Drug Resistance in Trypanosomes; Cross‐resistance Analyses

Williamson, J.; Rollo, I. M.

doi:10.1111/j.1476-5381.1959.tb00946.x

Cited by 20 publications

(18 citation statements)

References 36 publications

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“…3). No cross-resistance between DB829 and pentamidine was observed in this study, which included isolates from relapsed patients, in contrast to the crossresistance previously reported for pentamidine and melarsoprol (39,40). Transporters are known to be an important determinant for developing resistance in trypanosomes to pentamidine and melarsoprol (41)(42)(43)(44).…”

Section: Discussioncontrasting

confidence: 44%

Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis

Wenzler

Yang

Braissant

et al. 2013

Antimicrob Agents Chemother

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Section: Discussioncontrasting

confidence: 44%

Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis

Wenzler

Yang

Braissant

et al. 2013

Antimicrob Agents Chemother

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“…It has been known for a considerable time that trypanosomal resistance to melaminophenyl arsenicals such as cymelarsan (used against surra in camels) and melarsoprol is associated with cross-resistance to at least some of the aromatic diamidines (Williamson and Rollo, 1959;de Koning, 2008). We now know that pentamidine is salvaged by three distinct transport entities in bloodstream trypanosomes, the P2 aminopurine transporter, the high-affinity pentamidine transporter (HAPT1) and the low-affinity pentamidine transporter (LAPT1) (de Koning and Jarvis, 2001;de Koning, 2001;Matovu et al, 2003;Bridges et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The Diamidine Diminazene Aceturate Is a Substrate for the High-Affinity Pentamidine Transporter: Implications for the Development of High Resistance Levels in Trypanosomes

Teka

Kazibwe²,

El-Sabbagh³

et al. 2011

Mol Pharmacol

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African trypanosomiasis is a disease of humans and livestock in many areas south of the Sahara. Resistance to the few existing drugs is a major impediment to the control of these diseases, and we investigated how resistance to the main veterinary drug diminazene aceturate correlates with changes in drug transport in resistant strains. The strain tbat1(Ϫ/Ϫ), lacking the TbAT1/P2 aminopurine transporter implicated previously in diminazene transport, was adapted to higher levels of diminazene resistance. The resulting cell line was designated ABR and was highly cross-resistant to other diamidines and moderately resistant to cymelarsan. Procyclic trypanosomes were shown to be a convenient model to study diamidine uptake in Trypanosoma brucei brucei given the lack of TbAT1/P2 and a 10-fold higher activity of the high-affinity pentamidine transporter (HAPT1). Diminazene could be transported by HAPT1 in procyclic trypanosomes. This drug transport activity was lacking in the ABR line, as reported previously for the pentamidineadapted line B48. The K m for diminazene transport in bloodstream tbat1(Ϫ/Ϫ) trypanosomes was consistent with uptake by HAPT1. Diminazene transport in ABR and B48 cells was reduced compared with tbat1(Ϫ/Ϫ), but their resistance phenotype was different: B48 displayed higher levels of resistance to pentamidine and the melaminophenyl arsenicals, whereas ABR displayed higher resistance to diminazene. These results establish a loss of HAPT1 function as a contributing factor to diminazene resistance but equally demonstrate for the first time that adaptations other than those determining the initial rates of drug uptake contribute to diamidine and arsenical resistance in African trypanosomes.

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“…The corresponding widely used veterinary diamidine is diminazene aceturate (Berenil). The only new trypanocide to be developed in recent decades, DB75, is also a diamidine and currently in clinical trials as an orally available prodrug.It has been known for decades that cross-resistance between melaminophenyl arsenicals and diamidine drugs sometimes occurs (Fulton and Grant, 1955;Williamson and Rollo, 1959), but cross-resistance patterns can be unpredictable (Williamson, 1970). Kaminsky and Mä ser (2000) distinThis work was funded by the Wellcome Trust.…”

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confidence: 99%

“…It has been known for decades that cross-resistance between melaminophenyl arsenicals and diamidine drugs sometimes occurs (Fulton and Grant, 1955;Williamson and Rollo, 1959), but cross-resistance patterns can be unpredictable (Williamson, 1970). Kaminsky and Mä ser (2000) distin-guished six distinct resistance profiles in Trypanosoma brucei brucei laboratory strains and field isolates, presumably an indication that multiple factors determine (the level of) resistance to the various drugs.…”

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confidence: 99%

Loss of the High-Affinity Pentamidine Transporter Is Responsible for High Levels of Cross-Resistance between Arsenical and Diamidine Drugs in African Trypanosomes

Bridges¹,

Gould²,

Nerima³

et al. 2007

Mol Pharmacol

119

242

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Treatment of many infectious diseases is under threat from drug resistance. Understanding the mechanisms of resistance is as high a priority as the development of new drugs. We have investigated the basis for cross-resistance between the diamidine and melaminophenyl arsenical classes of drugs in African trypanosomes. We induced high levels of pentamidine resistance in a line without the tbat1 gene that encodes the P2 transporter previously implicated in drug uptake. We isolated independent clones that displayed very considerable crossresistance with melarsen oxide but not phenylarsine oxide and reduced uptake of [ 3 H]pentamidine. In particular, the highaffinity pentamidine transport (HAPT1) activity was absent in the pentamidine-adapted lines, whereas the low affinity pentamidine transport (LAPT1) activity was unchanged. The parental tbat1 Ϫ/Ϫ line was sensitive to lysis by melarsen oxide, and this process was inhibited by low concentrations of pentamidine, indicating the involvement of HAPT1. This pentamidine-inhibitable lysis was absent in the adapted line KO-B48. Likewise, uptake of the fluorescent diamidine 4Ј,6-diamidino-2-phenylindole dihydrochloride was much delayed in live KO-B48 cells and insensitive to competition with up to 10 M pentamidine. No overexpression of the Trypanosoma brucei brucei ATPbinding cassette transporter TbMRPA could be detected in KO-B48. We also show that a laboratory line of Trypanosoma brucei gambiense, adapted to high levels of resistance for the melaminophenyl arsenical drug melarsamine hydrochloride (Cymelarsan), had similarly lost TbAT1 and HAPT1 activity while retaining LAPT1 activity. It seems therefore that selection for resistance to either pentamidine or arsenical drugs can result in a similar phenotype of reduced drug accumulation, explaining the occurrence of cross-resistance.Trypanosoma brucei subspp. are protozoan parasites that cause human African trypanosomiasis (i.e., sleeping sickness) and the corresponding veterinary condition in livestock. Treatment of both the human and livestock diseases depends on a very small set of mostly very old drugs. The first-line treatment for the late stage of both West African and East African human African trypanosomiasis is melarsoprol, an organoarsenic compound of the melaminophenyl arsenical class, introduced in 1949 (Jannin and Cattand, 2004). A similar but water-soluble melaminophenyl arsenical, melarsamine hydrochloride (Cymelarsan), is increasingly used for animal trypanosomiasis. Early-stage West African sleeping sickness is routinely treated with the diamidine drug pentamidine, introduced in 1937 (Jannin and Cattand, 2004). The corresponding widely used veterinary diamidine is diminazene aceturate (Berenil). The only new trypanocide to be developed in recent decades, DB75, is also a diamidine and currently in clinical trials as an orally available prodrug.It has been known for decades that cross-resistance between melaminophenyl arsenicals and diamidine drugs sometimes occurs (Fulton and Grant, 1955;Williamson a...

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Drug Resistance in Trypanosomes; Cross‐resistance Analyses

Cited by 20 publications

References 36 publications

Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis

Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis

The Diamidine Diminazene Aceturate Is a Substrate for the High-Affinity Pentamidine Transporter: Implications for the Development of High Resistance Levels in Trypanosomes

Loss of the High-Affinity Pentamidine Transporter Is Responsible for High Levels of Cross-Resistance between Arsenical and Diamidine Drugs in African Trypanosomes

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