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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.
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.
Fulltext Gold Nanoparticles Conjugation Enhances Antiacanthamoebic Properties of Nystatin, Fluconazole and Amphotericin B

Anwar A, Siddiqui R, Raza Shah M, Ahmed Khan N

J Microbiol Biotechnol, 2019 Jan 28;29(1):171-177.
PMID: 30415525 DOI: 10.4014/jmb.1805.05028

Parasitic infections have remained a significant burden on human and animal health. In part, this is due to lack of clinically-approved, novel antimicrobials and a lack of interest by the pharmaceutical industry. An alternative approach is to modify existing clinically-approved drugs for efficient delivery formulations to ensure minimum inhibitory concentration is achieved at the target site. Nanotechnology offers the potential to enhance the therapeutic efficacy of drugs through modification of nanoparticles with ligands. Amphotericin B, nystatin, and fluconazole are clinically available drugs in the treatment of amoebal and fungal infections. These drugs were conjugated with gold nanoparticles. To characterize these gold-conjugated drug, atomic force microscopy, ultraviolet-visible spectrophotometry and Fourier transform infrared spectroscopy were performed. These drugs and their gold nanoconjugates were examined for antimicrobial activity against the protist pathogen, Acanthamoeba castellanii of the T4 genotype. Moreover, host cell cytotoxicity assays were accomplished. Cytotoxicity of these drugs and drug-conjugated gold nanoparticles was also determined by lactate dehydrogenase assay. Gold nanoparticles conjugation resulted in enhanced bioactivity of all three drugs with amphotericin B producing the most significant effects against Acanthamoeba castellanii (p ＜ 0.05). In contrast, bare gold nanoparticles did not exhibit antimicrobial potency. Furthermore, amoebae treated with drugs-conjugated gold nanoparticles showed reduced cytotoxicity against HeLa cells. In this report, we demonstrated the use of nanotechnology to modify existing clinically-approved drugs and enhance their efficacy against pathogenic amoebae. Given the lack of development of novel drugs, this is a viable approach in the treatment of neglected diseases.
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.
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.
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.
Impact of transportation infrastructure and urbanization on environmental pollution: evidence from novel wavelet quantile correlation approach

Malik MU, Rehman ZU, Sharif A, Anwar A

Environ Sci Pollut Res Int, 2024 Jan;31(2):3014-3030.
PMID: 38079035 DOI: 10.1007/s11356-023-31197-x

In terms of achieving sustainable development goals (SDGs), the developing economies are facing many issues, and one of the key issues is environmental degradation. Being a developing economy, Pakistan is also experiencing thought-provoking impacts of global warming and still far away from the ideal track of sustainable development. For addressing environment-related issue and achieving the targets of SDGs, a policy-level reorientation might be necessary. In this view, this study investigates the impact of economic growth, transport infrastructure, urbanization, financial development, and renewable energy consumption on CO2 emissions by using the data of Pakistan during 1990-2020. For this purpose, we use novel wavelet quantile correlation approach. The empirical results of wavelet quantile correlation approach demonstrate that economic growth, transport infrastructure, urbanization, and financial development are responsible for environmental pollution. Whereas, result also claims that renewable energy consumption is a useful tool for reducing environmental pollution in Pakistan. Moreover, the results of FMOLS approach show that 1% increase in economic growth, transportation infrastructure, urbanization, and financial development increases CO2 emissions by 0.240, 0.010, 0.478, and 0.102%, respectively. However, 1% increase in renewable energy usage reduces CO2 emission by 1.083%. Based on the empirical outcomes, this study proposes comprehensive policy framework for achieving the targets of SDG 7 (clean energy), SDG 8 (economic growth), SDG 11 (sustainable cities and communities), and SDG 13 (climate action).
Applications of photodynamic therapy in keratitis

Anwar A, Khan NA, Alharbi AM, Alhazmi A, Siddiqui R

Int Ophthalmol, 2024 Mar 15;44(1):140.
PMID: 38491335 DOI: 10.1007/s10792-024-03062-4

Keratitis is corneal inflammatory disease which may be caused by several reason such as an injury, allergy, as well as a microbial infection. Besides these, overexposure to ultraviolet light and unhygienic practice of contact lenses are also associated with keratitis. Based on the cause of keratitis, different lines of treatments are recommended. Photodynamic therapy is a promising approach that utilizes light activated compounds to instigate either killing or healing mechanism to treat various diseases including both communicable and non-communicable diseases. This review focuses on clinically-important patent applications and the recent literature for the use of photodynamic therapy against keratitis.
Fulltext Biologically active metabolite(s) from haemolymph of red-headed centipede Scolopendra subspinipes possess broad spectrum antibacterial activity

Ali SM, Khan NA, Sagathevan K, Anwar A, Siddiqui R

AMB Express, 2019 Jun 28;9(1):95.
PMID: 31254123 DOI: 10.1186/s13568-019-0816-3

The discovery of novel antimicrobials from animal species under pollution is an area untapped. Chinese red-headed centipede is one of the hardiest arthropod species commonly known for its therapeutic value in traditional Chinese medicine. Here we determined the antibacterial activity of haemolymph and tissue extracts of red-headed centipede, Scolopendra subspinipes against a panel of Gram-positive and Gram-negative bacteria. Lysates exhibited potent antibacterial activities against a broad range of bacteria tested. Chemical characterization of biologically active molecules was determined via liquid chromatography mass spectrometric analysis. From crude haemolymph extract, 12 compounds were identified including: (1) L-Homotyrosine, (2) 8-Acetoxy-4-acoren-3-one, (3) N-Undecylbenzenesulfonic acid, (4) 2-Dodecylbenzenesulfonic acid, (5) 3H-1,2-Dithiole-3-thione, (6) Acetylenedicarboxylate, (7) Albuterol, (8) Tetradecylamine, (9) Curcumenol, (10) 3-Butylidene-7-hydroxyphthalide, (11) Oleoyl Ethanolamide and (12) Docosanedioic acid. Antimicrobial activities of the identified compounds were reported against Gram-positive and Gram-negative bacteria, fungi, viruses and parasites, that possibly explain centipede's survival in harsh and polluted environments. Further research in characterization, molecular mechanism of action and in vivo testing of active molecules is needed for the development of novel antibacterials.
Fulltext Gold-Conjugated Curcumin as a Novel Therapeutic Agent against Brain-Eating Amoebae

Mungroo MR, Anwar A, Khan NA, Siddiqui R

ACS Omega, 2020 Jun 02;5(21):12467-12475.
PMID: 32548431 DOI: 10.1021/acsomega.0c01305

Balamuthia mandrillaris and Naegleria fowleri are free-living amoebae that cause infection of the central nervous system, granulomatous amoebic encephalitis (GAE) and primary amoebic meningoencephalitis (PAM), respectively. The fact that mortality rates for cases of GAE and PAM are more than 95% indicates the need for new therapeutic agents against those amoebae. Considering that curcumin exhibits a wide range of biological properties and has shown efficacy against Acanthamoeba castellanii, we evaluated the amoebicidal properties of curcumin against N. fowleri and B. mandrillaris. Curcumin showed significant amoebicidal activities with an AC50 of 172 and 74 μM against B. mandrillaris and N. fowleri, respectively. Moreover, these compounds were also conjugated with gold nanoparticles to further increase their amoebicidal activities. After conjugation with gold nanoparticles, amoebicidal activities of the drugs were increased by up to 56 and 37% against B. mandrillaris and N. fowleri, respectively. These findings are remarkable and suggest that clinically available curcumin and our gold-conjugated curcumin nanoparticles hold promise in the improved treatment of fatal infections caused by brain-eating amoebae and should serve as a model in the rationale development of therapeutic interventions against other infections.
Fulltext Draft genome of Brugia pahangi: high similarity between B. pahangi and B. malayi

Lau YL, Lee WC, Xia J, Zhang G, Razali R, Anwar A, et al.

Parasit Vectors, 2015;8:451.
PMID: 26350613 DOI: 10.1186/s13071-015-1064-2

Efforts to completely eradicate lymphatic filariasis from human population may be challenged by the emergence of Brugia pahangi as another zoonotic lymphatic filarial nematode. In this report, a genomic study was conducted to understand this species at molecular level.
Immortalization of epithelial cells in oral carcinogenesis as revealed by genome-wide array comparative genomic hybridization: A meta-analysis

Vincent-Chong VK, Salahshourifar I, Razali R, Anwar A, Zain RB

Head Neck, 2016 04;38 Suppl 1:E783-97.
PMID: 25914319 DOI: 10.1002/hed.24102

BACKGROUND: This purpose of this meta-analysis study was to identify the most frequent and potentially significant copy number alteration (CNA) in oral carcinogenesis.
METHODS: Seven oral squamous cell carcinoma (OSCC)-related publications, corresponding to 312 samples, were identified for this meta-analysis. The data were analyzed in a 4-step process that included the genome assembly coordination of multiple platforms, assignment of chromosomal position anchors, calling gains and losses, and functional annotation analysis.
RESULTS: Gains were more frequent than losses in the entire dataset. High-frequency gains were identified in chromosomes 5p, 14q, 11q, 7p, 17q, 20q, 8q, and 3q, whereas high-frequency losses were identified in chromosomes 3p, 8p, 6p, 18q, and 4q. Ingenuity pathway analysis showed that the top biological function was associated with immortalization of the epithelial cells (p = 1.93E-04).
CONCLUSION: This study has identified multiple recurrent CNAs that are involved in various biological annotations associated with oral carcinogenesis. © 2015 Wiley Periodicals, Inc. Head Neck 38: E783-E797, 2016.
Identification and characterization of antibacterial compound(s) of cockroaches (Periplaneta americana)

Ali SM, Siddiqui R, Ong SK, Shah MR, Anwar A, Heard PJ, et al.

Appl Microbiol Biotechnol, 2017 Jan;101(1):253-286.
PMID: 27743045 DOI: 10.1007/s00253-016-7872-2

Infectious diseases remain a significant threat to human health, contributing to more than 17 million deaths, annually. With the worsening trends of drug resistance, there is a need for newer and more powerful antimicrobial agents. We hypothesized that animals living in polluted environments are potential sources of antimicrobials. Under polluted milieus, organisms such as cockroaches encounter different types of microbes, including superbugs. Such creatures survive the onslaught of superbugs and are able to ward off disease by producing antimicrobial substances. Here, we characterized antibacterial properties in extracts of various body organs of cockroaches (Periplaneta americana) and showed potent antibacterial activity in crude brain extract against methicillin-resistant Staphylococcus aureus and neuropathogenic Escherichia coli K1. The size-exclusion spin columns revealed that the active compound(s) are less than 10 kDa in molecular mass. Using cytotoxicity assays, it was observed that pre-treatment of bacteria with lysates inhibited bacteria-mediated host cell cytotoxicity. Using spectra obtained with LC-MS on Agilent 1290 infinity liquid chromatograph, coupled with an Agilent 6460 triple quadruple mass spectrometer, tissues lysates were analysed. Among hundreds of compounds, only a few homologous compounds were identified that contained the isoquinoline group, chromene derivatives, thiazine groups, imidazoles, pyrrole-containing analogs, sulfonamides, furanones, and flavanones and known to possess broad-spectrum antimicrobial properties and anti-inflammatory, anti-tumour, and analgesic properties. Further identification, characterization, and functional studies using individual compounds can act as a breakthrough in developing novel therapeutics against various pathogens including superbugs.
Fabrication of biopolymer polyhydroxyalkanoate/chitosan and 2D molybdenum disulfide-doped scaffolds for antibacterial and biomedical applications

Mukheem A, Shahabuddin S, Akbar N, Anwar A, Sarih NM, Sudesh K, et al.

Appl Microbiol Biotechnol, 2020 Apr;104(7):3121-3131.
PMID: 32060693 DOI: 10.1007/s00253-020-10416-2

Antibiotic resistance in pathogenic bacteria is a major health challenge, as Infectious Diseases Society of America (IDSA) has recognized that the past simply drugs susceptible pathogens are now the most dangerous pathogens due to their nonstop growing resistance towards conventional antibiotics. Therefore, due to the emergence of multi-drug resistance, the bacterial infections have become a serious global problem. Acute infections feasibly develop into chronic infections because of many factors; one of them is the failure of effectiveness of antibiotics against superbugs. Modern research of two-dimensional nanoparticles and biopolymers are of great interest to attain the intricate bactericidal activity. In this study, we fabricated an antibacterial nanocomposite consisting of representative two-dimensional molybdenum disulfide (2D MoS2) nanoparticles. Polyhydroxyalkanoate (PHA) and chitosan (Ch) are used to encapsulate MoS2 nanoparticles into their matrix. This study reports the in vitro antibacterial activity and host cytotoxicity of novel PHA-Ch/MoS2 nanocomposites. PHA-Ch/MoS2 nanocomposites were subjected to time-dependent antibacterial assays at various doses to examine their antibacterial activity against multi-drug-resistant Escherichia coli K1 (Malaysian Type Culture Collection 710859) and methicillin-resistant Staphylococcus aureus (MRSA) (Malaysian Type Culture Collection 381123). Furthermore, the cytotoxicity of nanocomposites was examined against spontaneously immortalized human keratinocyte (HaCaT) cell lines. The results indicated significant antibacterial activity (p value
Fulltext Novel insights into the potential role of ion transport in sensory perception in Acanthamoeba

Siddiqui R, Roberts SK, Ong TYY, Mungroo MR, Anwar A, Khan NA

Parasit Vectors, 2019 Nov 14;12(1):538.
PMID: 31727139 DOI: 10.1186/s13071-019-3785-0

BACKGROUND: Acanthamoeba is well known to produce a blinding keratitis and serious brain infection known as encephalitis. Effective treatment is problematic, and can continue up to a year, and even then, recurrence can ensue. Partly, this is due to the capability of vegetative amoebae to convert into resistant cysts. Cysts can persist in an inactive form for decades while retaining their pathogenicity. It is not clear how Acanthamoeba cysts monitor environmental changes, and determine favourable conditions leading to their emergence as viable trophozoites.
METHODS: The role of ion transporters in the encystation and excystation of Acanthamoeba remains unclear. Here, we investigated the role of sodium, potassium and calcium ion transporters as well as proton pump inhibitors on A. castellanii encystation and excystation and their effects on trophozoites.
RESULTS: Remarkably 3',4'-dichlorobenzamil hydrochloride a sodium-calcium exchange inhibitor, completely abolished excystation of Acanthamoeba. Furthermore, lanthanum oxide and stevioside hydrate, both potassium transport inhibitors, resulted in the partial inhibition of Acanthamoeba excystation. Conversely, none of the ion transport inhibitors affected encystation or had any effects on Acanthamoeba trophozoites viability.
CONCLUSIONS: The present study indicates that ion transporters are involved in sensory perception of A. castellanii suggesting their value as potential therapeutic targets to block cellular differentiation that presents a significant challenge in the successful prognosis of Acanthamoeba infections.
Oleic Acid Coated Silver Nanoparticles Showed Better in Vitro Amoebicidal Effects against Naegleria fowleri than Amphotericin B

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

ACS Chem Neurosci, 2020 08 19;11(16):2431-2437.
PMID: 31347828 DOI: 10.1021/acschemneuro.9b00289

Naegleria fowleri (N. fowleri) causes primary amoebic meningoencephalitis (PAM) which almost always results in death. N. fowleri is also known as "brain-eating amoeba" due to its literal infestation of the brain leading to an inflammatory response in the brain tissues. Currently, there is no single drug that is available to treat PAM, and most treatments are combinations of antifungal, anticancer, and anti-inflammatory drugs. Recently nanotechnology has gained attention in chemotherapeutic research converging on drug delivery, while oleic acid (OA) has shown positive effects on the human immune system and inflammatory processes. In continuation of our recent research in which we reported the effects of oleic acid conjugated with silver nanoparticles (OA-AgNPs) against free-living amoeba Acanthamoeba castellanii, in this report, we show their antiamoebic effects against N. fowleri. OA alone and its nanoconjugates were tested against the amoeba by using amoebicidal and host cell cytopathogenicity assays. Trypan blue exclusion assay was used to determine cell viability. The results revealed that OA-AgNPs exhibited significantly enhanced antiamoebic effects (P < 0.05) against N. fowleri as compared to OA alone. Evidently, lactate dehydrogenase release shows reduced N. fowleri-mediated host cell cytotoxicity. Based on our study, we anticipate that further studies on OA-AgNPs could potentially provide an alternative treatment of PAM.
Novel antiacanthamoebic compounds belonging to quinazolinones

Anwar A, Shahbaz MS, Saad SM, Kanwal, Khan KM, Siddiqui R, et al.

Eur J Med Chem, 2019 Nov 15;182:111575.
PMID: 31415900 DOI: 10.1016/j.ejmech.2019.111575

We report one-pot synthesis of a series of new 3-aryl-8-methylquinazolin-4(3H)-ones (QNZ) and their antimicrobial activity against Acanthamoeba castellanii belonging to T4 genotype. A library of fifteen synthetic derivatives of QNZs was synthesized, and their structural elucidation was performed by using nuclear magnetic resonance (NMR) spectroscopy and electron impact mass spectrometry (EI-MS). Elemental analyses and high-resolution mass spectrometry data of all derivatives were found to be in agreeable range. Amoebicidal assays performed at concentrations ranging from 50 to 100 μg/mL revealed that all derivatives of QNZ significantly decreased the viability of A. castellanii and QNZ 2, 5, 8, and 13 were found to have efficient antiamoebic effects. Field emission scanning electron microscopy (FESEM) imaging of amoeba treated with compounds 5 and 15 showed that these compounds cause structural alterations on the walls of A. castellanii. Furthermore, several QNZs inhibited the encystation and excystationas as well as abolished A. castellanii-mediated host cells cytopathogenicity in human cells. Whereas, these QNZs showed negligible cytotoxicity when tested against human cells in vitro. Hence, this study identified potential lead molecules having promising properties for drug development against A. castellanii. A brief structure-activity relationship is also developed to optimize the hit of most potent compounds from the library. To the best of our knowledge, it is first of its kind medicinal chemistry approach on a single class of compounds i.e., quinazolinone against keratitis and brain infection causing free-living amoeba, A. castellanii.
Size selectivity in antibiofilm activity of 3-(diphenylphosphino)propanoic acid coated gold nanomaterials against Gram-positive Staphylococcus aureus and Streptococcus mutans

Ahmed D, Anwar A, Khan AK, Ahmed A, Shah MR, Khan NA

AMB Express, 2017 Nov 21;7(1):210.
PMID: 29164404 DOI: 10.1186/s13568-017-0515-x

Biofilm formation by pathogenic bacteria is one of the major threats in hospital related infections, hence inhibiting and eradicating biofilms has become a primary target for developing new anti-infection approaches. The present study was aimed to develop novel antibiofilm agents against two Gram-positive bacteria; Staphylococcus aureus (ATCC 43300) and Streptococcus mutans (ATCC 25175) using gold nanomaterials conjugated with 3-(diphenylphosphino)propionic acid (Au-LPa). Gold nanomaterials with different sizes as 2-3 nm small and 9-90 nm (50 nm average size) large were stabilized by LPa via different chemical synthetic strategies. The nanomaterials were fully characterized using atomic force microscope (AFM), transmission electron microscope, ultraviolet-visible absorption spectroscopy, and Fourier transformation infrared spectroscopy. Antibiofilm activity of Au-LPa nanomaterials was tested using LPa alone, Au-LPa and unprotected gold nanomaterials against the both biofilm-producing bacteria. The results showed that LPa alone did not inhibit biofilm formation to a significant extent below 0.025 mM, while conjugation with gold nanomaterials displayed manifold enhanced antibiofilm potential against both strains. Moreover, it was also observed that the antibiofilm potency of the Au-LPa nanomaterials varies with size variations of nanomaterials. AFM analysis of biofilms further complemented the assay results and provided morphological aspects of the antibiofilm action of Au-LPa nanomaterials.

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