Enhanced Killing of Acanthamoeba Cysts in vitro Using Dimethylsulfoxide

Saunders, P. P. R.; Proctor, E. M.; Rollins, David F.; Richards, J. Scott

doi:10.1016/s0161-6420(92)31823-8

Cited by 7 publications

(5 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All of these data agree with the results of Saunders et al (12), who found that propamidine isethionate clearly became cysticidal when it was combined with 30% dimethyl sulfoxide, which, according to those investigators, could act as a carrier.…”

Section: Discussionsupporting

confidence: 91%

Amoebicidal efficiencies of various diamidines against two strains of Acanthamoeba polyphaga

Perrine

Chenu

Georges

et al. 1995

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The first medical cure of Acanthamoeba keratitis was obtained by use of propamidine isethionate. Since then, it has been the basic drug recommended for use in treatment. Because some Acanthamoeba strains have been reported to be resistant to propamidine and propamidine was found to be only weakly cysticidal, superior homologs such as butamidine, pentamidine, hexamidine, heptamidine, octamidine, and nonamidine were tested for their amoebicidal effects on two Acanthamoeba strains isolated from patients with keratitis. Trophozoicidal and cysticidal efficiencies were found to be increased from propamidine to nonamidine; i.e., when the alkyl chain connecting the two benzene rings in their molecular structures was elongated, in comparison with propamidine, hexamidine and octamidine were the most amoebicidal molecules. As a result of these data, a kinetic study carried out on propamidine, hexamidine, and octamidine demonstrated that the amoebicidal effects resulted from two events: the diffusion of molecules through the plasma membrane or the double wall of trophozoites or cysts, respectively, and the lethal effects of molecules on amoebic protoplasm. The diffusion kinetics were increased when the alkyl chain was elongated, i.e., with an increase in the lipophilic properties of molecules. In contrast, the lethal effect kinetics were found to be unchanged by this elongation, indicating that they originated from the cationic surface-active properties induced by the protonated amidine groups attached to each benzene ring, which themselves remained unchanged from one molecule to the other. These results strongly advocate the immediate replacement of propamidine by hexamidine in the medical treatment of Acanthamoeba keratitis; in France, 0.1% hexamidine eyedrops are available (Desomedine). The results also advocate clinical investigations on the efficiency and toxicity of octamidine, which appears to be the most amoebicidal diamidine in vitro.Acanthamoeba keratitis is a serious and potentially devastating corneal infection generally seen in soft contact lens wearers. The responsible amoeba has been detected in the human cornea in two forms: as fragile trophozoites and as resistant dormant cysts. The medical treatment of this ocular infection remains very difficult because of the lack of antiamoebic drugs effective against cysts, which are responsible for frequent and serious recurrences.Since the first medical cure reported in 1985 (16), propamidine isethionate, an antimicrobial agent belonging to the diamidine family, has been the basic drug recommended for use in treatment, which includes the use of topical neomycin sulfate and various imidazoles (2,5,7,8,15). Unfortunately, propamidine is poorly cysticidal and the resistance of some Acanthamoeba strains has been reported (6, 10). In the present study, superior homologs of propamidine were tested for their amoebicidal effects both on trophozoites and cysts with the intent of finding whether some of them are more amoebicidal and, especially, cysticidal than propamidine. At...

show abstract

Section: Discussionsupporting

confidence: 91%

Amoebicidal efficiencies of various diamidines against two strains of Acanthamoeba polyphaga

Perrine

Chenu

Georges

et al. 1995

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…11 . 25 In keeping with the findings of 31 In the present ill I'itro study, additive effects were observed with cationic antiseptics plus propamidine or neomycin, and slight synergy between the antiseptics and pentamidine (Ta bles II, III).…”

Section: Discussionsupporting

confidence: 88%

Drug resistance and Acanthamoeba Keratitis: The quest for alternative antiprotozoal chemotherapy

Hay

Kirkness

Seal

et al. 1994

Eye

136

View full text Add to dashboard Cite

SUMMARYTrophozoites and cysts of 20 isolates of Acanthamoeba from the cornea and five from related samples were tested in vitro for sensitivity to ten drugs (three aromatic dia midines, two aminoglycosides, two macrolides, a polyene macrolide antibiotic, an organoarsenical and an anti metabolite) and two cationic antiseptics (chlorhexidine and polyhexamethylene biguanide, PHMB). Keratitis associated with Acanthamoeha infection is a relatively rare, sight-threatening condition occurring most often in contact lens wearers, I where there has been inappropriate or inadequate disinfection of contact lens systems." The clinical presentation of the disease is often mistakenly diagnosed as herpes simplex or fungal infec tion.3 This results in inappropriate anti-microbial agents being administered. Early features4-6 such as pain, photo phobia and recurrent epithelial breakdown with little infil-

show abstract

“…Four compounds (trovafloxacin, talazoparib, AZD2461, and azilsartan) at 20 μM exhibited no significant inhibition of A. castellanii trophozoite viability. These compounds could not be further concentrated for experimentation due to the toxic effects of DMSO ( Saunders et al., 1992 ; Siddiqui et al., 2016 ). Consequently, olaparib, venadaparib and AZ9482 were selected for further investigations.…”

Section: Resultsmentioning

confidence: 99%

Novel anti-Acanthamoeba effects elicited by a repurposed poly (ADP-ribose) polymerase inhibitor AZ9482

Chen,

Han,

Jing

et al. 2024

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

IntroductionAcanthamoeba infection is a serious public health concern, necessitating the development of effective and safe anti-Acanthamoeba chemotherapies. Poly (ADP-ribose) polymerases (PARPs) govern a colossal amount of biological processes, such as DNA damage repair, protein degradation and apoptosis. Multiple PARP-targeted compounds have been approved for cancer treatment. However, repurposing of PARP inhibitors to treat Acanthamoeba is poorly understood.MethodsIn the present study, we attempted to fill these knowledge gaps by performing anti-Acanthamoeba efficacy assays, cell biology experiments, bioinformatics, and transcriptomic analyses.ResultsUsing a homology model of Acanthamoeba poly (ADP-ribose) polymerases (PARPs), molecular docking of approved drugs revealed three potential inhibitory compounds: olaparib, venadaparib and AZ9482. In particular, venadaparib exhibited superior docking scores (−13.71) and favorable predicted binding free energy (−89.28 kcal/mol), followed by AZ9482, which showed a docking score of −13.20 and a binding free energy of −92.13 kcal/mol. Notably, the positively charged cyclopropylamine in venadaparib established a salt bridge (through E535) and a hydrogen bond (via N531) within the binding pocket. For comparison, AZ9482 was well stacked by the surrounding aromatic residues including H625, Y652, Y659 and Y670. In an assessment of trophozoites viability, AZ9482 exhibited a dose-and time-dependent anti-trophozoite effect by suppressing Acanthamoeba PARP activity, unlike olaparib and venadaparib. An Annexin V-fluorescein isothiocyanate/propidium iodide apoptosis assay revealed AZ9482 induced trophozoite necrotic cell death rather than apoptosis. Transcriptomics analyses conducted on Acanthamoeba trophozoites treated with AZ9482 demonstrated an atlas of differentially regulated proteins and genes, and found that AZ9482 rapidly upregulates a multitude of DNA damage repair pathways in trophozoites, and intriguingly downregulates several virulent genes. Analyzing gene expression related to DNA damage repair pathway and the rate of apurinic/apyrimidinic (AP) sites indicated DNA damage efficacy and repair modulation in Acanthamoeba trophozoites following AZ9482 treatment.DiscussionCollectively, these findings highlight AZ9482, as a structurally unique PARP inhibitor, provides a promising prototype for advancing anti-Acanthamoeba drug research.

show abstract

Enhanced Killing of Acanthamoeba Cysts in vitro Using Dimethylsulfoxide

Cited by 7 publications

References 9 publications

Amoebicidal efficiencies of various diamidines against two strains of Acanthamoeba polyphaga

Amoebicidal efficiencies of various diamidines against two strains of Acanthamoeba polyphaga

Drug resistance and Acanthamoeba Keratitis: The quest for alternative antiprotozoal chemotherapy

Novel anti-Acanthamoeba effects elicited by a repurposed poly (ADP-ribose) polymerase inhibitor AZ9482

Contact Info

Product

Resources

About