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Fulltext Anti-Acanthamoeba synergistic effect of chlorhexidine and Garcinia mangostana extract or α-mangostin against Acanthamoeba triangularis trophozoite and cyst forms

Sangkanu S, Mitsuwan W, Mahabusarakam W, Jimoh TO, Wilairatana P, Girol AP, et al.

Sci Rep, 2021 Apr 13;11(1):8053.
PMID: 33850179 DOI: 10.1038/s41598-021-87381-x

Acanthamoeba spp. can cause amoebic keratitis (AK). Chlorhexidine is effective for AK treatment as monotherapy, but with a relative failure on drug bioavailability in the deep corneal stroma. The combination of chlorhexidine and propamidine isethionate is recommended in the current AK treatment. However, the effectiveness of treatment depends on the parasite and virulence strains. This study aims to determine the potential of Garcinia mangostana pericarp extract and α-mangostin against Acanthamoeba triangularis, as well as the combination with chlorhexidine in the treatment of Acanthamoeba infection. The minimal inhibitory concentrations (MICs) of the extract and α-mangostin were assessed in trophozoites with 0.25 and 0.5 mg/mL, for cysts with 4 and 1 mg/mL, respectively. The MIC of the extract and α-mangostin inhibited the growth of A. triangularis trophozoites and cysts for up to 72 h. The extract and α-mangostin combined with chlorhexidine demonstrated good synergism, resulting in a reduction of 1/4-1/16 of the MIC. The SEM results showed that Acanthamoeba cells treated with a single drug and its combination caused damage to the cell membrane and irregular cell shapes. A good combination displayed by the extract or α-mangostin and chlorhexidine, described for the first time. Therefore, this approach is promising as an alternative method for the management of Acanthamoeba infection in the future.

Matched MeSH terms: Acanthamoeba Keratitis/drug therapy
Ointment tacrolimus for steroid resistant adenoviral nummular keratitis

Jamaluddin Ahmad M, Lott PW, Khaliddin N, Singh S

Med J Malaysia, 2020 07;75(4):461-463.
PMID: 32724020

A 33-year-old man presented with a four-day history of redness and blurring of vision of the right eye. A clinical diagnosis of adenoviral keratitis was made with a differential of microsporidia epithelial keratitis. The patient subsequently developed nummular keratitis which was resistant to topical steroids. He continued to develop multiple recurrences of the condition. Treatment with tacrolimus ointment was started as the patient had an elevated intraocular pressure due to prolonged steroid use. Tacrolimus ointment showed a favourable outcome in the management of recurrent nummular keratitis.

Matched MeSH terms: Keratitis/drug therapy*
Clinical utility of caspofungin eye drops in fungal keratitis

Neoh CF, Daniell M, Chen SC, Stewart K, Kong DC

Int J Antimicrob Agents, 2014 Aug;44(2):96-104.
PMID: 24933448 DOI: 10.1016/j.ijantimicag.2014.04.008

Treatment of fungal keratitis remains challenging. To date, only the polyenes and azoles are commonly used topically in the management of fungal keratitis. Natamycin, a polyene, is the only antifungal eye drop that is commercially available; the remainder are prepared in-house and are used in an 'off-label' manner. Failure of medical treatment for fungal keratitis is common, hence there is a need for more effective topical antifungal therapy. To increase the antifungal eye drop armamentarium, it is important to investigate the utility of other classes of antifungal agents for topical use. Caspofungin, an echinocandin antifungal agent, could potentially be used to address the existing shortcomings. However, little is known about the usefulness of topically administered caspofungin. This review will briefly explore the incidence, epidemiology and antifungal treatment of fungal keratitis. It will focus primarily on evidence related to the efficacy, safety and practicality of using caspofungin eye drops in fungal keratitis.

Matched MeSH terms: Keratitis/drug therapy*
Oleic acid-conjugated silver nanoparticles as efficient antiamoebic agent against Acanthamoeba castellanii

Anwar A, Abdalla SAO, Aslam Z, Shah MR, Siddiqui R, Khan NA

Parasitol Res, 2019 Jul;118(7):2295-2304.
PMID: 31093751 DOI: 10.1007/s00436-019-06329-3

Acanthamoeba castellanii belonging to the T4 genotype is an opportunistic pathogen which is associated with blinding eye keratitis and rare but fatal central nervous system infection. A. castellanii pose serious challenges in antimicrobial chemotherapy due to its ability to convert into resistant, hardy shell-protected cyst form that leads to infection recurrence. The fatty acid composition of A. castellanii trophozoites is known to be most abundant in oleic acid which chemically is an unsaturated cis-9-Octadecanoic acid and naturally found in animal and vegetable fats and oils. This study was designed to evaluate antiacanthamoebic effects of oleic acid against trophozoites, cysts as well as parasite-mediated host cell cytotoxicity. Moreover, oleic acid-conjugated silver nanoparticles (AgNPs) were also synthesized and tested against A. castellanii. Oleic acid-AgNPs were synthesized by chemical reduction method and characterized by ultraviolet-visible spectrophotometry, atomic force microscopy, dynamic light scattering analysis, and Fourier transform infrared spectroscopy. Viability, growth inhibition, encystation, and excystation assays were performed with 10 and 5 μM concentration of oleic acid alone and oleic acid-conjugated AgNPs. Bioassays revealed that oleic acid alone and oleic acid-conjugated AgNPs exhibited significant antiamoebic properties, whereas nanoparticle conjugation further enhanced the efficacy of oleic acid. Phenotype differentiation assays also showed significant inhibition of encystation and excystation at 5 μM. Furthermore, oleic acid and oleic acid-conjugated AgNPs also inhibited amoebae-mediated host cell cytotoxicity as determined by lactate dehydrogenase release. These findings for the first time suggest that oleic acid-conjugated AgNPs exhibit antiacanthamoebic activity that hold potential for therapeutic applications against A. castellanii.

Matched MeSH terms: Acanthamoeba Keratitis/drug therapy*
Antiamoebic activity of synthetic tetrazoles against Acanthamoeba castellanii belonging to T4 genotype and effects of conjugation with silver nanoparticles

Anwar A, Yi YP, Fatima I, Khan KM, Siddiqui R, Khan NA, et al.

Parasitol Res, 2020 Jun;119(6):1943-1954.
PMID: 32385711 DOI: 10.1007/s00436-020-06694-4

Acanthamoeba causes diseases such as Acanthamoeba keratitis (AK) which leads to permanent blindness and granulomatous Acanthamoeba encephalitis (GAE) where there is formation of granulomas in the brain. Current treatments such as chlorhexidine, diamidines, and azoles either exhibit undesirable side effects or require immediate and prolonged treatment for the drug to be effective or prevent relapse. Previously, antifungal drugs amphotericin B, nystatin, and fluconazole-conjugated silver with nanoparticles have shown significantly increased activity against Acanthamoeba castellanii. In this study, two functionally diverse tetrazoles were synthesized, namely 5-(3-4-dimethoxyphenyl)-1H-tetrazole and 1-(3-methoxyphenyl)-5-phenoxy-1H-tetrazole, denoted by T1 and T2 respectively. These compounds were evaluated for anti-Acanthamoeba effects at different concentrations ranging from 5 to 50 μM. Furthermore, these compounds were conjugated with silver nanoparticles (AgNPs) to enhance their efficacy. Particle size analysis showed that T1-AgNPs and T2-AgNPs had an average size of 52 and 70 nm respectively. After the successful synthesis and characterization of tetrazoles and tetrazole-conjugated AgNPs, they were subjected to anti-Acanthamoeba studies. Amoebicidal assay showed that at concentration 10 μM and above, T2 showed promising antiamoebic activities between the two compounds while encystation and excystation assays reveal that both T1 and T2 have inhibited differentiation activity against Acanthamoeba castellanii. Conjugation of T1 and T2 to AgNP also increased efficacy of tetrazoles as anti-Acanthamoeba agents. This may be due to the increased bioavailability as AgNP allows better delivery of treatment compounds to A. castellanii. Human cell cytotoxicity assay revealed that tetrazoles and AgNPs are significantly less toxic towards human cells compared with chlorhexidine which is known to cause undesirable side effects. Cytopathogenicity assay also revealed that T2 conjugated with AgNPs significantly reduced cytopathogenicity of A. castellanii compared with T2 alone, suggesting that T2-conjugated AgNP is an effective and safe anti-Acanthamoeba agent. The use of a synthetic azole compound conjugated with AgNPs can be an alternative strategy for drug development against A. castellanii. However, mechanistic and in vivo studies are needed to explore further translational values.

Matched MeSH terms: Acanthamoeba Keratitis/drug therapy
Ocular Permeation of Topical Tazocin and Its Effectiveness in the Treatment of Pseudomonas aeruginosa Induced Keratitis in Rabbits

Singh S, Agarwal R, Razak ZA, Ngu R, Nyein LL, Vasudevan S, et al.

J Ocul Pharmacol Ther, 2018 01 17;34(1-2):214-223.
PMID: 29341837 DOI: 10.1089/jop.2017.0098

PURPOSE: Pseudomonas aeruginosa is the most common causative organism for contact lens-associated corneal ulcer and is commonly treated with fluoroquinolones. With the emergence of resistant strains, it is important to investigate alternative therapies. Despite well-established efficacy of tazocin against systemic Pseudomonas infections, its topical use for the treatment of Pseudomonas keratitis has not been described, hence this study was aimed to find the ocular permeation of Tazocin and its efficacy in treating keratitis in rabbit eyes.
METHODS: We investigated the ocular permeation of topical tazocin after single drop application in normal rabbit eyes by estimating piperacillin and tazobactam concentrations in cornea, aqueous, and vitreous using a validated LC-MS/MS method. Furthermore, we determined the efficacy of repeated dose administration of tazocin against experimentally induced P. aeruginosa keratitis in rabbits in comparison to moxifloxacin. To determine the efficacy, clinical examination, histopathological examination, and estimation of bacterial load and inflammatory cytokines in cornea were done.
RESULTS: Significant corneal concentration of piperacillin and tazobactam was detected in normal rabbit corneas after single dose treatment with tazocin. In rabbits with Pseudomonas-induced keratitis, topical tazocin caused significant clinical and histopathological improvement. This improvement was associated with reduction in corneal bacterial load and inflammatory cytokines. Compared to moxifloxacin 0.5%, tazocin treated group showed greater clinical response which was associated with higher interleukin (IL)-1β, lower tumor necrosis factor (TNF)-α, a comparable level of IL-8, greater reduction in corneal bacterial load, and lesser inflammatory cell infiltration.
CONCLUSION: Tazocin showed good ocular penetration and was effective in treatment of Pseudomonas induced keratitis in rabbits.

Matched MeSH terms: Keratitis/drug therapy*
Anti-amoebic activity of acyclic and cyclic-samarium complexes on Acanthamoeba

Kusrini E, Hashim F, Gunawan C, Mann R, Azmi WNNWN, Amin NM

Parasitol Res, 2018 May;117(5):1409-1417.
PMID: 29532220 DOI: 10.1007/s00436-018-5814-x

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)2(EO5)](Pic)-and the cyclic complex [bis(picrato)(18-crown-6)samarium(III)] picrate-referred to as [Sm(Pic)2(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 IC50 of the acyclic complex (0.7 μg/mL) was ~ 10-fold lower than IC50 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 IC50 values of

Matched MeSH terms: Acanthamoeba Keratitis/drug therapy
Fulltext The Development of Drugs against Acanthamoeba Infections

Siddiqui R, Aqeel Y, Khan NA

Antimicrob Agents Chemother, 2016 11;60(11):6441-6450.
PMID: 27600042 DOI: 10.1128/AAC.00686-16

For the past several decades, there has been little improvement in the morbidity and mortality associated with Acanthamoeba keratitis and Acanthamoeba encephalitis, respectively. The discovery of a plethora of antiacanthamoebic compounds has not yielded effective marketed chemotherapeutics. The rate of development of novel antiacanthamoebic chemotherapies of translational value and the lack of interest of the pharmaceutical industry in developing such chemotherapies have been disappointing. On the other hand, the market for contact lenses/contact lens disinfectants is a multi-billion-dollar industry and has been successful and profitable. A better understanding of drugs, their targets, and mechanisms of action will facilitate the development of more-effective chemotherapies. Here, we review the progress toward phenotypic drug discovery, emphasizing the shortcomings of useable therapies.

Matched MeSH terms: Acanthamoeba Keratitis/drug therapy*
'Targeting the feast of a sleeping beast': Nutrient and mineral dependencies of encysted Acanthamoeba castellanii

Baig AM, Khan NA, Katyara P, Lalani S, Baig R, Nadeem M, et al.

Chem Biol Drug Des, 2021 01;97(1):18-27.
PMID: 32602961 DOI: 10.1111/cbdd.13755

Acanthamoeba spp. cause a corneal infection, Acanthamoeba keratitis (AK), and a cerebral infection, granulomatous amoebic encephalitis (GAE). Though aggressive chemotherapy has been able to kill the active trophozoite form of Acanthamoeba, the encysted form of this parasite has remained problematic to resist physiological concentrations of drugs. The emergence of encysted amoeba into active trophozoite form poses a challenge to eradicate this parasite. Acanthamoeba trophozoites have active metabolic machinery that furnishes energy in the form of ATPs by subjecting carbohydrates and lipids to undergo pathways including glycolysis and beta-oxidation of free fatty acids, respectively. However, very little is known about the metabolic preferences and dependencies of an encysted trophozoite on minerals or potential nutrients that it consumes to live in an encysted state. Here, we investigate the metabolic and nutrient preferences of the encysted trophozoite of Acanthamoeba castellanii and the possibility to target them by drugs that act on calcium ion dependencies of the encysted amoeba. The experimental assays, immunostaining coupled with bioinformatics tools show that the encysted Acanthamoeba uses diverse nutrient pathways to obtain energy in the quiescent encysted state. These findings highlight potential pathways that can be targeted in eradicating amoebae cysts successfully.

Matched MeSH terms: Keratitis/drug therapy
Development of anti-acanthamoebic approaches

Mungroo MR, Tong T, Khan NA, Anuar TS, Maciver SK, Siddiqui R

Int Microbiol, 2021 Aug;24(3):363-371.
PMID: 33754231 DOI: 10.1007/s10123-021-00171-3

Acanthamoeba keratitis is a sight-endangering eye infection, and causative organism Acanthamoeba presents a significant concern to public health, given escalation of contact lens wearers. Contemporary therapy is burdensome, necessitating prompt diagnosis and aggressive treatment. None of the contact lens disinfectants (local and international) can eradicate Acanthamoeba effectively. Using a range of compounds targeting cellulose, ion channels, and biochemical pathways, we employed bioassay-guided testing to determine their anti-amoebic effects. The results indicated that acarbose, indaziflam, terbuthylazine, glimepiride, inositol, vildagliptin and repaglinide showed anti-amoebic effects. Compounds showed minimal toxicity on human cells. Therefore, effects of the evaluated compounds after conjugation with nanoparticles should certainly be the subject of future studies and will likely lead to promising leads for potential applications.

Matched MeSH terms: Acanthamoeba Keratitis/drug therapy*
Fulltext Bacterial and fungal keratitis in Upper Egypt: in vitro screening of enzymes, toxins and antifungal activity

Gharamah AA, Moharram AM, Ismail MA, Al-Hussaini AK

Indian J Ophthalmol, 2014 Feb;62(2):196-203.
PMID: 24008795 DOI: 10.4103/0301-4738.116463

This work was conducted to study the ability of bacterial and fungal isolates from keratitis cases in Upper Egypt to produce enzymes, toxins, and to test the isolated fungal species sensitivity to some therapeutic agents.

Matched MeSH terms: Keratitis/drug therapy
Assessment of polymerase chain reaction in the detection of pseudomonas aeruginosa in contact lens-induced severe infectious keratitis

Subrayan V, Peyman M, Lek Yap S, Mohamed Ali NA, Devi S

Eye Contact Lens, 2010 Jul;36(4):201-3.
PMID: 20531205 DOI: 10.1097/ICL.0b013e3181e3efa3

PURPOSE: The aim of this study is to evaluate the role of real-time polymerase chain reaction (PCR) and conventional bacterial culture methods in the detection of Pseudomonas aeruginosa in contact lens-induced severe, partially treated corneal ulcers referred to a tertiary center.
METHODS: The study duration was 6 months. All patients with contact lens-related corneal ulcer, requiring admission during the study period were recruited. Samples from corneal scrapings were simultaneously sent at the time of admission for PCR and culture testing. An in-house real-time PCR was developed to detect the P. aeruginosa lasA gene. The results of PCR and culture were compared using McNemar's chi2 test.
RESULTS: Ten patients were recruited. The mean age was 33 years (20-45 years). All the patients had contact lens-related keratitis (>4 mm) of which eight (80%) were found positive for P. aeruginosa by PCR or culture. There was no significant difference between PCR and culture in detecting P. aeruginosa (P<0.05).
CONCLUSIONS: PCR is, at least, as good as conventional cultures in detecting P. aeruginosa. It is a rapid assay as compared with culture, and early detection enables prompt treatment thus reducing the destructive effect of the organism on the cornea.

Matched MeSH terms: Keratitis/drug therapy
Metformin-coated silver nanoparticles exhibit anti-acanthamoebic activities against both trophozoite and cyst stages

Anwar A, Soomaroo A, Anwar A, Siddiqui R, Khan NA

Exp Parasitol, 2020 Aug;215:107915.
PMID: 32461112 DOI: 10.1016/j.exppara.2020.107915

Acanthamoeba castellanii is an opportunistic protozoan responsible for serious human infections including Acanthamoeba keratitis and granulomatous amoebic encephalitis. Despite advances in antimicrobial therapy and supportive care, infections due to Acanthamoeba are a major public concern. Current methods of treatment are not fully effective against both the trophozoite and cyst forms of A. castellanii and are often associated with severe adverse effects, host cell cytotoxicity and recurrence of infection. Therefore, there is an urgent need to develop new therapeutic approaches for the treatment and management of Acanthamoebic infections. Repurposing of clinically approved drugs is a viable avenue for exploration and is particularly useful for neglected and rare diseases where there is limited interest by pharmaceutical companies. Nanotechnology-based drug delivery systems offer promising approaches in the biomedical field, particularly in diagnosis and drug delivery. Herein, we conjugated an antihyperglycemic drug, metformin with silver nanoparticles and assessed its anti-acanthamoebic properties. Characterization by ultraviolet-visible spectrophotometry and atomic force microscopy showed successful formation of metformin-coated silver nanoparticles. Amoebicidal and amoebistatic assays revealed that metformin-coated silver nanoparticles reduced the viability and inhibited the growth of A. castellanii significantly more than metformin and silver nanoparticles alone at both 5 and 10 μM after 24 h incubation. Metformin-coated silver nanoparticles also blocked encystation and inhibited the excystation in Acanthamoeba after 72 h incubation. Overall, the conjugation of metformin with silver nanoparticles was found to enhance its antiamoebic effects against A. castellanii. Furthermore, the pretreatment of A. castellanii with metformin and metformin-coated silver nanoparticles for 2 h also reduced the amoebae-mediated host cell cytotoxicity after 24 h incubation from 73% to 10% at 10 μM, indicating that the drug-conjugated silver nanoparticles confer protection to human cells. These findings suggest that metformin-coated silver nanoparticles hold promise in the improved treatment and management of Acanthamoeba infections.

Matched MeSH terms: Acanthamoeba Keratitis/drug therapy

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