ABCMdb

ABCC2 p.Thr420Asn

Predicted by SNAP2:	A: D (63%), C: D (59%), D: D (80%), E: D (80%), F: D (75%), G: D (75%), H: D (75%), I: N (72%), K: D (80%), L: D (71%), M: N (61%), N: D (71%), P: D (80%), Q: D (71%), R: D (85%), S: D (63%), V: N (61%), W: D (80%), Y: D (75%),
Predicted by PROVEAN:	A: N, C: N, D: D, E: D, F: N, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: N, V: N, W: D, Y: N,

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[hide] Treatment failure and miltefosine susceptibility i... Antimicrob Agents Chemother. 2014;58(1):144-52. doi: 10.1128/AAC.01023-13. Epub 2013 Oct 21. Obonaga R, Fernandez OL, Valderrama L, Rubiano LC, Castro Mdel M, Barrera MC, Gomez MA, Gore Saravia N
Treatment failure and miltefosine susceptibility in dermal leishmaniasis caused by Leishmania subgenus Viannia species.
Antimicrob Agents Chemother. 2014;58(1):144-52. doi: 10.1128/AAC.01023-13. Epub 2013 Oct 21., [PMID:24145529]

Abstract [show]
Treatment failure and parasite drug susceptibility in dermal leishmaniasis caused by Leishmania (Viannia) species are poorly understood. Prospective evaluation of drug susceptibility of strains isolated from individual patients before drug exposure and at clinical failure allows intrinsic and acquired differences in susceptibility to be discerned and analyzed. To determine whether intrinsic susceptibility or loss of susceptibility to miltefosine contributed to treatment failure, we evaluated the miltefosine susceptibility of intracellular amastigotes and promastigotes of six Leishmania (Viannia) braziliensis and six Leishmania (Viannia) panamensis strains isolated sequentially, at diagnosis and treatment failure, from two children and four adults >/=55 years old with concurrent conditions. Four patients presented only cutaneous lesions, one had mucosal disease, and one had disseminated mucocutaneous disease. Expression of the Leishmania drug transporter genes abca2, abca3, abcc2, abcc3, abcg4, abcg6, and LbMT was evaluated by quantitative reverse transcription-PCR (qRT-PCR). Intracellular amastigotes (median 50% effective concentration [EC50], 10.7 mumol/liter) were more susceptible to miltefosine than promastigotes (median EC50, 55.3 mumol/liter) (P < 0.0001). Loss of susceptibility at failure, demonstrated by a miltefosine EC50 of >32 mumol/liter (the upper limit of intracellular amastigote assay), occurred in L. panamensis infection in a child and in L. braziliensis infection in an adult and was accompanied by decreased expression of the miltefosine transporter LbMT (LbMT/beta-tubulin, 0.42- to 0.26-fold [P = 0.039] and 0.70- to 0.57-fold [P = 0.009], respectively). LbMT gene polymorphisms were not associated with susceptibility phenotype. Leishmania ABCA3 transporter expression was inversely correlated with miltefosine susceptibility (r = -0.605; P = 0.037). Loss of susceptibility is one of multiple factors involved in failure of miltefosine treatment in dermal leishmaniasis.

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No. Sentence Comment
93 The presence of C1259A (T420N) and T2567C (L856P) polymorphisms in the LbMT gene, previously reported to be associated with experimentally derived miltefosine resistance (9), and G630A (W210*) analyzed in VL and post-kala-azar dermal leishmaniasis (PKDL) strains of L. donovani (19) were characterized by sequence analysis of PCR products. Login to comment
95 PCR was carried out using primer sets W210*-F (5=-AGGCGTTCATTG ACACATGC-3=) and W210*-R (5=-TACAGGAACTGGTTCAGCGAC- 3=); T420N-F (5=-TGGAGTACATGAACAACCGCT-3=) and T420N-R (5=- CTCTTCCTCCTTGCGCAGTC-3=), and L856P-F (5=-TCATTGGGCTGG AAGGTTCA-3=) and L856P-R (5=-GTGTTAGTCCCGAGAAGCCA-3=). Login to comment