Alterations in membrane fluidity, lipid metabolism, mitochondrial activity, and lipophosphoglycan expression in pentamidine-resistant Leishmania

Basselin, Mireille; Robert-Géro, Malka

doi:10.1007/s004360050361

Cited by 47 publications

(36 citation statements)

References 18 publications

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“…Previous studies have pointed to a diminution of mitochondrial membrane potential in pentamidine-resistant Leishmania spp. (11), and accumulation of rhodamine-123 also indicates that mitochondrial membrane potential is diminished in the drug-resistant lines analyzed in this study.…”

Section: Discussionmentioning

confidence: 99%

Resistance to Pentamidine in Leishmania mexicana Involves Exclusion of the Drug from the Mitochondrion

Basselin

Denise

Coombs

et al. 2002

Antimicrob Agents Chemother

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134

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The uptake of [3 H]pentamidine into wild-type and drug-resistant strains of Leishmania mexicana was compared. Uptake was carrier mediated. Pentamidine-resistant parasites showed cross-resistance to other toxic diamidine derivatives. A substantial decrease in accumulation of the drug accompanied the resistance phenotype, although the apparent affinity for pentamidine by its carrier was not altered when initial uptake velocity was measured. The apparent V max , however, was reduced. An efflux of pentamidine could be measured in both wild-type and resistant cells. Only a relatively small proportion of the total accumulated pentamidine was available for efflux in wild-type cells, while in resistant cells the majority of loaded pentamidine was available for release. Pharmacological reagents which diminish the mitochondrial membrane potential reduced pentamidine uptake in wild-type parasites, and the mitochondrial membrane potential was shown to be reduced in resistant cells. A fluorescent analogue of pentamidine, 4,6-diamidino-2-phenylindole, accumulated in the kinetoplast of wild-type but not resistant parasites. These data together indicate that diamidine drugs accumulate in the Leishmania mitochondrion and that the development of the resistance phenotype is accompanied by lack of mitochondrial accumulation of the drug and its exclusion from the parasites.

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Section: Discussionmentioning

confidence: 99%

Resistance to Pentamidine in Leishmania mexicana Involves Exclusion of the Drug from the Mitochondrion

Basselin

Denise

Coombs

et al. 2002

Antimicrob Agents Chemother

Self Cite

134

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“…Although terbinafine (TERB) is approved for the treatment of superficial fungal infections including onychomycosis and tinea pedis, this drug attracted great interest in 17,1999). This combination is very interesting and should be pursued further.…”

Section: Newer Antifungals In Combinationmentioning

confidence: 99%

Combination Treatment of Invasive Fungal Infections

et al. 2005

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The persistence of high morbidity and mortality from systemic fungal infections despite the availability of novel antifungals points to the need for effective treatment strategies. Treatment of invasive fungal infections is often hampered by drug toxicity, tolerability, and specificity issues, and added complications often arise due to the lack of diagnostic tests and to treatment complexities. Combination therapy has been suggested as a possible approach to improve treatment outcome. In this article, we undertake a historical review of studies of combination therapy and also focus on recent studies involving newly approved antifungal agents. The limitations surrounding antifungal combinations include nonuniform interpretation criteria, inability to predict the likelihood of clinical success, strain variability, and variations in pharmacodynamic/pharmacokinetic properties of antifungals used in combination. The issue of antagonism between polyenes and azoles is beginning to be addressed, but data regarding other drug combinations are not adequate for us to draw definite conclusions. However, recent data have identified potentially useful combinations. Standardization of assay methods and adoption of common interpretive criteria are essential to avoid discrepancies between different in vitro studies. Larger clinical trials are needed to assess whether combination therapy improves survival and treatment outcome in the most seriously debilitated patients afflicted with life-threatening fungal infections

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“…They suggested that the decrease in rhodamine 123 fluorescence could be used to detect sensitivity to drugs in this parasite. An FCM multiparameter approach was developed by Basselin et al (21) to study the differences between pentamidine-resistant and -nonresistant Leishmania. They detected variations in mitochondrial membrane potential and lipid metabolism in pentamidine-resistant cells.…”

Section: Antiparasite Susceptibilitymentioning

confidence: 99%