Increased miltefosine tolerance in clinical isolates of Leishmania donovani is associated with reduced drug accumulation, increased infectivity and resistance to oxidative stress

Deep, Deepak Kumar; Singh, Ruchi; Bhandari, Vasundhra; Verma, Aditya; Sharma, Vikash; Wajid, Saima; Sundar, Shyam; Ramesh, V.; Dujardin, Jean Claude; Salotra, Poonam

doi:10.1371/journal.pntd.0005641

Cited by 67 publications

(63 citation statements)

References 39 publications

(63 reference statements)

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“…Post-treatment relapse in the field has been linked to only a minor decrease in MIL susceptibility, with this 'intermediate' resistant phenotype behaving similarly to the non-exposed wild-type strains [35]. This contrasts with other studies describing an increased infectivity for relapse-derived strains [3,5] which is actually unexpected given the detrimental changes in fitness upon aqcuisition of full resistance [13,14,29].…”

Section: Discussionmentioning

confidence: 82%

“…Since efflux rates are not significantly increased (Additional file 1: Figure S1), outward drug transporters are likely not primarily involved in the observed decrease in MIL susceptibility. Similarly, clinical isolates with an increased tolerance to MIL have been reported to show a decreased drug uptake [5]. The lower steady-state MIL accumulation correlates with a lower LdMT gene copy number that probably arose from the parasite's extreme genomic plasticity under stress conditions [36].…”

Section: Discussionmentioning

confidence: 97%

“…The multifactorial causes of treatment failure are still not fully understood and involvement of the parasite's (epi-) phenotype has been suggested [3,4]. Clinical isolates from relapse patients revealed alterations in parasite fitness rather than in drug susceptibility [3,5]; however, the lack of large sets of paired pre-and post-treatment samples precludes direct comparison of syngeneic strains. Most laboratory studies circumvented this problem by repeatedly exposing promastigotes to MIL, hence generating resistant strains retaining an identical genetic background to the parent wild-type (WT).…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection

et al. 2020

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Background: Since the introduction of miltefosine (MIL) as first-line therapy in the kala-azar elimination programme in the Indian subcontinent, treatment failure rates have been increasing. Since parasite infectivity and virulence may become altered upon treatment relapse, this laboratory study assessed the phenotypic effects of repeated in vitro and in vivo MIL exposure. Methods: Syngeneic Leishmania donovani lines either or not exposed to MIL were compared for drug susceptibility, rate of promastigote multiplication and metacyclogenesis, macrophage infectivity and behaviour in the sand fly vector, Lutzomyia longipalpis. Results: Promastigotes of both in vitro and in vivo MIL-selected strains displayed a slightly reduced drug susceptibility that was associated with a reduced MIL-accumulation linked to a lower copy number (disomic state) of chromosome 13 harboring the miltefosine transporter (LdMT) gene. In vitro selected promastigotes showed a lower rate of metacyclogenesis whereas the in vivo derived promastigotes displayed a moderately increased growth rate. Repeated MIL exposure did neither influence the parasite load nor metacyclogenesis in the sand fly vector. Conclusions: Recurrent in vitro and in vivo MIL exposure evokes a number of very subtle phenotypic and genotypic changes which could make promastigotes less susceptible to MIL without attaining full resistance. These changes did not significantly impact on infection in the sand fly vector.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection

et al. 2020

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“…Lipase and the lipase precursor involved in free fatty acid metabolism provide an alternate source of energy generation during stress (15). Therefore, we chose to investigate the role of the lipase precursor, which showed consistently high expression levels in all L. donovani isolates from cases that relapsed after MIL treatment (19). Lip encodes a putative enzyme lipase precursor that is supposedly involved in free fatty acid metabolism via the beta oxidation pathway and helps parasites to evade drug-induced oxidative stress by providing extra energy.…”

Section: Discussionmentioning

confidence: 99%

“…Lipase-mediated hydrolysis of triacylglycerol leads to products that compromise host immunity, thus allowing the pathogen to survive within host cell (27). Increased infectivity and increased metacyclogenesis have been associated with MIL tolerance and documented in L. donovani from relapse cases after MIL treatment in the Indian subcontinent (19,28).…”

Section: Discussionmentioning

confidence: 99%

Lipase Precursor-Like Protein Promotes Miltefosine Tolerance in Leishmania donovani by Enhancing Parasite Infectivity and Eliciting Anti-inflammatory Responses in Host Macrophages

Deep

Singh

Kulshrestha

et al. 2018

Antimicrob Agents Chemother

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The oral drug miltefosine (MIL) was introduced in the Indian subcontinent in the year 2002 for the treatment of visceral leishmaniasis (VL). However, recent reports on its declining efficacy and increasing relapse rates pose a serious concern. An understanding of the factors contributing to MIL tolerance in Leishmania parasites is critical. In the present study, we assessed the role of the lipase precursor-like protein (Lip) in conferring tolerance to miltefosine by episomally overexpressing Lip in Leishmania donovani (LdLip++). We observed a significant increase (∼3-fold) in the MIL 50% inhibitory concentration (IC50) at both the promastigote (3.90 ± 0.68 µM; P < 0.05) and intracellular amastigote (9.10 ± 0.60 µM; P < 0.05) stages compared to the wild-type counterpart (LdNeo) (MIL IC50s of 1.49 ± 0.20 µM at the promastigote stage and 3.95 ± 0.45 µM at the amastigote stage). LdLip++ parasites exhibited significantly (P < 0.05) increased infectivity to host macrophages and increased metacyclogenesis and tolerance to MIL-induced oxidative stress. The susceptibility of LdLip++ to other antileishmanial drugs (sodium antimony gluconate and amphotericin B) remained unchanged. In comparison to LdNeo, the LdLip++ parasites elicited high host interleukin-10 (IL-10) cytokine expression levels (1.6-fold; P < 0.05) with reduced expression of the cytokine tumor necrosis factor alpha (TNF-α) (1.5-fold; P < 0.05), leading to a significantly (P < 0.01) increased ratio of IL-10/TNF-α. The above-described findings suggest a role of lipase precursor-like protein in conferring tolerance to the oral antileishmanial drug MIL in L. donovani parasites.

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Synthesis and in vitro antileishmanial efficacy of novel benzothiadiazine‐1,1‐dioxide derivatives

Mangwegape

Zuma

Aucamp

et al. 2021

Archiv der Pharmazie

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Leishmaniasis is a major vector-borne parasitic disease that affects thousands of people in tropical and subtropical developing countries. In 2019 alone, it killed 26,000-65,000 individuals. Leishmaniasis is curable, yet its eradication and elimination are hampered by major hurdles, such as the availability of only a handful of clinical toxic drugs and the emergence of pathogenic resistance against them. This

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Increased miltefosine tolerance in clinical isolates of Leishmania donovani is associated with reduced drug accumulation, increased infectivity and resistance to oxidative stress

Cited by 67 publications

References 39 publications

Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection

Phenotypic adaptations of Leishmania donovani to recurrent miltefosine exposure and impact on sand fly infection

Lipase Precursor-Like Protein Promotes Miltefosine Tolerance in Leishmania donovani by Enhancing Parasite Infectivity and Eliciting Anti-inflammatory Responses in Host Macrophages

Synthesis and in vitro antileishmanial efficacy of novel benzothiadiazine‐1,1‐dioxide derivatives

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