Repositioning of Guanabenz in Conjugation with Gold and Silver Nanoparticles against Pathogenic Amoebae Acanthamoeba castellanii and Naegleria fowleri

Brain-eating amoebae cause devastating infections in the central nervous system of humans, resulting in a mortality rate of 95%. There are limited effective therapeutic options available clinically for treating granulomatous amoebic encephalitis and primary amoebic meningoencephalitis caused by Acanthamoeba castellanii (A. castellanii) and Naegleria fowleri (N. fowleri), respectively. Here, we report for the first time that guanabenz conjugated to gold and silver nanoparticles has significant antiamoebic activity against both A. castellanii and N. fowleri. Gold and silver conjugated guanabenz nanoparticles were synthesized by the one-phase reduction method and were characterized by ultraviolet–visible spectrophotometry and atomic force microscopy. Both metals were facilely stabilized by the coating of guanabenz, which was examined by surface plasmon resonance determination. The average size of gold nanoconjugated guanabenz was found to be 60 nm, whereas silver nanoparticles were produced in a larger size distribution with the average diameter of around 100 nm. Guanabenz and its noble metal nanoconjugates exhibited potent antiamoebic effects in the range of 2.5 to 100 μM against both amoebae. Nanoparticle conjugation enhanced the antiamoebic effects of guanabenz, as more potent activity was observed at a lower effective concentration (2.5 and 5 μM) compared to the drug alone. Moreover, encystation and excystation assays revealed that guanabenz inhibits the interconversion between the trophozoite and cyst forms of A. castellanii. Cysticdal effects against N. fowleri were also observed. Notably, pretreatment of A. castellanii with guanabenz and its nanoconjugates exhibited a significant reduction in the host cell cytopathogenicity from 65% to 38% and 2% in case of gold and silver nanoconjugates, respectively. Moreover, the cytotoxic evaluation of guanabenz and its nanoconjugates revealed negligible cytotoxicity against human cells. Guanabenz is already approved for hypertension and crosses the blood–brain barrier; the results of our current study suggest that guanabenz and its conjugated gold and silver nanoparticles can be repurposed as a potential drug for treating brain-eating amoebic infections

Identification of In-Vitro effects of synthesized heterocycles against Balamuthia Mandrillaris and Naegleria Fowleri

Naegleria fowleri and Balamuthia mandrillaris are protist pathogens that infect the central nervous system, causing primary amoebic meningoencephalitis and granulomatous amoebic encephalitis, with mortality rates of over 95%, indicating lack of effective treatments. Quinazolinones, benzimidazole, indole, indazole, tetrazole and thiazole possess a wide spectrum of biological properties and it was recently reported that nanoparticles-based materials have improved in vitro activity against brain-eating amoebae. In this study, 34 novel quinazolinones were synthesized along with benzimidazole, indole, indazole, tetrazole and thiazole compounds, containing varying moieties. These molecules were tested for the first time against N. fowleri and B. mandrillaris. We also conjugated quinazolinones and heterocyclic scaffolds with silver nanoparticles to increase their amoebicidal activities. Synthesized compounds were tested for their amoebicidal and amoebistatic properties against B. mandrillaris and N. fowleri. The results revealed that quinazolinones decreased the number of viable B. mandrillaris and N. fowleri cells by up to 89% and 77%, respectively. Also, quinazolinones inhibited growth of B. mandrillaris and N. fowleri by up to 77% and 47%, respectively. The heterocyclic scaffolds showed up to 65% and 72% amoebicidal activity against B. mandrillaris and N. fowleri, respectively, and expressed up to 73% and 75% amoebistatic effects, respectively. We also showed that activities of the compounds were successfully enhanced by up to 65% and 71%, against N. fowleri and B. mandrillaris, respectively, due to conjugation with silver nanoparticles. Given the challenges in developing new drugs, enhancing anti-amoebic effects of compounds using nanotechnology is a worthwhile avenue with promise in improving treatment of brain-eating amoebae infections

Novel Coronavirus: Current Understanding of Clinical Features, Diagnosis, Pathogenesis, and Treatment Options

Since December 2019, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in devastating consequences worldwide and infected more than 350,000 individuals and killed more than 16,000 people. SARS-CoV-2 is the seventh member of the coronavirus family to affect humans. Symptoms of COVID-19 include fever (88%), cough (68%), vomiting (5%) and diarrhoea (3.7%), and transmission of SARS-CoV-2 is thought to occur from human to human via respiratory secretions released by the infected individuals when coughing and sneezing. COVID-19 can be detected through computed tomography scans and confirmed through molecular diagnostics tools such as polymerase chain reaction. Currently, there are no effective treatments against SARS-CoV-2, hence antiviral drugs have been used to reduce the development of respiratory complications by reducing viral load. The purpose of this review is to provide a comprehensive update on the pathogenesis, clinical aspects, diagnosis, challenges and treatment of SARS-CoV-2 infections

Balamuthia mandrillaris: pathogenesis, diagnosis, and treatment

Introduction: Balamuthia mandrillaris is known to cause a fatal infection of the central nervous system termed granulomatous amoebic encephalitis (GAE). Cases of GAE by B. mandrillaris are usually fatal indicating the inefficacy of currently available regimens used to treat the disease and the virulent nature of the amoebae.Areas covered: This review discusses the current treatment options, diagnosis, and pathogenesis of Balamuthia mandrillaris. In this regard, a PubMed search using pathogenesis, treatment, and diagnosis, combined with B. mandrillaris as keywords, was performed. In addition, conference proceedings, and discussions in Free-Living-Amoebae meetings over the past 20 years were reviewed.Expert opinion: Despite the current treatment and diagnostic options, the mortality rates due to B. mandrillaris infections remain alarmingly high. The actual number of GAE cases due to B. mandrillaris are much higher than the currently reported number. Information on the pathogenesis of the amoebae is limited, highlighting the need for further studies on the pathogenesis of B. mandrillaris. This would provide useful information to improve both diagnostic and treatment options. Similarly, new molecules that are targeted toward B. mandrillaris and can penetrate the blood-brain barrier should be established. Theranostics may be the way forward for the treatment of B. mandrillaris

Novel Coronavirus: Current Understanding of Clinical Features, Diagnosis, Pathogenesis, and Treatment Options

Since December 2019, coronavirus disease 2019 (COVID-19) caused by severe acuterespiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in devastating consequencesworldwide and infected more than 350,000 individuals and killed more than 16,000 people.SARS-CoV-2 is the seventh member of the coronavirus family to affect humans. Symptoms ofCOVID-19 include fever (88%), cough (68%), vomiting (5%) and diarrhoea (3.7%), and transmissionof SARS-CoV-2 is thought to occur from human to human via respiratory secretions released by theinfected individuals when coughing and sneezing. COVID-19 can be detected through computedtomography scans and confirmed through molecular diagnostics tools such as polymerase chainreaction. Currently, there are no effective treatments against SARS-CoV-2, hence antiviral drugshave been used to reduce the development of respiratory complications by reducing viral load.The purpose of this review is to provide a comprehensive update on the pathogenesis, clinical aspects,diagnosis, challenges and treatment of SARS-CoV-2 infections

SARS-CoV-2 invasion of the central nervous: a brief review.

There is increasing evidence of the ability of the novel coronavirus to invade the central nervous system (CNS). But how does a respiratory virus invade the highly protected CNS? Here, we reviewed available literature and case reports to determine CNS involvement in COVID-19, and to identify potential regions of the brain that may be affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its possible route of entry into the brain to identify its pathogenicity. Based on the symptoms, the parietal lobe and the cerebellum are the likely targets of SARS-CoV-2; however, further work is needed to elucidate this. The presence of ACE2, used by SARS-CoV-2 for cell entry, in the brain as well as detection of the virus in the cerebrospinal fluid, further assert that SARS-COV-2 targets the brain, and therefore, medical practitioners should take that into account when dealing with patients suffering from COVID-19

War of the microbial world: Acanthamoeba spp. interactions with microorganisms

Acanthamoeba is known to interact with a plethora of microorganisms such as bacteria, fungi and viruses. In these interactions, the amoebae can be predatory in nature, transmission vehicle or an incubator. Amoebae consume microorganisms, especially bacteria, as food source to fulfil their nutritional needs by taking up bacteria through phagocytosis and lysing them in phagolysosomes and hence play an eminent role in the regulation of bacterial density in the nature and accountable for eradication of around 60% of the bacterial population in the environment. Acanthamoeba can also act as a “Trojan horse” for microbial transmission in the environment. Additionally, Acanthamoeba may serve as an incubator-like reservoir for microorganisms, including those that are pathogenic to humans, where the microorganisms use amoebae’s defences to resist harsh environment and evade host defences and drugs, whilst growing in numbers inside the amoebae. Furthermore, amoebae can also be used as a “genetic melting pot” where exchange of genes as well as adaptation of microorganisms, leading to higher pathogenicity, may arise. Here, we describe bacteria, fungi and viruses that are known to interact with Acanthamoeba spp

Mycobacterium leprae: Pathogenesis, diagnosis, and treatment options

Mycobacterium leprae is known to cause leprosy, a neurological and dermatological disease. In the past 20 years, 16 million leprosy cases have been recorded and more than 200,000 new cases were registered each year, indicating that the disease is still progressing without hindrance. M. leprae, an intracellular bacterium, infects the Schwann cells of the peripheral nervous system. Several types of leprosy have been described, including indeterminate, tuberculoid, borderline tuberculoid, mid-borderline, borderline lepromatous and lepromatous, and three different forms of leprosy reactions, namely type 1, 2 and 3, have been designated. Microscopic detection, serological diagnostic test, polymerase chain reaction and flow tests are employed in the diagnosis of leprosy. The recommended treatment for leprosy consists of rifampicin, dapsone, clofazimine, ofloxacin and minocycline and vaccines are also available. However, relapse may occur after treatment has been halted and hence patients must be educated on the signs of relapse to allow proper treatment and reduce severity. In this review, we depict the current understanding of M. leprae pathogenicity, clinical aspects and manifestations. Transmission of leprosy, diagnosis and treatment are also discussed

Brain-eating Amoebae Infection: Challenges and Opportunities in Chemotherapy

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