In-vitro development of an effective treatment for Acanthamoeba keratitis

Ortillés, Ángel; Belloc, J.; Rubio, Encarnación Sonia Soriano; Fernández, María Teresa; Benito, M.; Cristobal, Ja; Calvo, Begoña; Goñi, Pilar

doi:10.1016/j.ijantimicag.2017.03.033

Cited by 25 publications

(16 citation statements)

References 41 publications

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“…As the treatment of FLA remains empirical and the in vitro activities of antiacanthamoebal drugs reported in the literature are variable depending on the time of treatment or the Acanthamoeba species used ( Duma and Finley, 1976 , Elder et al., 1994 , Ondarza et al., 2006 , Martin-Navarro et al., 2013 , Carrijo-Carvalho et al., 2017 , Nakaminami et al., 2017 , Ortilles et al., 2017 ), the main objective of this study was to determine in our conditions the in vitro efficiency of clinically used antimicrobial agents on A. castellanii at different times of treatment in order to propose a rationale for their use in therapy. This approach was completed by a study deciphering the mechanism of action of amphotericin B showing a surprising evolution of antiacanthamoebal activity as a function of time.…”

Section: Discussionmentioning

confidence: 99%

In vitro evaluation of antimicrobial agents on Acanthamoeba sp. and evidence of a natural resilience to amphotericin B

Taravaud

Loiseau

Pomel

2017

International Journal for Parasitology: Drugs and Drug Resistan

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The free-living amoeba (FLA) Acanthamoeba sp. is an opportunistic pathogen that can cause amoebic keratitis (AK) or granulomatous amoebic encephalitis (GAE). While current treatments of AK are long with some relapses, no consensus therapy has been developed for GAE remaining lethal in 90% of the cases. In this context, efficient antiacanthamoebal drugs have to be identified. In this work, 15 drugs used in the treatment of AK or GAE or in other parasitic diseases were evaluated for their in vitro activity on A. castellanii. Hexamidine, voriconazole and clotrimazole exhibited the highest activities with IC50 values at 0.05 μM, 0.40 μM and 0.80 μM, respectively, while rifampicin, metronidazole and cotrimoxazole were inactive. Among 15 drug associations evaluated, no synergistic effect was observed, and one antagonism was determined between hexamidine and chlorhexidine. Interestingly, amphotericin B was the only drug presenting an increase of IC50 as a function of treatment duration. The amoebae susceptibility to amphotericin B cultured in the presence of 250 μM of the drug was similar to the one of a naive control, revealing that no resistant strain could be selected. However, the amoebae susceptibility always returned to an initial level at each passage. This natural and non-acquired adaptation to amphotericin B, qualified as resilience, was observed in several strains of A. castellanii and A. polyphaga. Using a pharmacological approach with effectors of different cellular mechanisms or transports, and an ultrastructural analysis of amphotericin B-treated amoebae, the involvement of several mitochondria-dependent pathways as well as multidrug resistant transporters was determined in amphotericin B resilience. Based on the observations from this study, the relevance of using amphotericin B in GAE treatments may be reconsidered, while the use of some other drugs, such as rifampicin or cotrimoxazole, is not relative to intrinsic antiacanthamoebal activity.

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Section: Discussionmentioning

confidence: 99%

In vitro evaluation of antimicrobial agents on Acanthamoeba sp. and evidence of a natural resilience to amphotericin B

Taravaud

Loiseau

Pomel

2017

International Journal for Parasitology: Drugs and Drug Resistan

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“…The life cycle of Acanthamoeba consists of two developmental stagesan actively feeding trophozoite stage and a dormant cyst stage (Ibrahim et al 2007). Trophozoites are known to be susceptible to most of the amoebicidal agents but the cysticidal activities of these agents are limited (Ortillés et al 2017). These challenges, along with the risk factors that are associated with Acanthamoeba being present worldwide (Marciano-Cabral and Cabral 2003), demand for an urgent need for the development of new anti-amoebic drugs with improved efficacy against this pathogen.…”

Section: Introductionmentioning

confidence: 99%

Anti-amoebic activity of acyclic and cyclic-samarium complexes on Acanthamoeba

et al. 2018

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This work investigated the anti-amoebic activity of two samarium (Sm) complexes, the acyclic complex [bis(picrato)(pentaethylene glycol)samarium(III)] picrate-referred to as [Sm(Pic)(EO5)](Pic)-and the cyclic complex [bis(picrato)(18-crown-6)samarium(III)] picrate-referred to as [Sm(Pic)(18C6)](Pic). Both Sm complexes caused morphological transformation of the protozoa Acanthamoeba from its native trophozoite form carrying a spine-like structure called acanthopodia, to round-shaped cells with loss of the acanthopodia structure, a trademark response to environmental stress. Further investigation, however, revealed that the two forms of the Sm complexes exerted unique cytotoxicity characteristics. Firstly, the IC of the acyclic complex (0.7 μg/mL) was ~ 10-fold lower than IC of the cyclic Sm complex (6.5 μg/mL). Secondly, treatment of the Acanthamoeba with the acyclic complex caused apoptosis of the treated cells, while the treatment with the cyclic complex caused necrosis evident by the leakage of the cell membrane. Both treatments induced DNA damage in Acanthamoeba. Finally, a molecular docking simulation revealed the potential capability of the acyclic complex to form hydrogen bonds with profilin-a membrane protein present in eukaryotes, including Acanthamoeba, that plays important roles in the formation and degradation of actin cytoskeleton. Not found for the cyclic complex, such potential interactions could be the underlying reason, at least in part, for the much higher cytotoxicity of the acyclic complex and also possibly, for the observed differences in the cytotoxicity traits. Nonetheless, with IC values of < 10 μg/mL, both the acyclic and cyclic Sm complexes feature a promising potential as cytotoxic agents to fight amoebic infections.

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“…Acanthamoeba trophozoites can convert itself into highly resistant cyst form, which diminishes the effectiveness of available therapeutic agents [ 4 ]. For this reason, new and more efficacious treatment options against cysts have been proposed and are still being examined [ 5 – 8 ].…”

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confidence: 99%

Effect of 2, 6-Dichlorobenzonitrile on Amoebicidal Activity of Multipurpose Contact Lens Disinfecting Solutions

et al. 2018

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Multipurpose contact lens disinfecting solutions (MPDS) are widely used to cleanse and disinfect microorganisms. However, disinfection efficacy of these MPDS against Acanthamoeba cyst remain insufficient. 2, 6-dichlorobenzonitrile (DCB), a cellulose synthesis inhibitor, is capable of increasing the amoebical effect against Acanthamoeba by inhibiting its encystation. In this study, we investigated the possibility of DCB as a disinfecting agent to improve the amoebicidal activity of MPDS against Acanthamoeba cyst. Eight commercial MPDS (from a to h) were assessed, all of which displayed insufficient amoebicidal activity against the mature cysts. Solution e, f, and h showed strong amoebicidal effect on the immature cysts. Amoebicidal efficacy against mature cysts remained inadequate even when the 8 MPDS were combined with 100 μM DCB. However, 4 kinds of MPDS (solution d, e, f, and h) including 100 μM DCB demonstrated strong amoebicidal activity against the immature cysts. The amoebicidal activity of solution d was increased by addition of DCB. Cytotoxicity was absent in human corneal epithelial cells treated with either DCB or mixture of DCB with MPDS. These results suggested that DCB can enhance the amoebicical activity of MPDS against Acanthamoeba immature cyst in vitro.

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In-vitro development of an effective treatment for Acanthamoeba keratitis

Cited by 25 publications

References 41 publications

In vitro evaluation of antimicrobial agents on Acanthamoeba sp. and evidence of a natural resilience to amphotericin B

In vitro evaluation of antimicrobial agents on Acanthamoeba sp. and evidence of a natural resilience to amphotericin B

Anti-amoebic activity of acyclic and cyclic-samarium complexes on Acanthamoeba

Effect of 2, 6-Dichlorobenzonitrile on Amoebicidal Activity of Multipurpose Contact Lens Disinfecting Solutions

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