Evidence of a drug-specific impact of experimentally selected paromomycin and miltefosine resistance on parasite fitness in<i>Leishmania infantum</i>

Hendrickx, Sarah; Beyers, Jolien; Mondelaers, Annelies; Eberhardt, E.; Lachaud, Laurence; Delputte, Peter; Cos, Paul; Maes, Louis

doi:10.1093/jac/dkw096

Cited by 36 publications

(40 citation statements)

References 36 publications

(37 reference statements)

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“…Although drug resistance appears to be costly in Plasmodium spp. and schistosomes (Vanaerschot et al ., ), no costs of paromycin resistance were found in L. donovani (Hendrickx et al ., ); in L. infantum , miltefosine resistance was costly, but paromycin resistance resulted in increased growth and enhanced tolerance to stress (Hendrickx et al ., ). Resistance to pro‐oxidant antimonial drugs can actually improve L. donovani infectivity and establishment in hosts, presumably because the superior antioxidant defences of resistant lines allow them to tolerate host immune responses and the stress of initial establishment (Vanaerschot et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Evolution of resistance to single and combined floral phytochemicals by a bumble bee parasite

Palmer‐Young¹,

Sadd

Adler³

2016

J of Evolutionary Biology

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Repeated exposure to inhibitory compounds can drive the evolution of resistance, which weakens chemical defence against antagonists. Floral phytochemicals in nectar and pollen have antimicrobial properties that can ameliorate infection in pollinators, but evolved resistance among parasites could diminish the medicinal efficacy of phytochemicals. However, multicompound blends, which occur in nectar and pollen, present simultaneous chemical challenges that may slow resistance evolution. We assessed evolution of resistance by the common bumble bee gut parasite Crithidia bombi to two floral phytochemicals, singly and combined, over 6 weeks (~100 generations) of chronic exposure. Resistance of C. bombi increased under single and combined phytochemical exposure, without any associated costs of reduced growth under phytochemical‐free conditions. After 6 weeks’ exposure, phytochemical concentrations that initially inhibited growth by > 50%, and exceeded concentrations in floral nectar, had minimal effects on evolved parasite lines. Unexpectedly, the phytochemical combination did not impede resistance evolution compared to single compounds. These results demonstrate that repeated phytochemical exposure, which could occur in homogeneous floral landscapes or with therapeutic phytochemical treatment of managed hives, can cause rapid evolution of resistance in pollinator parasites. We discuss possible explanations for submaximal phytochemical resistance in natural populations. Evolved resistance could diminish the antiparasitic value of phytochemical ingestion, weakening an important natural defence against infection.

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Section: Discussionmentioning

confidence: 99%

Evolution of resistance to single and combined floral phytochemicals by a bumble bee parasite

Palmer‐Young¹,

Sadd

Adler³

2016

J of Evolutionary Biology

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“…The clear difference in intrinsic susceptibility between both strains is in line with inter-strain variability reported for different parasite species and clinical isolates [26–30]. Although the selection of MIL resistance on amastigotes proved to be very challenging in vitro , it could be hypothesized that the enhanced fitness profile associated with PMM resistance could facilitate development of resistance towards other drugs [17]. Our susceptibility analyses did not reveal any direct cross-resistance between PMM and MIL in the individual resistant lines.…”

Section: Discussionmentioning

confidence: 83%

“…In those endemic areas with large-scale Sb-resistance and an increasing number of MIL and AmB treatment failures, a switch from monotherapy towards combination therapies has been advised whereby the short-term combination of PMM and MIL was already shown to be a safe and efficacious alternative [24]. However, concerns regarding drug resistance have already been raised for both PMM and MIL monotherapy [10–14, 17, 22, 25]. Given these concerns a better understanding of the possible implications of large scale implementation of PMM-MIL combination therapy seems essential.…”

Section: Discussionmentioning

confidence: 99%

“…donovani derived from treatment failures in the Indian subcontinent, the first actual MIL-resistant clinical Leishmania isolates did already surface [10–12]. Rapid development of laboratory-induced PMM-resistance has been demonstrated [11, 13–15] which also proved to be associated with a potential fitness gain [16, 17] paving a way to rapid emergence and spread of PMM-resistance upon its routine use in the field. Although drug resistance would theoretically arise slower for drug combinations, it remains essential to assess the potential effect of introducing PMM-MIL combination therapy on a large scale, given the above mentioned limitations of PMM- or MIL-monotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Combined treatment of miltefosine and paromomycin delays the onset of experimental drug resistance in Leishmania infantum

et al. 2017

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BackgroundSince miltefosine monotherapy against visceral leishmaniasis (VL) caused by Leishmania donovani has been discontinued in the Indian subcontinent due to an increase in the number of treatment failures, single dose liposomal amphotericin B is now advocated as a treatment option of choice. Paromomycin-miltefosine combination therapy can be used as substitute first-line treatment in regions without cold-chain potential. Previous laboratory studies in the closely related species Leishmania infantum have demonstrated that paromomycin monotherapy fairly rapidly selects for resistance producing a phenotype with increased fitness. Given the possible clinical implications of these findings for the current field situation, the present study aimed to identify the potential hazards of paromomycin-miltefosine combination therapy.Principal findingsDrug interaction studies using the fixed-ratio isobologram method revealed an indifferent interaction between paromomycin and miltefosine. In hamsters infected with L. infantum, the combination resulted in cumulative efficacy in reducing parasite burdens in the liver, spleen and bone marrow. Selected resistant lines against the single drugs did not display cross-resistance. When the intracellular amastigote stage was repeatedly exposed to the paromomycin-miltefosine combination, either in vitro or in vivo, no significant susceptibility decrease towards either drug was noted.ConclusionsThese results suggest that implementation of paromomycin-miltefosine combination therapy indeed could represent a safe and affordable treatment option for L. donovani VL as miltefosine appears to overrule the anticipated rapid development of PMM resistance.

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“…Later on, MIL resistance was linked to mutations in the putative L. donovani MIL transporter (LdMT) and/ or its β-subunit LdRos3, leading to a defective inward drug transport [10][11][12]. Although the broader impact of these mutations is still a topic of debate and may even be species-related [13,14], MIL resistance definitely appears to be associated with alterations in parasite fitness. Although selection on promastigotes fairly rapidly resulted in resistance, repeated exposure of intracellular amastigotes both in vitro and in vivo did not result in reduced MIL susceptibility [15,16].…”

Section: Introductionmentioning

confidence: 99%

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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Evidence of a drug-specific impact of experimentally selected paromomycin and miltefosine resistance on parasite fitness inLeishmania infantum

Cited by 36 publications

References 36 publications

Evolution of resistance to single and combined floral phytochemicals by a bumble bee parasite

Evolution of resistance to single and combined floral phytochemicals by a bumble bee parasite

Combined treatment of miltefosine and paromomycin delays the onset of experimental drug resistance in Leishmania infantum

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

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