Mechanism of action of amphotericin B on Leishmania donovani promastigotes

Saha, Ahindra K.; Mukherjee, Tanmoy; Bhaduri, Amar

doi:10.1016/0166-6851(86)90001-0

Cited by 86 publications

(17 citation statements)

References 13 publications

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“…This finding is in line with the CNV results, suggesting that decreased levels of functional S-adenosylmethionine synthetase reduce allopurinol's inhibitory effect on the parasite. Amphotericin B, which exerts an inhibitory effect on Leishmania through its influence on membrane sterols (Saha et al, 1986), had an opposite effect on allopurinol IC 50. The latter finding, suggests that results found with cycloleucine were not caused by a generic response to additional stress or to a mere growth inhibition by a second drug used in combination with allopurinol.…”

Section: Discussionmentioning

confidence: 99%

Resistance of Leishmania infantum to allopurinol is associated with chromosome and gene copy number variations including decrease in the S-adenosylmethionine synthetase (METK) gene copy number

Yasur-Landau

Jaffe

David

et al. 2018

International Journal for Parasitology: Drugs and Drug Resistan

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Leishmania infantum is one of the causative agents of visceral leishmaniasis (VL), a widespread, life-threatening disease. This parasite is responsible for the majority of human VL cases in Brazil, the Middle East, China, Central Asia and the Mediterranean basin. Its main reservoir are domestic dogs which, similar to human patients, may develop severe visceral disease and die if not treated. The drug allopurinol is used for the long-term maintenance of dogs with canine leishmaniasis. Following our report of allopurinol resistance in treated relapsed dogs, we investigated the mechanisms and markers of resistance to this drug. Whole genome sequencing (WGS) of clinical resistant and susceptible strains, and laboratory induced resistant parasites, was carried out in order to detect genetic changes associated with resistance. Significant gene copy number variation (CNV) was found between resistant and susceptible isolates at several loci, including a locus on chromosome 30 containing the genes LinJ.30.3550 through LinJ.30.3580. A reduction in copy number for LinJ.30.3560, encoding the S-adenosylmethionine synthetase (METK) gene, was found in two resistant clinical isolates and four induced resistant clonal strains. Using quantitative real time PCR, this reduction in METK copy number was also found in three additional resistant clinical isolates. Furthermore, inhibition of S-adenosylmethionine synthetase encoded by the METK gene in allopurinol susceptible strains resulted in increased allopurinol resistance, confirming its role in resistance to allopurinol. In conclusion, this study identified genetic changes associated with L. infantum resistance to allopurinol and the reduction in METK copy number identified may serve as a marker for resistance in dogs, and reduced protein activity correlated with increased allopurinol resistance.

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Section: Discussionmentioning

confidence: 99%

Resistance of Leishmania infantum to allopurinol is associated with chromosome and gene copy number variations including decrease in the S-adenosylmethionine synthetase (METK) gene copy number

Yasur-Landau

Jaffe

David

et al. 2018

International Journal for Parasitology: Drugs and Drug Resistan

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“…AmpB works by targeting membrane sterols on the surface of the parasite resulting in enhanced membrane permeability (Saha et al, 1986). As seen in Fig.…”

Section: Discussionmentioning

confidence: 99%

Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles

Collier

Peine

Gautam

et al. 2016

International Journal of Pharmaceutics

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Leishmaniasis is a disease caused by parasites of Leishmania sp., which effects nearly 12 million people worldwide and is associated with treatment complications due to widespread parasite resistance toward pathogen-directed therapeutics. The current treatments for visceral leishmaniasis (VL), the systemic form of the disease, involve pathogen-mediated drugs and have long treatment regimens, increasing the risk of forming resistant strains. One way to limit emergence of resistant pathogens is through the use of host-mediated therapeutics. The host-mediated therapeutic AR-12, which is FDA IND-approved for cancer treatment, has shown activity against a broad spectrum of intracellular pathogens; however, due to hydrophobicity and toxicity, it is difficult to reach therapeutic doses. We have formulated AR-12 into microparticles (AR-12/MPs) using the novel biodegradable polymer acetalated dextran (Ace-DEX) and used this formulation for the systemic treatment of VL. Treatment with AR-12/MPs significantly reduced liver, spleen, and bone marrow parasite loads in infected mice, while combinatorial therapies with amphotericin B had an even more significant effect. Overall, AR-12/MPs offer a unique, host-mediated therapy that could significantly reduce the emergence of drug resistance in the treatment of VL.

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“…This effect persisted even after three days exposure to all test concentrations of AmB, emphasizing the significance of LdAI in conferring drug resistance phenotype. Previous reports have mentioned the importance of membrane ergosterol content in conferring AmB resistance phenotype (Purkait et al., 2012, Saha et al., 1986). The enzyme reported to be malfunctioning/absent in the resistant phenotypes is S-adenosyl-L-methionine-C24 Δ-sterol methyl transferase (SCMT) responsible for synthesis of ergosterol from cholesta-5,7,24-trien-3β-ol (Pourshafie et al., 2004, Brotherton et al., 2014).…”

Section: Discussionmentioning

confidence: 99%

“…In this line, exposure to membrane altering agents such as polyene antibiotic Amphotericin B (AmB) has been successful in treating this parasite. AmB interacts with ergosterol within the membrane, altering its permeability through the formation of non-aqueous and aqueous pores resulting in positive K + /H + gradient (Palacios and Serrano, 1978, Jiang et al., 1994, Herec et al., 2005, Cohen, 2010, Saha et al., 1986, Luque-Ortega et al., 2003). This in turn follows a caspase-3 dependent apoptosis of the pathogen (Saha et al., 1986, Cohen, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…AmB interacts with ergosterol within the membrane, altering its permeability through the formation of non-aqueous and aqueous pores resulting in positive K + /H + gradient (Palacios and Serrano, 1978, Jiang et al., 1994, Herec et al., 2005, Cohen, 2010, Saha et al., 1986, Luque-Ortega et al., 2003). This in turn follows a caspase-3 dependent apoptosis of the pathogen (Saha et al., 1986, Cohen, 2010). Additionally, this antibiotic is known to exhibit immunomodulatory effects and foster parasitic clearance by stimulating the transcription and production of proinflammatory cytokines like TNF-α, IL-1β, MCP-1, MIP-1β, nitric oxide, prostaglandins and intercellular adhesion molecule-1 from murine and human immune cells (Mesa-Arango et al., 2012, Sau et al., 2003).…”

Section: Introductionmentioning

confidence: 99%

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L-Asparaginase of Leishmania donovani: Metabolic target and its role in Amphotericin B resistance

Singh¹,

Khan²,

Yadav³

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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Emergence of Amphotericin B (AmB) resistant Leishmania donovani has posed major therapeutic challenge against the parasite. Consequently, combination therapy aimed at multiple molecular targets, based on proteome wise network analysis has been recommended. In this regard we had earlier identified and proposed L-asparaginase of Leishmania donovani (LdAI) as a crucial metabolic target. Here we report that both LdAI overexpressing axenic amastigote and promastigote forms of L. donovani survives better when challenged with AmB as compared to wild type strain. Conversely, qRT-PCR analysis showed an upregulation of LdAI in both forms upon AmB treatment. Our data demonstrates the importance of LdAI in imparting immediate protective response to the parasite upon AmB treatment. In the absence of structural and functional information, we modeled LdAI and validated its solution structure through small angle X-ray scattering (SAXS) analysis. We identified its specific inhibitors through ligand and structure-based approach and characterized their effects on enzymatic properties (Km, Vmax, Kcat) of LdAI. We show that in presence of two of the inhibitors L1 and L2, the survival of L. donovani is compromised whereas overexpression of LdAI in these cells restores viability. Taken together, our results conclusively prove that LdAI is a crucial metabolic enzyme conferring early counter measure against AmB treatment by Leishmania.

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Mechanism of action of amphotericin B on Leishmania donovani promastigotes

Cited by 86 publications

References 13 publications

Resistance of Leishmania infantum to allopurinol is associated with chromosome and gene copy number variations including decrease in the S-adenosylmethionine synthetase (METK) gene copy number

Resistance of Leishmania infantum to allopurinol is associated with chromosome and gene copy number variations including decrease in the S-adenosylmethionine synthetase (METK) gene copy number

Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles

L-Asparaginase of Leishmania donovani: Metabolic target and its role in Amphotericin B resistance

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