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Nanovehicles in the improved treatment of infections due to brain-eating amoebae

Mungroo MR, Khan NA, Anwar A, Siddiqui R

Int Microbiol, 2021 Aug 09.
PMID: 34368912 DOI: 10.1007/s10123-021-00201-0

Pathogenic free-living amoebae are known to cause fatal central nervous system infections with extremely high mortality rates. High selectivity of the blood-brain barrier hampers delivery of drugs and untargeted delivery of drugs can cause severe side effects. Nanovehicles can be used for targeted drug delivery across the blood-brain barrier. Inorganic nanoparticles have been explored as carriers for various biomedical applications and can be modified with various ligands for efficient targeting and cell selectivity while lipid-based nanoparticles have been extensively used in the development of both precision and colloidal nanovehicles. Nanomicelles and polymeric nanoparticles can also serve as nanocarriers and may be modified so that responsiveness of the nanoparticles and release of the loads are linked to specific stimuli. These nanoparticles are discussed here in the context of the treatment of central nervous system infections due to pathogenic amoebae. It is anticipated that these novel strategies can be utilized in tandem with novel drug leads currently in the pipeline and yield in the development of much needed treatments against these devastating parasites.
Gut bacteria of Varanus salvator possess potential antitumour molecules

Soopramanien M, Khan NA, Sagathevan K, Siddiqui R

Int Microbiol, 2021 Jan;24(1):47-56.
PMID: 32737845 DOI: 10.1007/s10123-020-00139-9

Pollution, unhygienic conditions and organic waste are detrimental to human health. On the contrary, animals living in polluted environments, feeding on organic waste and exposed to noxious agents such as heavy metals must possess remarkable properties against contracting diseases. Species such as cockroaches and water monitor lizards thrive in unhygienic conditions and feed on decaying matter. Here, we investigated the antitumour properties of metabolites produced by gut bacteria isolated from Varanus salvator (Asian water monitor lizard). An adult water monitor lizard and a juvenile water monitor lizard were acquired, and dissected. Their aerobic gut bacteria were isolated and identificated through 16S rDNA sequencing. Next, bacterial conditioned media (CM) were prepared and utilised for subsequent assays. Growth inhibition, MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay, cytotoxicity and cell survival assays were accomplished against a panel of cancer cells as well as a normal cell line. Furthermore, liquid chromatography-mass spectrometry (LC-MS) was employed to identify potential antitumour molecules. A plethora of bacteria were isolated from the gut of juvenile and adult V. salvator respectively. Moreover, CM prepared from selected bacteria exhibited antitumour activity. Of note, LC-MS results indicated the presence of several molecules with reported antitumour activity, namely, 3-butylidene-7-hydroxyphthalide, C75, enigmol, estrone 16-oxime, proglumide and S-allyl-L-cysteine. Furthermore, 356 potentially novel molecules from juvenile V. salvator and 184 from adult V. salvator were depicted. Thus, the gut microbiota of V. salvator might be considered as a great niche of antitumour molecules; however, further in vitro and in vivo studies are needed to assess the antitumour properties of these molecules.
Anticancer Properties of Asian Water Monitor Lizard (Varanus salvator), Python (Malayopython reticulatus) and Tortoise (Cuora kamaroma amboinensis)

Jeyamogan S, Khan NA, Sagathevan K, Siddiqui R

Anticancer Agents Med Chem, 2020;20(13):1558-1570.
PMID: 32364082 DOI: 10.2174/1871520620666200504103056

BACKGROUND: Cancer contributes to significant morbidity and mortality despite advances in treatment and supportive care. There is a need for the identification of effective anticancer agents. Reptiles such as tortoise, python, and water monitor lizards are exposed to heavy metals, tolerate high levels of radiation, feed on rotten/germ-infested feed, thrive in unsanitary habitat and yet have prolonged lifespans. Such species are rarely reported to develop cancer, suggesting the presence of anticancer molecules/mechanisms.
METHODS: Here, we tested effects from sera of Asian water monitor lizard (Varanus salvator), python (Malayopython reticulatus) and tortoise (Cuora kamaroma amboinensis) against cancer cells. Sera were collected and cytotoxicity assays were performed using prostate cancer cells (PC3), Henrietta Lacks cervical adenocarcinoma cells (HeLa) and human breast adenocarcinoma cells (MCF7), as well as human keratinized skin cells (Hacat), by measuring lactate dehydrogenase release as an indicator for cell death. Growth inhibition assays were performed to determine the effects on cancer cell proliferation. Liquid chromatography mass spectrometry was performed for molecular identification.
RESULTS: The findings revealed that reptilian sera, but not bovine serum, abolished viability of Hela, PC3 and MCF7 cells. Samples were subjected to liquid chromatography mass spectrometry, which detected 57 molecules from V. salvator, 81 molecules from Malayopython reticulatus and 33 molecules from C. kamaroma amboinensis and putatively identified 9 molecules from V. salvator, 20 molecules from Malayopython reticulatus and 9 molecules from C. kamaroma amboinensis when matched against METLIN database. Based on peptide amino acid composition, binary profile, dipeptide composition and pseudo-amino acid composition, 123 potential Anticancer Peptides (ACPs) were identified from 883 peptides from V. salvator, 306 potential ACPs from 1074 peptides from Malayopython reticulatus and 235 potential ACPs from 885 peptides from C. kamaroma amboinensis.
CONCLUSION: To our knowledge, for the first time, we reported comprehensive analyses of selected reptiles' sera using liquid chromatography mass spectrometry, leading to the identification of potentially novel anticancer agents. We hope that the discovery of molecules from these animals will pave the way for the rational development of new anticancer agents.
Synthetic Dihydropyridines as Novel Antiacanthamoebic Agents

Anwar A, Siddiqui R, Hameed A, Shah MR, Khan NA

Med Chem, 2020;16(7):841-847.
PMID: 31544702 DOI: 10.2174/1573406415666190722113412

BACKGROUND: Acanthamoeba is an opportunistic pathogen widely spread in the environment. Acanthamoeba causes excruciating keratitis which can lead to blindness. The lack of effective drugs and its ability to form highly resistant cyst are one of the foremost limitations against successful prognosis. Current treatment involves mixture of drugs at high doses but still recurrence of infection can occur due to ineffectiveness of drugs against the cyst form. Pyridine and its natural and synthetic derivatives are potential chemotherapeutic agents due to their diverse biological activities.
OBJECTIVE: To study the antiamoebic effects of four novel synthetic dihydropyridine (DHP) compounds against Acanthamoeba castellanii belonging to the T4 genotype. Furthermore, to evaluate their activity against amoeba-mediated host cells cytopathogenicity as well as their cytotoxicity against human cells.
METHODS: Dihydropyridines were synthesized by cyclic dimerization of alkylidene malononitrile derivatives. Four analogues of functionally diverse DHPs were tested against Acanthamoeba castellanii by using amoebicidal, encystation and excystation assays. Moreover, Lactate dehydrogenase assays were carried out to study cytopathogenicity and cytotoxicity against human cells.
RESULTS: These compounds showed significant amoebicidal and cysticidal effects at 50 μM concentration, whereas, two of the DHP derivatives also significantly reduced Acanthamoebamediated host cell cytotoxicity. Moreover, these DHPs were found to have low cytotoxicity against human cells suggesting a good safety profile.
CONCLUSION: The results suggest that DHPs have potential against Acanthamoeba especially against the more resistant cyst stage and can be assessed further for drug development.
Fulltext Scorpion and Frog Organ Lysates are Potential Source of Antitumour Activity

Soopramanien M, Khan NA, Abdalla SAO, Sagathevan K, Siddiqui R

Asian Pac J Cancer Prev, 2020 Oct 01;21(10):3011-3018.
PMID: 33112561 DOI: 10.31557/APJCP.2020.21.10.3011

OBJECTIVES: It is noteworthy that several animal species are known to withstand high levels of radiation, and are exposed to heavy metals but rarely been reported to develop cancer. For example, the scorpion has been used as folk medicine in ancient civilizations of Iran and China, while amphibian skin is known to possess medicinal properties. Here, we elucidated the anti-tumour activity of the scorpion (Uropygi) and frog (Lithobates catesbeianus).
MATERIALS AND METHODS: Animals were procured and their organ lysates and sera were prepared and tested against Michigan Cancer Foundation-7 breast cancer (MCF-7), prostate cancer (PC3), Henrietta Lacks cervical cancer (HeLa), and normal human keratinocyte cells. Exoskeleton, appendages and hepatopancreas were dissected from the scorpion, whereas liver, lungs, heart, oviduct, gastrointestinal tract, gall bladder, kidneys, eggs and sera were collected from frog and organ lysates/sera were prepared. Growth inhibition assays and cytotoxicity assays were performed.
RESULTS: Appendages, exoskeleton lysates, and hepatopancreas from scorpion exhibited potent growth inhibition, and cytotoxic effects. Furthermore, lungs, liver, gastrointestinal tract, heart, oviduct, kidneys, eggs, and sera from frog displayed growth inhibition and cytotoxic effects.
CONCLUSION: Organ lysates, sera of scorpion, and amphibians possess anti-tumour activities. This is a worthy area of research as the molecular identity of the active molecule(s) together with their mechanism of action will lead to the rational development of novel anticancer agent(s).
Fulltext Gold Nanoparticle Conjugation Enhances the Antiacanthamoebic Effects of Chlorhexidine

Aqeel Y, Siddiqui R, Anwar A, Shah MR, Khan NA

Antimicrob Agents Chemother, 2015;60(3):1283-8.
PMID: 26666949 DOI: 10.1128/AAC.01123-15

Acanthamoeba keratitis is a serious infection with blinding consequences and often associated with contact lens wear. Early diagnosis, followed by aggressive topical application of drugs, is a prerequisite in successful treatment, but even then prognosis remains poor. Several drugs have shown promise, including chlorhexidine gluconate; however, host cell toxicity at physiologically relevant concentrations remains a challenge. Nanoparticles, subcolloidal structures ranging in size from 10 to 100 nm, are effective drug carriers for enhancing drug potency. The overall aim of the present study was to determine whether conjugation with gold nanoparticles enhances the antiacanthamoebic potential of chlorhexidine. Gold-conjugated chlorhexidine nanoparticles were synthesized. Briefly, gold solution was mixed with chlorhexidine and reduced by adding sodium borohydride, resulting in an intense deep red color, indicative of colloidal gold-conjugated chlorhexidine nanoparticles. The synthesis was confirmed using UV-visible spectrophotometry that shows a plasmon resonance peak of 500 to 550 nm, indicative of gold nanoparticles. Further characterization using matrix-assisted laser desorption ionization-mass spectrometry showed a gold-conjugated chlorhexidine complex at m/z 699 ranging in size from 20 to 100 nm, as determined using atomic force microscopy. To determine the amoebicidal and amoebistatic effects, amoebae were incubated with gold-conjugated chlorhexidine nanoparticles. For controls, amoebae also were incubated with gold and silver nanoparticles alone, chlorhexidine alone, neomycin-conjugated nanoparticles, and neomycin alone. The findings showed that gold-conjugated chlorhexidine nanoparticles exhibited significant amoebicidal and amoebistatic effects at 5 μM. Amoebicidal effects were observed by parasite viability testing using a Trypan blue exclusion assay and flow-cytometric analysis using propidium iodide, while amoebistatic effects were observed using growth assays. In contrast, chlorhexidine alone, at a similar concentration, showed limited effects. Notably, neomycin alone or conjugated with nanoparticles did not show amoebicidal or amoebistatic effects. Pretreatment of A. castellanii with gold-conjugated chlorhexidine nanoparticles reduced amoeba-mediated host cell cytotoxicity from 90% to 40% at 5 μM. In contrast, chlorhexidine alone, at similar concentrations, had no protective effects for the host cells. Similarly, amoebae treated with neomycin alone or neomycin-conjugated nanoparticles showed no protective effects. Overall, these findings suggest that gold-conjugated chlorhexidine nanoparticles hold promise in the improved treatment of A. castellanii keratitis.
Fulltext Gold Nanoparticle-Conjugated Cinnamic Acid Exhibits Antiacanthamoebic and Antibacterial Properties

Anwar A, Siddiqui R, Shah MR, Khan NA

Antimicrob Agents Chemother, 2018 09;62(9).
PMID: 29967024 DOI: 10.1128/AAC.00630-18

trans-Cinnamic acid (CA) is a natural organic compound. Using amoebicidal assays, for the first time we showed that CA affected the viability of the protist pathogen Acanthamoeba castellanii Conjugation with gold nanoparticles (AuNPs) enhanced the antiamoebic effects of CA. CA-coated AuNPs (CA-AuNPs) also exhibited significant excystation and encystation activity, compared to CA and AuNPs alone. Pretreatment of amoebae with CA-AuNPs inhibited A. castellanii-mediated host cell cytotoxicity. Moreover, CA-AuNPs exhibited potent effects against methicillin-resistant Staphylococcus aureus and neuropathogenic Escherichia coli K1 and protected host cells against bacteria-mediated host cell death.
Applications of medicinal chemistry for drug discovery against Acanthamoeba infections

Ahmed U, Anwar A, Ong SK, Anwar A, Khan NA

Med Res Rev, 2021 Sep 02.
PMID: 34472107 DOI: 10.1002/med.21851

Acanthamoeba is a genus of free-living amoebae, pervasively found in the environment. Most of its pathogenic species are the causative agent of sight-threatening Acanthamoeba keratitis and fatal granulomatous amoebic encephalitis. Despite the advancements in the field of chemotherapy, treating Acanthamoeba infections is still challenging due to incomplete knowledge of the complicated pathophysiology. In case of infection, the treatment regimen for the patients is often ineffective due to delayed diagnosis, poor specificity, and side-effects. Besides the resistance of Acanthamoeba cysts to most of the drugs, the recurrence of infection further complicates the recovery. Thus, it is necessary to develop an effective treatment which can eradicate these rare, but serious infections. Based on various computational and in vitro studies, it has been established that the synthetic scaffolds such as heterocyclic compounds may act as potential drug leads for the development of antiamoebic drugs. In this review, we report different classes of synthetic compounds especially heterocyclic compounds which have shown promising results against Acanthamoeba. Moreover, the antiamoebic activities of synthetic compounds with their possible mode of actions against Acanthamoeba, have been summarized and discussed in this review.
Effect of non-steroidal anti-inflammatory drugs on biological properties of Acanthamoeba castellanii belonging to the T4 genotype

Siddiqui R, Lakhundi S, Iqbal J, Khan NA

Exp Parasitol, 2016 Jul 2;168:45-50.
PMID: 27381503 DOI: 10.1016/j.exppara.2016.06.011

Non-steroidal anti-inflammatory drug, Diclofenac, targeting COX have shown promise in the treatment of Acanthamoeba keratitis, but the underlying mechanisms remain unknown. Using various NSAIDs, Diclofenac sodium, Indomethacin, and Acetaminophen, here we determined the effects of NSAIDs on the biological properties of Acanthamoeba castellanii belonging to the T4 genotype. Using amoebicidal assays, the results revealed that Diclofenac sodium, and Indomethacin affected growth of A. castellanii. In contrast, none of the compounds tested had any effect on the viability of A. castellanii. Importantly, all NSAIDs tested abolished A. castellanii encystation. This is a significant finding as the ability of amoebae to transform into the dormant cyst form presents a significant challenge in the successful treatment of infection. The NSAIDs inhibit production of cyclo-oxegenase, which regulates the synthesis of prostaglandins suggesting that cyclooxygenases (COX-1 and COX-2) and prostaglandins play significant role(s) in Acanthamoeba biology. As NSAIDs are routinely used in the clinical practice, these findings may help design improved preventative strategies and/or of therapeutic value to improve prognosis, when used in combination with other anti-amoebic drugs.
Biology and pathogenesis of Naegleria fowleri

Siddiqui R, Ali IK, Cope JR, Khan NA

Acta Trop, 2016 Dec;164:375-394.
PMID: 27616699 DOI: 10.1016/j.actatropica.2016.09.009

Naegleria fowleri is a protist pathogen that can cause lethal brain infection. Despite decades of research, the mortality rate related with primary amoebic meningoencephalitis owing to N. fowleri remains more than 90%. The amoebae pass through the nose to enter the central nervous system killing the host within days, making it one of the deadliest opportunistic parasites. Accordingly, we present an up to date review of the biology and pathogenesis of N. fowleri and discuss needs for future research against this fatal infection.
Fulltext Cytotoxic effects of Benzodioxane, Naphthalene diimide, Porphyrin and Acetamol derivatives on HeLa cells

Jeyamogan S, Khan NA, Anwar A, Shah MR, Siddiqui R

SAGE Open Med, 2018;6:2050312118781962.
PMID: 30034805 DOI: 10.1177/2050312118781962

Objectives: To synthesize novel compounds belonging to Benzodioxane, Naphthalene diimide, Aminophenol derivatives and Porphyrin classes and test their potential anticancer properties.
Methods: Several compounds were synthesized and their molecular identity was confirmed using nuclear magnetic resonance. Potential anticancer properties were determined using cytopathogenicity assays and growth inhibition assays using cervical cancer cells (HeLa). Cells were incubated with different concentrations of compounds belonging to Benzodioxane, Naphthalene diimide, Aminophenol derivatives and Porphyrins and effects were determined. HeLa cells cytopathogenicity was determined by measuring lactate dehydrogenase release using cytotoxicity detection assay. Growth inhibition assays were performed by incubating 50% semi-confluent HeLa cells with Benzodioxane, Naphthalene diimide, Aminophenol derivatives and Porphyrin compounds and HeLa cell proliferation was observed. Growth inhibition and host cell death were compared in the presence and absence of drugs.
Results: Cytopathogenicity assays showed that the selected compounds were cytotoxic against HeLa cells, killing up to 90% of cells. Growth inhibition assays exhibited 100% growth inhibition. These effects are likely via oxidative stress, production of reactive oxygen species, changes in cytosolic and intracellular calcium/adenine nucleotide homeostasis, inhibition of ribonucleotide reductase/cyclooxygenase and/or glutathione depletion.
Conclusions: Benzodioxane, Naphthalene diimide, Aminophenol derivatives and Porphyrins exhibited potent anticancer properties. These findings are promising and should pave the way in the rationale development of anticancer drugs. Using different cancer cell lines, future studies will determine their potential as anti-tumour agents as well as their precise molecular mode of action.
Clinically Approved Drugs against CNS Diseases as Potential Therapeutic Agents To Target Brain-Eating Amoebae

Anwar A, Rajendran K, Siddiqui R, Raza Shah M, Khan NA

ACS Chem Neurosci, 2019 01 16;10(1):658-666.
PMID: 30346711 DOI: 10.1021/acschemneuro.8b00484

Central nervous system (CNS) infections caused by free-living amoebae such as Acanthamoeba species and Naegleria fowleri are rare but fatal. A major challenge in the treatment against the infections caused by these amoebae is the discovery of novel compounds that can effectively cross the blood-brain barrier to penetrate the CNS. It is logical to test clinically approved drugs against CNS diseases for their potential antiamoebic effects since they are known for effective blood-brain barrier penetration and affect eukaryotic cell targets. The antiamoebic effects of clinically available drugs for seizures targeting gamma-amino butyric acid (GABA) receptor and ion channels were tested against Acanthamoeba castellanii belonging to the T4 genotype and N. fowleri. Three such drugs, namely, diazepam (Valium), phenobarbitone (Luminal), phenytoin (Dilantin), and their silver nanoparticles (AgNPs) were evaluated against both trophozoites and cysts stage. Drugs alone and drug conjugated silver nanoparticles were tested for amoebicidal, cysticidal, and host-cell cytotoxicity assays. Nanoparticles were synthesized by sodium borohydride reduction of silver nitrate with drugs as capping agents. Drug conjugated nanoconjugates were characterized by ultraviolet-visible (UV-vis) and Fourier transform infrared (FT-IR) spectroscopies and atomic force microscopy (AFM). In vitro moebicidal assay showed potent amoebicidal effects for diazepam, phenobarbitone, and phenytoin-conjugated AgNPs as compared to drugs alone against A. castellanii and N. fowleri. Furthermore, both drugs and drug conjugated AgNPs showed compelling cysticidal effects. Drugs conjugations with silver nanoparticles enhanced their antiacanthamoebic activity. Interestingly, amoeba-mediated host-cell cytotoxicity was also significantly reduced by drugs alone as well as their nanoconjugates. Since, these drugs are being used to target CNS diseases, their evaluation against brain-eating amoebae seems feasible due to advantages such as permeability of the blood-brain barrier, established pharmacokinetics and dynamics, and United States Food and Drug Administration (FDA) approval. Given the limited availability of effective drugs against brain-eating amoebae, the clinically available drugs tested here present potential for further in vivo studies.
Sera/Organ Lysates of Selected Animals Living in Polluted Environments Exhibit Cytotoxicity against Cancer Cell Lines

Jeyamogan S, Khan NA, Sagathevan K, Siddiqui R

Anticancer Agents Med Chem, 2019;19(18):2251-2268.
PMID: 31660845 DOI: 10.2174/1871520619666191011161314

BACKGROUND: Species of crocodiles and cockroaches can withstand high radiation, reside in unsanitary conditions, thrive on germ-infested feed, and are exposed to heavy metals, yet they are not reported to develop cancer. It has been postulated that such species have mechanisms to defend themselves against developing cancer. Here, selected species have been tested for potential cytotoxicity against selected cancer cell lines.
METHODS: In this study, various species of vertebrates and invertebrates were procured including Columba livia, Gallus gallus domesticus, Varanus salvator, Cuora kamamora amboinensis, Reticulatus malayanus, Oreochromis mossambicus, Rattus rattus, American bullfrog, Donax sp., Polymesoda coaxans, Tenebrio molitor, Lumbricus terrestris, Blatta lateralis, Grammostola rosea, and Penaeus monodon. Species were dissected and their organ lysates/sera/haemolymph were prepared. Cytotoxicity assays were performed using Prostate Cancer cells (PC3), Henrietta Lacks cervical adenocarcinoma cells (HeLa) and human breast adenocarcinoma cells (MCF7) as well as human keratinized skin cells (Hacat), by measuring lactate dehydrogenase release as an indicator for cell death. Growth inhibition assays were performed to determine the effects on cancer cell proliferation. Liquid Chromatography-Mass Spectrometry (LC-MS/MS) was performed for molecular identification.
RESULTS: The results revealed that body lysates of Polymesoda coaxans demonstrated more than 99% growth inhibition of all cancer cell lines tested but not on normal Hacat cells. More importantly, the serum of M. reticulatus abolished growth and produced cytotoxicity. Hence these samples were subjected to Liquid Chromatography- Mass Spectrometry (LC-MS/MS), which detected 81 small molecules and putatively identified 20 molecules when matched against the METLIN database. Out of 1094 peptides, 21 peptides were identified, while 1074 peptides were categorized as novel peptides. Based on properties such as peptide amino acid composition, binary profile, dipeptide composition and pseudo-amino acid composition, 306 potential peptides were identified.
CONCLUSION: To our knowledge, here for the first time, we report a comprehensive analysis of sera exhibiting cytotoxicity against cancer cell lines tested and identified several molecules using LC-MS/MS.
Brain-eating Amoebae Infection: Challenges and Opportunities in Chemotherapy

Mungroo MR, Anwar A, Khan NA, Siddiqui R

Mini Rev Med Chem, 2019;19(12):980-987.
PMID: 30868950 DOI: 10.2174/1389557519666190313161854

Pathogenic free-living amoeba are known to cause a devastating infection of the central nervous system and are often referred to as "brain-eating amoebae". The mortality rate of more than 90% and free-living nature of these amoebae is a cause for concern. It is distressing that the mortality rate has remained the same over the past few decades, highlighting the lack of interest by the pharmaceutical industry. With the threat of global warming and increased outdoor activities of public, there is a need for renewed interest in identifying potential anti-amoebic compounds for successful prognosis. Here, we discuss the available chemotherapeutic options and opportunities for potential strategies in the treatment and diagnosis of these life-threatening infections.
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.
Fulltext 5G and IoT Based Reporting and Accident Detection (RAD) System to Deliver First Aid Box Using Unmanned Aerial Vehicle

Alkinani MH, Almazroi AA, Jhanjhi NZ, Khan NA

Sensors (Basel), 2021 Oct 18;21(20).
PMID: 34696118 DOI: 10.3390/s21206905

Internet of Things (IoT) and 5G are enabling intelligent transportation systems (ITSs). ITSs promise to improve road safety in smart cities. Therefore, ITSs are gaining earnest devotion in the industry as well as in academics. Due to the rapid increase in population, vehicle numbers are increasing, resulting in a large number of road accidents. The majority of the time, casualties are not appropriately discovered and reported to hospitals and relatives. This lack of rapid care and first aid might result in life loss in a matter of minutes. To address all of these challenges, an intelligent system is necessary. Although several information communication technologies (ICT)-based solutions for accident detection and rescue operations have been proposed, these solutions are not compatible with all vehicles and are also costly. Therefore, we proposed a reporting and accident detection system (RAD) for a smart city that is compatible with any vehicle and less expensive. Our strategy aims to improve the transportation system at a low cost. In this context, we developed an android application that collects data related to sound, gravitational force, pressure, speed, and location of the accident from the smartphone. The value of speed helps to improve the accident detection accuracy. The collected information is further processed for accident identification. Additionally, a navigation system is designed to inform the relatives, police station, and the nearest hospital. The hospital dispatches UAV (i.e., drone with first aid box) and ambulance to the accident spot. The actual dataset from the Road Safety Open Repository is used for results generation through simulation. The proposed scheme shows promising results in terms of accuracy and response time as compared to existing techniques.
Acanthamoeba castellanii interactions with Streptococcus pneumoniae and Streptococcus pyogenes

Siddiqui R, Yee Ong TY, Jung SY, Khan NA

Exp Parasitol, 2017 Dec;183:128-132.
PMID: 28823705 DOI: 10.1016/j.exppara.2017.08.005

Among the genus Streptococcus, S. pyogenes and S. pneumoniae are the major causes of pharyngitis, impetigo, pneumonia and meningitis in humans. Streptococcus spp. are facultative anaerobes that are nutritionally fastidious, yet survive in the environment and target the predisposed population. Antibacterial disinfectants have been partially effective only, indicating the need for novel preventative measures and to understand mechanisms of bacterial resistance. Acanthamoeba is a free-living protist that is known to harbour microbial pathogens, provide shelter, and assist in their transmission to susceptible population. The overall aim of this study was to determine whether S. pyogenes and S. pneumoniae can interact with A. castellanii by associating, invading, and surviving inside trophozoites and cysts. It was observed that both S. pyogenes and S. pneumoniae were able to associate as well as invade and/or taken up by the phagocytic A. castellanii trophozoite. Notably, S. pyogenes and S. pneumoniae survived the encystation process, avoided phagocytosis, multiplied, and exhibited higher recovery from the mature cysts, compared with the trophozoite stage (approximately 2 bacteria per amoebae ratio for cyst stage versus 0.02 bacteria per amoeba ration for trophozoite stage). As Acanthamoeba cysts are resilient and can disperse through the air, A. castellanii can act as a vector in providing shelter, facilitating growth and possibly genetic exchanges. In addition, these interactions may contribute to S. pyogenes and S. pneumoniae survival in harsh environments, and transmission to susceptible population and possibly affecting their virulence. Future studies will determine the molecular mechanisms associated with Acanthamoeba interactions with Streptococcus and the evolution of pathogenic bacteria and in turn expedite the discovery of novel therapeutic and/or preventative measures.
Brain-Eating Amoebae: Silver Nanoparticle Conjugation Enhanced Efficacy of Anti-Amoebic Drugs against Naegleria fowleri

Rajendran K, Anwar A, Khan NA, Siddiqui R

ACS Chem Neurosci, 2017 12 20;8(12):2626-2630.
PMID: 29206032 DOI: 10.1021/acschemneuro.7b00430

The overall aim of this study was to determine whether conjugation with silver nanoparticles enhances effects of available drugs against primary amoebic meningoencephalitis due to Naegleria fowleri. Amphotericin B, Nystatin, and Fluconazole were conjugated with silver nanoparticles, and synthesis was confirmed using UV-visible spectrophotometry. Atomic force microscopy determined their size in range of 20-100 nm. To determine amoebicidal effects, N. fowleri were incubated with drugs-conjugated silver nanoparticles, silver nanoparticles alone, and drugs alone. The findings revealed that silver nanoparticles conjugation significantly enhanced antiamoebic effects of Nystatin and Amphotericin B but not Fluconazole at micromolar concentrations, compared with the drugs alone. For the first time, our findings showed that silver nanoparticle conjugation enhances efficacy of antiamoebic drugs against N. fowleri. Given the rarity of the disease and challenges in developing new drugs, it is hoped that modifying existing drugs to enhance their antiamoebic effects is a useful avenue that holds promise in improving the treatment of brain-eating amoebae infection due to N. fowleri.
Status of the effectiveness of contact lens disinfectants in Malaysia against keratitis-causing pathogens

Abjani F, Khan NA, Jung SY, Siddiqui R

Exp Parasitol, 2017 Dec;183:187-193.
PMID: 28919333 DOI: 10.1016/j.exppara.2017.09.007

The aim of this study was (i) to assess the antimicrobial effects of contact lens disinfecting solutions marketed in Malaysia against common bacterial eye pathogens and as well as eye parasite, Acanthamoeba castellanii, and (ii) to determine whether targeting cyst wall would improve the efficacy of contact lens disinfectants. Using ISO 14729 Stand-Alone Test for disinfecting solutions, bactericidal and amoebicidal assays of six different contact lens solutions including Oxysept®, AO SEPT PLUS, OPTI-FREE® pure moist®, Renu® fresh™, FreshKon® CLEAR and COMPLETE RevitaLens™ were performed using Manufacturers Minimum recommended disinfection time (MRDT). The efficacy of contact lens solutions was determined against keratitis-causing microbes, namely: Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, and Acanthamoeba castellanii. In addition, using chlorhexidine as an antiamoebic compound and cellulase enzyme to disrupt cyst wall structure, we determined whether combination of both agents can enhance efficacy of marketed contact lens disinfectants against A. castellanii trophozoites and cysts, in vitro. The results revealed that all contact lens disinfectants tested showed potent bactericidal effects exhibiting 100% kill against all bacterial species tested. In contrast, none of the contact lens disinfectants had potent effects against Acanthamoeba cysts viability. When tested against trophozoites, two disinfectants, Oxysept Multipurpose and AO-sept Multipurpose showed partial amoebicidal effects. Using chlorhexidine as an antiamoebic compound and cellulase enzyme to disrupt cyst wall structure, the findings revealed that combination of both agents in contact lens disinfectants abolished viability of A. castellanii cysts and trophozoites. Given the inefficacy of contact lens disinfectants tested in this study, these findings present a significant concern to public health. These findings revealed that targeting cyst wall by using cyst wall degrading molecules in contact lens disinfecting solutions will enhance their efficacy against this devastating eye infection.
Modular nanotheranostic agents for protistan parasitic diseases: Magic bullets with tracers

Maciver SK, Abdelnasir S, Anwar A, Siddiqui R, Khan NA

Mol Biochem Parasitol, 2023 Feb;253:111541.
PMID: 36603708 DOI: 10.1016/j.molbiopara.2022.111541

Protistan parasitic infections contribute significantly to morbidity and mortality, causing more than 2 billion human infections annually. However, current treatments are often limited; due to ineffective drugs and drug resistance, thus better options are urgently required. In the present context, theranostics agents are those that offer simultaneous detection, diagnosis and even treatment of protistan parasitic diseases. "Nanotheranostics" is the term used to describe such agents, that are around 100 nm or less in size. Anti-parasitic activity of nanoparticles (NPs) has been reported, and many have useful intrinsic imaging properties, but it is perhaps their multifunctional nature that offers the greatest potential. NPs may be used as adapters onto which various subunits with different functions may be attached. These subunits may facilitate targeting parasites, coupled with toxins to eradicate parasites, and probe subunits for detection of particles and/or parasites. The modular nature of nano-platforms promises a "mix and match" approach for the construction of tailored agents by using combinations of these subunits against different protistan parasites. Even though many of the subunits have shown promise alone, these have not yet been put together convincingly enough to form working theranostics against protistan parasites. Although the clinical application of nanotheranostics to protistan parasitic infections in humans requires more research, we conclude that they offer not just a realisation of Paul Ehrlich's long imagined "magic bullet" concept, but potentially are magic bullets combined with tracer bullets.

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