in murine macrophages infected with each of two independent ⌬odc knockout lines were decreased ϳ80% compared to their wild-type counterpart. Furthermore, ␣-difluoromethylornithine, a suicide inhibitor of ODC, inhibited growth of wild-type L. donovani amastigotes and effectively cured macrophages of parasites, thereby preventing host cell destruction. Strikingly, however, parasitemias of both ⌬odc null mutants were reduced by 6 and 3 orders of magnitude, respectively, in livers and spleens of BALB/c mice. The compromised infectivity phenotypes of the ⌬odc knockouts in both macrophages and mice were rescued by episomal complementation of the genetic lesion. These genetic and pharmacological studies strongly implicate ODC as an essential cellular determinant that is necessary for the viability and growth of both L. donovani promastigotes and amastigotes and intimate that pharmacological inhibition of ODC is a promising therapeutic paradigm for the treatment of visceral and perhaps other forms of leishmaniasis.

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“…The single-passage selection method described here for obtaining a decoquinate-resistant line is much faster and less laborious than the repeated passaging of coccidia through chicks given progressively greater suboptimal doses of drug (see McLoughlin, 1970;Chapman, 1982Chapman, , 1985Chapman, , 1986bGeary et al, 1985) or the continuous recycling of infections through chicks on litter (Ryley & Betts, 1973;Geary et al, 1985), and also involves a minimal risk of contamination with extraneous coccidia. Furthermore, the use of a range of drug concentrations both for the selection passages and for the sensitivity tests is more reliable (Ryley & Betts, 1973) than comparisons, on the basis of anticoccidial indices, made between lines passaged through the same single concentration that is used for the sensitivity test (e.g.…”

Section: Demonstration Of Single-passage Selection Of Drugresistant Mmentioning

confidence: 99%

“…Cuckler et al, 1969;Joyner, 1970;McLoughlin, 1970;Ryley & Betts, 1973;Chapman, 1978Chapman, , 1982Chapman, , 1984Chapman, , 1986aJeffers, 1978Jeffers, , 1989Ryley, 1980;Geary et al, 1985). In recent years, attention has been directed to mechanisms of resistance and experimental methods of inducing resistance (Ryley, 1980;Chapman, 1982;Geary et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

“…Attempts to develop a standard laboratory test that can consistently predict the likely speed of emergence of resistance to a new anticoccidial drug in the field have so far failed (see Joyner, 1970;Ryley, 1980;Geary et al, 1985). Furthermore, Norton & Joyner (1975) found it impossible to standardize a schedule of inoculations and drug administration which would enable the development of resistance to different drugs to be compared directly.…”

Section: Introductionmentioning

confidence: 99%

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A laboratory method for the single‐passage selection of drug‐resistant mutants from populations ofEimeriaspecies in chickens and its potential value in the choice of field use concentrations for new anticoccidial drugs

Williams¹

1998

Avian Pathology

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Populations of Eimeria species in chickens frequently include mutants that are resistant to an anticoccidial drug without having been previously exposed to it. Such mutants are described here as 'inherently resistant'. A novel laboratory method of selecting them from their parent populations is described. Selection may be achieved in a single in vivo passage in chickens. Decoquinate-resistant mutants were selected from a previously unexposed E. tenella strain: they tolerated > 0.625% w/w decoquinate in the food of chicks, whilst the rest of the population was sensitive to < 0.002% w/w. This single-passage method has a unique advantage over others; development of resistance to different drugs may be validly compared by using a single criterion, the lowest selective concentration (LSC), all other experimental factors remaining constant. Furthermore, the method is economical with time, facilities and experimental animals, and may have a predictive value in the choice of use concentrations for new anticoccidial agents. A potential selection index (PSI), the proposed or actual field use concentration of a drug divided by its LSC, is defined. It is suggested that a field use concentration for a new drug should be somewhat lower than the LSC, and the overall PSI for all Eimeria species and strains tested should therefore be < 1. In the present study, the PSI for decoquinate and E. tenella was 8.00, which is consistent with the very rapid development of resistance to quinolones that occurred in the field.

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Drug Resistance in Protozoa

Cited by 13 publications

References 152 publications

Spermidine Synthase Is Required for Virulence of Leishmania donovani

Spermidine Synthase Is Required for Virulence of Leishmania donovani

Leishmania donovani Ornithine Decarboxylase Is Indispensable for Parasite Survival in the Mammalian Host

A laboratory method for the single‐passage selection of drug‐resistant mutants from populations ofEimeriaspecies in chickens and its potential value in the choice of field use concentrations for new anticoccidial drugs

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