Leishmania amazonensis: Metabolic adaptations induced by resistance to an ABC transporter blocker

Machuca, Claudia; Rodríguez, Adriana; Herrera, Marymar; Silva, Sónia; Ponte-Sucre, Alicia

doi:10.1016/j.exppara.2006.02.008

Cited by 18 publications

(9 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This finding led to the suggestion that these transporters might afford a route for drug entrance and that their down-regulation would favor the survival of the yeast in the presence of the drug. In support of this hypothesis, Uzcategui et al [46] reported a decrease of 80% in glucose transport in a strain of L. amazonensis resistant to glibenclamide (GLIB), an inhibitor of ABC transporters, while Machuca et al [47] showed that glucose accumulation in a GLIB-resistant strain of this parasite was 4.5-fold slower than that of the susceptible parental strain. Decreased glucose accumulation has also been observed in GLIB-resistant cell lines of L. major [47].…”

Section: Discussionmentioning

confidence: 98%

“…In support of this hypothesis, Uzcategui et al [46] reported a decrease of 80% in glucose transport in a strain of L. amazonensis resistant to glibenclamide (GLIB), an inhibitor of ABC transporters, while Machuca et al [47] showed that glucose accumulation in a GLIB-resistant strain of this parasite was 4.5-fold slower than that of the susceptible parental strain. Decreased glucose accumulation has also been observed in GLIB-resistant cell lines of L. major [47]. The results of the present study suggest that the BZ resistant population 17 LER presents a decreasing glucose uptake in response to drug pressure, and that this could favor the survival of the parasite in the presence of BZ since less toxic compounds would enter into the cell.…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Molecular characterization of the hexose transporter gene in benznidazole resistant and susceptible populations of Trypanosoma cruzi

et al. 2012

View full text Add to dashboard Cite

BackgroundHexose transporters (HT) are membrane proteins involved in the uptake of energy-supplying glucose and other hexoses into the cell. Previous studies employing the Differential Display technique have shown that the transcription level of the HT gene from T. cruzi (TcrHT) is higher in an in vitro-induced benznidazole (BZ)-resistant population of the parasite (17 LER) than in its susceptible counterpart (17 WTS).MethodsIn the present study, TcrHT has been characterized in populations and strains of T. cruzi that are resistant or susceptible to BZ. We investigated the copy number and chromosomal location of the gene, the levels of TcrHT mRNA and of TcrHT activity, and the phylogenetic relationship between TcrHT and HTs from other organisms.ResultsIn silico analyses revealed that 15 sequences of the TcrHT gene are present in the T. cruzi genome, considering both CL Brener haplotypes. Southern blot analyses confirmed that the gene is present as a multicopy tandem array and indicated a nucleotide sequence polymorphism associated to T. cruzi group I or II. Karyotype analyses revealed that TcrHT is located in two chromosomal bands varying in size from 1.85 to 2.6 Mb depending on the strain of T. cruzi. The sequence of amino acids in the HT from T. cruzi is closely related to the HT sequences of Leishmania species according to phylogenetic analysis. Northern blot and quantitative real-time reverse transcriptase polymerase chain reaction analyses revealed that TcrHT transcripts are 2.6-fold higher in the resistant 17 LER population than in the susceptible 17 WTS. Interestingly, the hexose transporter activity was 40% lower in the 17 LER population than in all other T. cruzi samples analyzed. This phenotype was detected only in the in vitro-induced BZ resistant population, but not in the in vivo-selected or naturally BZ resistant T. cruzi samples. Sequencing analysis revealed that the amino acid sequences of the TcrHT from 17WTS and 17LER populations are identical. This result suggests that the difference in glucose transport between 17WTS and 17LER populations is not due to point mutations, but probably due to lower protein expression level.ConclusionThe BZ resistant population 17 LER presents a decrease in glucose uptake in response to drug pressure.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Molecular characterization of the hexose transporter gene in benznidazole resistant and susceptible populations of Trypanosoma cruzi

et al. 2012

View full text Add to dashboard Cite

show abstract

“…1). Decrease glucose uptake, for example by minimizing reactive oxygen species, was suggested as a general mechanism associated with drug resistance in L. amazonensis [51]. Future work will be required to test this.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling and Molecular Characterization of Antimony Resistance in Leishmania amazonensis

et al. 2011

View full text Add to dashboard Cite

BackgroundDrug resistance is a major problem in leishmaniasis chemotherapy. RNA expression profiling using DNA microarrays is a suitable approach to study simultaneous events leading to a drug-resistance phenotype. Genomic analysis has been performed primarily with Old World Leishmania species and here we investigate molecular alterations in antimony resistance in the New World species L. amazonensis.Methods/Principal FindingsWe selected populations of L. amazonensis promastigotes for resistance to antimony by step-wise drug pressure. Gene expression of highly resistant mutants was studied using DNA microarrays. RNA expression profiling of antimony-resistant L. amazonensis revealed the overexpression of genes involved in drug resistance including the ABC transporter MRPA and several genes related to thiol metabolism. The MRPA overexpression was validated by quantitative real-time RT-PCR and further analysis revealed that this increased expression was correlated to gene amplification as part of extrachromosomal linear amplicons in some mutants and as part of supernumerary chromosomes in other mutants. The expression of several other genes encoding hypothetical proteins but also nucleobase and glucose transporter encoding genes were found to be modulated.Conclusions/SignificanceMechanisms classically found in Old World antimony resistant Leishmania were also highlighted in New World antimony-resistant L. amazonensis. These studies were useful to the identification of resistance molecular markers.

show abstract

“…We have to design an inhibitor with multiple binding sites which can block the phenomenon of drug efflux from the ABC transporter thereby keeping the basic structure intact. The inhibition of ABC transporter with resistance modifying agent will allow accumulation of drug SAG (sodium antimony gluconate) and parasite killing within macrophage [9]. Another possible way to circumvent resistance would be to provide a combination therapy consisting of drugs and an inhibitor that has been shown useful in Leishmaniasis.…”

Section: Resultsmentioning

confidence: 99%

Antimony resistance during Visceral Leishmaniasis: A possible consequence of serial mutations in ABC transporters of Leishmania species

Sinha¹,

Sundaram²,

Kumar³

et al. 2011

Bioinformation

View full text Add to dashboard Cite

Visceral Leishmaniasis is a macrophage associated disorder for the treatment of which antimony based drugs like SAG and SSG were the first choice in the recent past. The clinical value of antimony therapy is now declined against VL because increasing cases of Sodium Antimony Gluconate (SAG) resistance have reached outstanding proportion in Bihar, India. Within this context we looked into the protein sequences of ABC transporters of Leishmania spp associated with Visceral Leishmaniasis that are known to play a crucial role in the development of multidrug resistance (MDR). Our studies consisting of ClustalW, Phylogeny and TCOFFEE have pinpointed that ABC transporters have enormously diverged during the process of evolution even within the identical species strains resulting in insignificant homology and subdued conservation amongst the aminoacid residues. Moreover these amino acid residues remain susceptible to mutations in evolutionary era as indicated by high frequency of variations by the variability studies. Hence we predict that during the process of evolution a series of frequent mutations might have led to changes in the ABC transporters favorable to effluxing the drug thereby making the Leishmania species prone to resistance against the efficient first line drug SAG, used for combating VL. This selection has made them to survive efficiently in the adverse circumstances of antimony based antileishmanial therapy regime.

show abstract

Leishmania amazonensis: Metabolic adaptations induced by resistance to an ABC transporter blocker

Cited by 18 publications

References 54 publications

Molecular characterization of the hexose transporter gene in benznidazole resistant and susceptible populations of Trypanosoma cruzi

Molecular characterization of the hexose transporter gene in benznidazole resistant and susceptible populations of Trypanosoma cruzi

Gene Expression Profiling and Molecular Characterization of Antimony Resistance in Leishmania amazonensis

Antimony resistance during Visceral Leishmaniasis: A possible consequence of serial mutations in ABC transporters of Leishmania species

Contact Info

Product

Resources

About