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Novel anti-Acanthamoebic properties of raloxifene sulfonate/sulfamate derivatives
Ruqaiyyah Siddiqui1, Mohammed I El-Gamal2, Sreedevi Sajeev3
1College of Arts and Sciences, American University of Sharjah, Sharjah 26666, United Arab Emirates; Microbiota Research Center, Istinye University, Istanbul 34010, Turkey.
Abstract:
Acanthamoeba are known to cause a vision threatening eye infection typically due to contact lens wear, and an infection of the central nervous system. The ability of these amoebae to switch phenotypes, from an active trophozoite to a resistant cyst form is not well understood; the cyst stage is often resistant to chemotherapy, which is of concern given the rise of contact lens use and the ineffective disinfectants available, versus the cyst stage. Herein, for the first time, a range of raloxifene sulfonate/sulfamate derivatives which target nucleotide pyrophosphatase/phosphodiesterase enzymes, were assessed using amoebicidal and excystation tests versus the trophozoite and cyst stage of Acanthamoeba. Moreover, the potential for cytopathogenicity inhibition in amoebae was assessed. Each of the derivatives showed considerable anti-amoebic activity as well as the ability to suppress phenotypic switching (except for compound 1a). Selected raloxifene derivatives reduced Acanthamoeba-mediated host cell damage using lactate dehydrogenase assay. These findings suggest that pyrophosphatase/phosphodiesterase enzymes may be valuable targets against Acanthamoeba infections.
Insights
New raloxifene derivatives show promise in combating Acanthamoeba infections by targeting trophozoite and cyst stages. These compounds also inhibit phenotypic switching and reduce host cell damage, offering potential new treatments for vision-threatening Acanthamoeba keratitis.
Area of Science:
- Microbiology
- Parasitology
- Medicinal Chemistry
Background:
- Acanthamoeba infections, particularly Acanthamoeba keratitis, pose a significant threat to vision, often linked to contact lens wear.
- The resistant cyst stage of Acanthamoeba is difficult to eradicate with current therapies, exacerbated by increasing contact lens usage.
- Understanding Acanthamoeba's phenotypic switching between active trophozoite and resistant cyst forms is crucial for developing effective treatments.
Purpose of the Study:
- To evaluate novel raloxifene sulfonate/sulfamate derivatives as potential anti-Acanthamoeba agents.
- To assess the efficacy of these derivatives against both Acanthamoeba trophozoite and cyst stages.
- To investigate the compounds' ability to inhibit phenotypic switching and reduce Acanthamoeba-mediated cytopathogenicity.
Main Methods:
- Amoebicidal and excystation assays were performed on Acanthamoeba trophozoites and cysts using various raloxifene derivatives.
- Phenotypic switching suppression was evaluated for the tested compounds.
- Lactate dehydrogenase assays were used to measure the inhibition of Acanthamoeba-mediated host cell damage.
Main Results:
- All tested raloxifene derivatives demonstrated significant amoebicidal activity against Acanthamoeba trophozoites and cysts.
- Most derivatives effectively suppressed the phenotypic switching of Acanthamoeba from trophozoite to cyst, with one exception (compound 1a).
- Selected derivatives significantly reduced host cell damage induced by Acanthamoeba.
Conclusions:
- Raloxifene sulfonate/sulfamate derivatives exhibit potent anti-Acanthamoeba activity, targeting both active and resistant stages.
- These compounds show potential in preventing the crucial phenotypic switching to the resistant cyst form.
- Targeting nucleotide pyrophosphatase/phosphodiesterase enzymes with these derivatives represents a promising therapeutic strategy against Acanthamoeba infections.
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