Acquired Resistance to ‘Melarsen’, Tryparsamide and Amidines in Pathogenic Trypanosomes after Treatment with ‘Melarsen’ Alone

Rollo, I. M.; Williamson, J.

doi:10.1038/167147a0

Cited by 43 publications

(29 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Melarsoprol/pentamidine cross resistance (MPXR) is a well-known phenomenon in HAT, first described by Rollo and Williamson (1951); and although the cause was never completely resolved, it has long been clear that it was linked to reduced drug accumulation (Damper and Patton, 1976; Frommel and Balber, 1987; de Koning, 2001a). The first drug transporter identified in trypanosomes was the P2 adenosine/adenine transporter, which was originally connected to melarsoprol uptake (Carter and Fairlamb, 1993) and subsequently to diamidine transport (Barrett et al, 1995; Carter et al, 1995, 1999; de Koning and Jarvis, 2001; de Koning et al, 2004).…”

Section: Drug Resistance and Transportersmentioning

confidence: 99%

Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

2015

View full text Add to dashboard Cite

Drug resistance in pathogenic protozoa is very often caused by changes to the ‘transportome’ of the parasites. In Trypanosoma brucei, several transporters have been implicated in uptake of the main classes of drugs, diamidines and melaminophenyl arsenicals. The resistance mechanism had been thought to be due to loss of a transporter known to carry both types of agents: the aminopurine transporter P2, encoded by the gene TbAT1. However, although loss of P2 activity is well-documented as the cause of resistance to the veterinary diamidine diminazene aceturate (DA; Berenil®), cross-resistance between the human-use arsenical melarsoprol and the diamidine pentamidine (melarsoprol/pentamidine cross resistance, MPXR) is the result of loss of a separate high affinity pentamidine transporter (HAPT1). A genome-wide RNAi library screen for resistance to pentamidine, published in 2012, gave the key to the genetic identity of HAPT1 by linking the phenomenon to a locus that contains the closely related T. brucei aquaglyceroporin genes TbAQP2 and TbAQP3. Further analysis determined that knockdown of only one pore, TbAQP2, produced the MPXR phenotype. TbAQP2 is an unconventional aquaglyceroporin with unique residues in the “selectivity region” of the pore, and it was found that in several MPXR lab strains the WT gene was either absent or replaced by a chimeric protein, recombined with parts of TbAQP3. Importantly, wild-type AQP2 was also absent in field isolates of T. b. gambiense, correlating with the outcome of melarsoprol treatment. Expression of a wild-type copy of TbAQP2 in even the most resistant strain completely reversed MPXR and re-introduced HAPT1 function and transport kinetics. Expression of TbAQP2 in Leishmania mexicana introduced a pentamidine transport activity indistinguishable from HAPT1. Although TbAQP2 has been shown to function as a classical aquaglyceroporin it is now clear that it is also a high affinity drug transporter, HAPT1. We discuss here a possible structural rationale for this remarkable ability.

show abstract

Section: Drug Resistance and Transportersmentioning

confidence: 99%

Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

2015

View full text Add to dashboard Cite

show abstract

“…Two observations were made recurrently, namely (i) reduced drug uptake by drug resistant trypanosomes [9]–[14] and (ii) cross-resistance between melarsoprol and pentamidine [15], [16]. Both phenomena were attributed to the fact that melarsoprol and pentamidine are taken up by trypanosomes via the same transporters, which appeared to be lacking in drug-resistant mutants.…”

Section: Introductionmentioning

confidence: 99%

Aquaporin 2 Mutations in Trypanosoma brucei gambiense Field Isolates Correlate with Decreased Susceptibility to Pentamidine and Melarsoprol

et al. 2013

View full text Add to dashboard Cite

The predominant mechanism of drug resistance in African trypanosomes is decreased drug uptake due to loss-of-function mutations in the genes for the transporters that mediate drug import. The role of transporters as determinants of drug susceptibility is well documented from laboratory-selected Trypanosoma brucei mutants. But clinical isolates, especially of T. b. gambiense, are less amenable to experimental investigation since they do not readily grow in culture without prior adaptation. Here we analyze a selected panel of 16 T. brucei ssp. field isolates that (i) have been adapted to axenic in vitro cultivation and (ii) mostly stem from treatment-refractory cases. For each isolate, we quantify the sensitivity to melarsoprol, pentamidine, and diminazene, and sequence the genomic loci of the transporter genes TbAT1 and TbAQP2. The former encodes the well-characterized aminopurine permease P2 which transports several trypanocides including melarsoprol, pentamidine, and diminazene. We find that diminazene-resistant field isolates of T. b. brucei and T. b. rhodesiense carry the same set of point mutations in TbAT1 that was previously described from lab mutants. Aquaglyceroporin 2 has only recently been identified as a second transporter involved in melarsoprol/pentamidine cross-resistance. Here we describe two different kinds of TbAQP2 mutations found in T. b. gambiense field isolates: simple loss of TbAQP2, or loss of wild-type TbAQP2 allele combined with the formation of a novel type of TbAQP2/3 chimera. The identified mutant T. b. gambiense are 40- to 50-fold less sensitive to pentamidine and 3- to 5-times less sensitive to melarsoprol than the reference isolates. We thus demonstrate for the first time that rearrangements of the TbAQP2/TbAQP3 locus accompanied by TbAQP2 gene loss also occur in the field, and that the T. b. gambiense carrying such mutations correlate with a significantly reduced susceptibility to pentamidine and melarsoprol.

show abstract

“…We found that this strain was unexpectedly, and almost totally, resistant also to trypanocidal diguanidines and diamidines (Rollo and Williamson, 1951). Subsequently we tested a wider variety of trypanocides against this and five other different resistant strains (Williamson and Rollo, 1952;Goodwin and Rollo, 1955), using these "therapeutic sieves," in Ehrlich's analogy, to sift out any common factors of activity not otherwise apparent among unrelated drug types.…”

mentioning

confidence: 94%

Drug Resistance in Trypanosomes; Cross‐resistance Analyses

Williamson

Rollo

1959

British Journal of Pharmacology and Chemotherapy

Self Cite

View full text Add to dashboard Cite

Eight strains of Trypanosoma rhodesiense, made resistant respectively to atoxyl, butarsen, acriflavine, stilbamidine, Surfen C, suramin, and pontamine sky blue 5BX, have been examined for cross-resistance to representatives of nine structurally dissimilar groups of trypanocide. On the basis of their predominant ionic form at blood pH, these groups are considered in three main classes: (a) feebly ionized (neutral aromatic arsenicals), (b) ionized as cations (melaminyl arsenicals and antimonials, acridine derivatives, diguanidines and diamidines, 6-aminoquinoline and 6-aminocinnoline derivatives, phenanthridinium derivatives, triphenylmethane dyes), and (c) ionized as anions (carboxylated aromatic arsenicals and sulphonated naphthylamine derivatives). The results are discussed in relation to those of other workers and to possible modes of trypanocidal drug action. Cross-resistance behaviour is not wholly explicable on an ionic basis; the results suggest that stereospecific structural changes associated with initial drug uptake occur in resistant trypanosomes.

show abstract

Acquired Resistance to ‘Melarsen’, Tryparsamide and Amidines in Pathogenic Trypanosomes after Treatment with ‘Melarsen’ Alone

Cited by 43 publications

References 6 publications

Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

Transport proteins determine drug sensitivity and resistance in a protozoan parasite, Trypanosoma brucei

Aquaporin 2 Mutations in Trypanosoma brucei gambiense Field Isolates Correlate with Decreased Susceptibility to Pentamidine and Melarsoprol

Drug Resistance in Trypanosomes; Cross‐resistance Analyses

Contact Info

Product

Resources

About