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Mechanism of Amphotericin B Resistance in Clinical Isolates of Leishmania donovani

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Field Value
 
Title Mechanism of Amphotericin B Resistance in Clinical Isolates
of Leishmania donovani
 
Creator Purkait, Bidyut
Kumar, Ashish
Nandi, Nilay
Sardar, Abul Hasan
Das, Sushmita
Kumar, Sudeep
Pandey, Krishna
Kumar, Manish
De, Tripti
Singh, Dharmendra
Das, Pradeep
 
Subject Infectious Diseases and Immunology
 
Description The clinical value of amphotericin B, the mainstay therapy for visceral leishmaniasis in sodium antimony gluconatenonresponsive
zones of Bihar, India, is now threatened by the emergence of acquired drug resistance, and a comprehensive understanding
of the underlying mechanisms is the need of the hour. We have selected an amphotericin B-resistant clinical isolate
which demonstrated 8-fold-higher 50% lethal doses (LD50) than an amphotericin B-sensitive strain to explore the mechanism of
amphotericin B resistance. Fluorimetric analysis demonstrated lower anisotropy in the motion of the diphenylhexatriene fluorescent
probe in the resistant strain, which indicated a higher fluidity of the membrane for the resistant strain than for the sensitive
strain. The expression patterns of the two transcripts of S-adenosyl-L-methionine:C-24-�-sterol methyltransferase and the
absence of ergosterol, replaced by cholesta-5,7,24-trien-3�-ol in the membrane of the resistant parasite, indicate a decreased
amphotericin B affinity, which is evidenced by decreased amphotericin B uptake. The expression level of MDR1 is found to be
higher in the resistant strain, suggesting a higher rate of efflux of amphotericin B. The resistant parasite also possesses an upregulated
tryparedoxin cascade and a more-reduced intracellular thiol level, which helps in better scavenging of reactive oxygen
species produced by amphotericin B. The resistance to amphotericin B was partially reverted by the thiol metabolic pathway and
ABC transporter inhibitors. Thus, it can be concluded that altered membrane composition, ATP-binding cassette transporters,
and an upregulated thiol metabolic pathway have a role in conferring amphotericin B resistance in clinical isolates of Leishmania donovani.
 
Publisher American Society for Microbiology
 
Date 2012
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1479/1/ANTIMICROBIAL_AGENTS_AND_CHEMOTHERAPY___56(_2)1031%2D1041;2012[59].pdf
Purkait, Bidyut and Kumar, Ashish and Nandi, Nilay and Sardar, Abul Hasan and Das, Sushmita and Kumar, Sudeep and Pandey, Krishna and Kumar, Manish and De, Tripti and Singh, Dharmendra and Das, Pradeep (2012) Mechanism of Amphotericin B Resistance in Clinical Isolates of Leishmania donovani. Antimicrobial Agents and Chemotherapy, 56 (2). pp. 1031-1041.
 
Relation http://dx.doi.org/10.1128/AAC.00030-11.
http://www.eprints.iicb.res.in/1479/