Drug resistance in leishmaniasis

Chakravarty, Jaya; Sundar, Shyam

doi:10.4103/0974-777x.62887

Cited by 216 publications

(157 citation statements)

References 84 publications

(99 reference statements)

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“…To determine signaling molecules eventually leading to MDR1 upregulation, Mϕs were infected with either Sb R LD or Sb S LD or treated with rIL-10 (200 pg/mL) for different periods of time (6,12,18,24, and 48 h). When Mϕs were infected with Sb R LD, the IL-10 level showed a slight increase at 18 h, peaked at 24 h (P < 0.0001; four-to sixfold), and remained unaltered until 48 h (Fig.…”

Section: Sb R Ld Drives Host Mϕs To Produce Il-10 Through Their Terminalmentioning

confidence: 99%

“…However, the toxicity, together with the high treatment failure rate (up to 65%) and the emergence of resistance in Bihar State, India, made the drug obsolete in the Indian subcontinent (4,5). Nevertheless, it is still used as a first-line treatment in Africa and Latin America (6). Interestingly, 78% of the recent clinical isolates from the hyperendemic zone of Bihar State still showed in vitro resistance to antimonials (7), which might be explained by an increased fitness of the corresponding parasites (8).…”

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confidence: 99%

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Antimony-resistant but not antimony-sensitiveLeishmania donovaniup-regulates host IL-10 to overexpress multidrug-resistant protein 1

Mukherjee

Mukhopadhyay

Bannerjee

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The molecular mechanism of antimony-resistant Leishmania donovani (Sb R LD)-driven up-regulation of IL-10 and multidrug-resistant protein 1 (MDR1) in infected macrophages (Mϕs) has been investigated. This study showed that both promastigote and amastigote forms of Sb R LD, but not the antimony-sensitive form of LD, express a unique glycan with N-acetylgalactosamine as a terminal sugar. Removal of it either by enzyme treatment or by knocking down the relevant enzyme, galactosyltransferase in Sb R LD (KD Sb R LD), compromises the ability to induce the above effects. Infection of Mϕs with KD Sb R LD enhanced the sensitivity toward antimonials compared with infection with Sb R LD, and infection of BALB/c mice with KD Sb R LD caused significantly less organ parasite burden compared with infection induced by Sb R LD. The innate immune receptor, Toll-like receptor 2/6 heterodimer, is exploited by Sb R LD to activate ERK and nuclear translocation of NF-κB involving p50/c-Rel leading to IL-10 induction, whereas MDR1 up-regulation is mediated by PI3K/Akt and the JNK pathway. Interestingly both recombinant IL-10 and Sb R LD up-regulate MDR1 in Mϕ with different time kinetics, where phosphorylation of PI3K was noted at 12 h and 48 h, respectively, but Mϕs derived from IL-10 −/− mice are unable to show MDR1 up-regulation on infection with Sb R LD. Thus, it is very likely that an IL-10 surge is a prerequisite for MDR1 up-regulation. The transcription factor important for IL-10-driven MDR1 up-regulation is c-Fos/c-Jun and not NF-κB, as evident from studies with pharmacological inhibitors and promoter mapping with deletion constructs.visceral leishmaniasis | antimony resistance | glycoconjugate | antimony efflux K ala-azar or visceral leishmaniasis, which is caused by the protozoan parasite Leishmania donovani (LD), is (re)emerging and spreading worldwide, essentially because of humanmade and environmental changes, immunosuppression, and drug resistance (1, 2). To combat the disease, organic pentavalent antimonials were introduced in the Indian subcontinent almost 9 decades ago (3) with dramatic clinical success. However, the toxicity, together with the high treatment failure rate (up to 65%) and the emergence of resistance in Bihar State, India, made the drug obsolete in the Indian subcontinent (4, 5). Nevertheless, it is still used as a first-line treatment in Africa and Latin America (6). Interestingly, 78% of the recent clinical isolates from the hyperendemic zone of Bihar State still showed in vitro resistance to antimonials (7), which might be explained by an increased fitness of the corresponding parasites (8).Recently, we have demonstrated three unique characteristics of antimony-resistant LD (Sb R LD). First, it shows a higher concentration of terminal glycoconjugates (N-acetylgalactosamine residues) on its surface than antimony-sensitive LD (Sb S LD) (7).Second, on infection of macrophages (Mϕs), Sb R LD induces a surge of IL-10 (7, 9). Third, we also observed that Sb R LD modulates host cells to overexpress the ATP-b...

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Section: Sb R Ld Drives Host Mϕs To Produce Il-10 Through Their Terminalmentioning

confidence: 99%

mentioning

confidence: 99%

Antimony-resistant but not antimony-sensitiveLeishmania donovaniup-regulates host IL-10 to overexpress multidrug-resistant protein 1

Mukherjee

Mukhopadhyay

Bannerjee

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Not only do trusted treatments cause many side-effects in patients, but there is still the problem of parasites developing resistance to the drugs (Kaur and Rajput 2014). In addition, there is a lack of knowledge regarding the action mechanism of the drugs, and current treatment regimens are expensive (Alvar et al 1997;Laguna et al 2003;Chakravarty and Sundar 2010;Kaur and Rajput 2014).…”

Section: Liposomal Systems As Carriers For Bioactive Compoundsmentioning

confidence: 99%

Liposomal systems as carriers for bioactive compounds

et al. 2015

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Since the revolutionary discovery that phospholipids can form closed bilayered structures in aqueous systems, the study of liposomes has become a very interesting area of research. The versatility and amazing biocompatibility of liposomes has resulted in their wide-spread use in many scientific fields, and many of their applications, especially in medicine, have yielded breakthroughs in recent decades. Specifically, their easy preparation and various structural aspects have given rise to broadly usable methodologies to internalize different compounds, with either lipophilic or hydrophilic properties. The study of compounds with potential biotechnological application(s) is generally related to evaluation and risk assessment of the possible cytotoxic or therapeutic effects of the compound under study. In most cases, undesirable sideeffects are associated with an interaction of the liposome with the cell membrane and/or its absorption and subsequent interaction with a cellular biomolecule. Liposomal carrier systems have an unprecedented potential for delivering bioactive substances to specific molecular targets due to their biocompatibility, biodegradability and low toxicity. Liposomes are therefore considered to be an invaluable asset in applied biotechnology studies due to their potential for interaction with both hydrophilic and lipophilic compounds.

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“…A limited number of drugs is available and each has various shortcomings. Traditional antileishmanial systemic agents such as antimonials, pentamidine and amphotericin are limited by severe toxic side effects, emerging drug resistance and their requirement for parenteral administration (8)(9)(10)(11)(12). Newer agents such as oral miltefosine have shown efficacy and tolerability, although the efficacy of this compound has not been demonstrated for all Leishmania species.…”

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confidence: 99%