COVID-19: From the Molecular Mechanisms to Treatment

The 2019 novel coronavirus (SARS-CoV-2) causes severe pneumonia called COVID-19 and leads to severe acute respiratory syndrome with a high mortality rate. The SARS-CoV-2 virus in the human body leads to jumpstarting immune reactions and multi-organ inflammation, which has poorer outcomes in the presence of predisposing conditions, including hypertension, dyslipidemia, dysglycemia, abnormal adiposity, and even endothelial dysfunction via biomolecular mechanisms. In addition, leucopenia, hypoxemia, and high levels of both cytokines and chemokines in the acute phase of this disease, as well as some abnormalities in chest CT images, were reported in most patients. The spike protein in SARS-CoV-2, the primary cell surface protein, helps the virus anchor and enter the human host cells. Additionally, new mutations have mainly happened for spike protein, which has promoted the infection's transmissibility and severity, which may influence manufactured vaccines' efficacy. The exact mechanisms of the pathogenesis, besides molecular aspects of COVID-19 related to the disease stages, are not well known. The altered molecular functions in the case of immune responses, including T CD4+, CD8+, and NK cells, besides the overactivity in other components and outstanding factors in cytokines like interleukin-2, were involved in severe cases of SARS-CoV-2. Accordingly, it is highly needed to identify the SARS-CoV-2 bio-molecular characteristics to help identify the pathogenesis of COVID-19. This study aimed to investigate the bio-molecular aspects of SARS-CoV-2 infection, focusing on novel SARS-CoV-2 variants and their effects on vaccine efficacy.Copyright © 2022 NRITLD, National Research Institute of Tuberculosis and Lung Disease, Iran.

Characterization and antibiogram study of pneumonia causing bacteria isolated from blood culture of children in northern Bangladesh

Children are usually affected by pneumonia, which is a common ailment caused by Pathogenic Streptococcus pneumoniae. This study's objective was to isolate and identify S. pneumoniae, which was recovered from blood samples of suspected paediatric pneumonia patients using conventional techniques, such as antibiotic sensitivity profiles and molecular approaches. In this study, forty (40) samples from three major hospitals in the Dinajpur region of Bangladesh were collected and assessed using various bacteriological, biochemical, antibiotic susceptibility test, and molecular techniques. 37.5% of the 40 samples tested positive for pneumonia, and 15 isolates were discovered. In terms of age, pneumonia was more common in children aged 3-5 years (50%) than in those aged 6 to 8 (33.33%), 9 to 11 (25%) and 12 to 15 (20%). According to the results of the current study, the study area had no statistically significant impact (P > 0.05), while age and socioeconomic status had a significant impact on the prevalence of pneumonia in patients with pneumonia (P 0.05). The age group for which pneumonia was most prevalent (at 50%) was that for children between the ages of 3-5. Poor socioeconomic status was associated with the highest prevalence of pneumonia (54.54%). By sequencing the 16S rRNA gene, S. pneumoniae was identified as S. pneumoniae NBRC102642. In the antibiotic investigation, S. pneumoniae was found to be extremely resistant to ciprofloxacin, amikacin, vancomycin, and cefexime, but responsive to erythromycin and azithromycin, as well as neomycin, kanamycin, streptomycin, and bacitracin. S. pneumoniae causes serious complications in paediatric patients, and this scenario requires prevention through vaccination and the development of new, efficient antibiotic therapies for pneumonia. If specific laboratory features of paediatric patients with pneumonia are understood, sepsis will be easier to detect early, treat, and reduce mortality.

Identification of Multi Drug Resistant Bacteria from Drinking Water Samples - A Microbial Survey

Antimicrobial resistance may result from rising resistance patterns of commercially available antibiotics, which is one of the most serious threats to global health and should not be overlooked while the world is focused on the COVID-19 disaster. Waterborne resistant bacteria have been shown to be capable of spreading to people in a lot of circumstances, particularly crowded places in urban living environment with heavy human behavior, such as drinking in public systems and swimming pools. Four hundred drinking water samples were collected from different zones in district Lahore, Pakistan. Multidrug resistance bacterial strains of waterborne pathogens have been isolated and characterized on the basis of colony characteristics, microscopic visuality and biochemical tests. The outcomes of this project revealed that Staphylococcus aureus was (26%), Escheria coli was (45%), Salmonella typhi (15%), Shigella dysenteriae (10%) and Enterococcus faecalis (4%) in district Lahore, Pakistan. These multidrug resistance bacteria showed high resistant patterns against amoxicillin, penicillin, streptomycin, tetracycline, erythromycin, gentamycin, amikacin whereas susceptible for chloramphenicol, cefixime, ofloxacin and ciprofloxacin. The prevalence of associated risk factors such as polluted drinking water (32%), children<5year age (22%), adults >45year age (18%), excessive use of antibiotics (8%), health status of individual (5%), smoking habits (6%), and emotional variables (6%) were observed in this research. These investigations have demonstrated infectious bacterial contamination in surface and groundwater, which caused significant bowel syndrome.Copyright © 2022 Indian Veterinary Assocaition. All rights reserved.

Macrophage membrane-biomimetic adhesive polycaprolactone nanocamptothecin for improving cancer-targeting efficiency and impairing metastasis

The recent remarkable success and safety of mRNA lipid nanoparticle technology for producing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has stimulated intensive efforts to expand nanoparticle strategies to treat various diseases. Numerous synthetic nanoparticles have been developed for pharmaceutical delivery and cancer treatment. However, only a limited number of nanotherapies have enter clinical trials or are clinically approved. Systemically administered nanotherapies are likely to be sequestered by host mononuclear phagocyte system (MPS), resulting in suboptimal pharmacokinetics and insufficient drug concentrations in tumors. Bioinspired drug-delivery formulations have emerged as an alternative approach to evade the MPS and show potential to improve drug therapeutic efficacy. Here we developed a biodegradable polymer-conjugated camptothecin prodrug encapsulated in the plasma membrane of lipopolysaccharide-stimulated macrophages. Polymer conjugation revived the parent camptothecin agent (e.g., 7-ethyl-10-hydroxy-camptothecin), enabling lipid nanoparticle encapsulation. Furthermore, macrophage membrane cloaking transformed the nonadhesive lipid nanoparticles into bioadhesive nanocamptothecin, increasing the cellular uptake and tumor-tropic effects of this biomimetic therapy. When tested in a preclinical murine model of breast cancer, macrophage-camouflaged nanocamptothecin exhibited a higher level of tumor accumulation than uncoated nanoparticles. Furthermore, intravenous administration of the therapy effectively suppressed tumor growth and the metastatic burden without causing systematic toxicity. Our study describes a combinatorial strategy that uses polymeric prodrug design and cell membrane cloaking to achieve therapeutics with high efficacy and low toxicity. This approach might also be generally applicable to formulate other therapeutic candidates that are not compatible or miscible with biomimetic delivery carriers. © 2022 The Authors

UNDERSTANDING THE NEED FOR A BROAD DIFFERENTIAL DIAGNOSIS: A CASE OF PNEUMONIC TULAREMIA

SESSION TITLE: Disseminated Bacterial Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 10:15 am - 11:10 am INTRODUCTION: Tularemia is a rare infectious disease caused by Francisella Tularensis that typically affects the skin, eyes, lymph nodes, and lungs. There are a variety of forms of tularemia with varying rates of contagiousness and mortality. Respiratory tularemia has a high mortality rate if left untreated and presents with non-specific viral like symptoms occurring in conjunction with respiratory symptoms: cough, hemoptysis, and pleuritic chest pain. In this COVID ARDS era, it is important to evaluate a broad differential diagnosis. Therefore, the authors describe a patient presenting with flu-like respiratory symptoms whom was ultimately was diagnosed with acute respiratory distress syndrome (ARDS) due to F. Tulerensis. CASE PRESENTATION: A 44-year-old male presented with a four-day history of night sweats, shortness of breath, a productive cough which progressed to hemoptysis, and oliguria. Prior to admission, his initial symptoms were treated as chronic sinusitis with varied antibiotics. Social history including tobacco abuse and deer hunting 1 month prior to presentation. Vitals were stable except for tachycardia, hypoxia, and tachypnea. Laboratory findings were significant for AKI, lactic acidosis, mild transaminitis, hyperbilirubinemia, and leukocytosis with predominant neutrophilia. Thoracic CTA showed bilateral diffused pulmonary edema without evidence of pulmonary embolism. Due to the patient's worsening respiratory status, he was intubated for support. The patient progressed to Severe ARDS per Berlin Criteria eventually requiring pronation and continuous paralyzing. Bronchoscopy was performed with bronchial lavage. Bacterial, viral, and fungal cultures did not show growth while vasculitic work-up was negative. Empiric antibiotic treatment did not show improvement until the patient was diagnosed with F. Taularensis via serological testing with an IgM of 20 U/mL, and patient was transitioned to gentamycin. Ultimately, the patient was extubated, transitioned to oral doxycycline, and discharged home. DISCUSSION: Approximately 250 cases of tularemia are reported to CDC each year. Respiratory tularemia has a mortality rate up to 30% if not treated. For this reason, F. tularensis is a potential biological weapon and is categorized as a Group A pathogenic agent. Serological testing may be negative early in disease progression;therefore, early inflammatory markers with clinical suspicion are essential to diagnose the disease early in its course. DNA microarray has high specificity and sensitivity for rapid diagnosis of tularemia while being cost effective. After prompt diagnosis, intravenous aminoglycosides;such as gentamycin or streptomycin;must be started. CONCLUSIONS: In the above case, we illustrate the gradual onset and rapid patient deterioration when treatment is delayed;yet, there is rapid recovery once appropriate treatment is used. Reference #1: 1. Ranjbar, Reza, Payam Behzadi, and Caterina Mammina. "Respiratory tularemia: Francisella tularensis and microarray probe designing.” The open microbiology journal 10 (2016): 176. Reference #2: 2. Akhvlediani, N., I. Burjanadze, D. Baliashvili, T. Tushishvili, M. Broladze, A. Navdarashvili, S. Dolbadze et al. "Tularemia transmission to humans: a multifaceted surveillance approach.” Epidemiology & Infection 146, no. 16 (2018): 2139-2145. Reference #3: 3. Tularemia in British Columbia: A case report and review. Issue: BCMJ, vol. 52, No. 6, July August 2010 (Pages 303- 307). Megan Isaac-Renton, BSc, Muhammad Morshed, PhD, SCCM Eleni Galanis, MD, MPH, FRCPC Sunny Mak, MSc Vicente Loyola, MD, FRCPC, Linda M.N. Hoang, MD, MHSc, FRCPC DISCLOSURES: No relevant relationships by Munish Adhikari No relevant relationships by Ashma Ul Husna No relevant relationships by Yan Jiang No relevant relationships by Divya Kharel No relevant relationships by Gregory Polcha

Coordination Chemistry, Antibacterial Screening, and In Silico ADME Study of Mononuclear NiII and CuII Complexes of Asymmetric Schiff Base of Streptomycin and Aniline

Two novel metal complexes, that is, Ni (StmAn)2(4) and Cu (StmAn)2(5), were synthesized from unsymmetrical Schiff base ligand StmAn (3). The ligand was prepared by refluxing streptomycin (2) and aniline (1). They were characterized by elemental microanalysis, conductivity measurements, and spectroscopic techniques such as 1H NMR, FT-IR, ESI-mass, and electronic absorption spectral study. Interestingly, the study revealed metal coordination through azomethine nitrogen and N-atom of NH-CH3 of N-methyl-L-glucosamine unit of streptomycin. The electronic absorption spectral study supported an octahedral geometry for complex 4 and a tetrahedral geometry for complex 5. Particle size calculation by Scherrer’s formula indicated their nanocrystalline nature. The geometry optimization of the complexes was achieved by running an MM2 job in Gaussian supported Cs-ChemOffice ultra-12.0.1 and ArgusLab 4.0.1 version software. Based on SwissADME predictions, a theoretical drug profile was generated by analyzing absorption, distribution, metabolism, excretion, and toxicity (ADMET) scores of the compounds. They were screened for in vitro antibacterial activity study against four clinical pathogens such as E. coli, S. pneumoniae, P. vulgaris, and S. aureus. Minimum inhibitory concentration (MIC) study demonstrated greater inhibitory potency of complex (4) (0.024 g/L) for S. aureus relative to ligand (3) and complex (5). Studies show that metal complexes are more toxic to bacteria.

Effectiveness of anti-TB medicines in treating patients experiencing COVID-19 symptoms

Introduction: COVID-19, the life-threatening disease caused by the pathogenic SARS-CoV-2 virus, has limited treatment or measures for curing the infected persons. However, many antibiotics have been tried with varied results.

Migratory birds as the vehicle of transmission of multi drug resistant extended spectrum ß lactamase producing Escherichia fergusonii, an emerging zoonotic pathogen.

The acquisition of multi-drug resistance (MDR) genes by pathogenic bacterial bugs and their dispersal to different food webs has become a silent pandemic. The multiplied use of different antibacterial therapeutics during COVID-19 pandemic has accelerated the process among emerging pathogens. Wild migratory birds play an important role in the spread of MDR pathogens and MDR gene flow due to the consumption of contaminated food and water. Escherichia fergusonii is an emerging pathogen of family Enterobacteriaceae and commonly causes disease in human and animals. The present study focused on the isolation of E. fergusonii from blood, saliva, and intestine of selected migratory birds of the Hazara Division. The sensitivity of isolated strains was assessed against ten different antibiotics. The isolation frequency of E. fergusonii was 69%. In blood samples, a high rate of resistance was observed against ceftriaxone (80%) followed by ampicillin (76%) whereas, in oral and intestinal samples, ceftriaxone resistant strains were 56% and 57% while ampicillin resistance was 49% and 52% respectively. The overall ceftriaxone and ampicillin-resistant cases in all three sample sources were 71% and 65% respectively. In comparison to oral and intestinal samples, high numbers of ceftriaxone-resistant strains were isolated from the blood of mallard while ampicillin-resistant strains were observed in blood samples of cattle egrets. 16S rRNA-based confirmed strains of E. fergusonii were processed for detection of CTX-M and TEM-1 gene through Polymerase chain reaction (PCR) after DNA extraction. Hundred percent ceftriaxone resistant isolates possessed CTX-M and all ampicillin-resistant strains harbored TEM-1 genes. Amplified products were sequenced by using the Sanger sequencing method and the resulted sequences were checked for similarity in the nucleotide Database through the BLAST program. TEM-1 gene showed 99% and the CTX-M gene showed 98% similar sequences in the Database. The 16S rRNA sequence and nucleotide sequences for TEM-1 and CTX-M genes were submitted to Gene Bank with accession numbers LC521304, LC521306, LC521307 respectively. We posit to combat MDR gene flow among the bacterial pathogens across different geographical locations, regular surveillance of new zoonotic pathogens must be conducted.

Repurposing of approved drugs and nutraceuticals to identify potential inhibitors of SARS-COV-2’s entry into human host cells: a structural analysis using induced-fit docking, MMGBSA and molecular dynamics simulation approach

The objective of this research work is to identify molecules through an advanced computational screening technique from a database of approved drugs/nutraceuticals that would inhibit transmembrane protease serine 2 (TMPRSS2) and thereby prevent SARS-CoV-2’s entry into human host cells. A homology model was built for TMPRSS2 and the standard inhibitors nafamostat and camostat were docked on the model. Ligand-based screening, flexible ligand docking and induced-fit docking followed by free binding energy calculations were carried out as part of the screening technique to generate hits. Eventually, molecular dynamics (MD) simulation was done for all the hits, and the results were compared with that of the standard inhibitors to validate our claims. From our computational study, we determined that streptomycin, doxorubicin and tetrahydrofolic acid are potential inhibitors of TMPRSS2. By analysing the MD simulation results, we also propose that streptomycin had the highest potential to inhibit TMPRSS2 among the three molecules. The three molecules we identified are most likely to show the efficacy when tested in vitro by prevention of entry of SARS-CoV-2 into human cells. These molecules can be taken further for clinical trials, and we expect fast processing since they are already approved by FDA and EMA for other diseases. [ FROM AUTHOR] Copyright of Molecular Simulation is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Melioidosis: A Neglected Infection in Bangladesh

Bangladesh is an example of a highly populous, agricultural country where melioidosis may be a significantly under diagnosed cause of infection and death. A recent regression model predicted 16,931 cases annually in Bangladesh with a mortality rate of 56%. However, we only manage to confirm (culture) around 80 cases in last 60 years. A lack of awareness among microbiologists and clinicians and a lack of diagnostic microbiology infrastructure are factors that are likely to lead to the underreporting of melioidosis. Melioidosis transmits through inoculation, inhalation and ingestion. Diabetes mellitus is the most common risk factor (12 times higher chance of getting the infection) predisposing individuals to melioidosis and is present in >50% of all patients. The clinical presentation is widely varied and can be mistaken for other diseases such as tuberculosis or more common forms of pneumonia giving rise to its nickname as the “great mimicker”. Disease manifestations vary from pneumonia or localized abscess to acute septicemias, or may present as a chronic infection. Culture is considered the current gold-standard for diagnosis and culture-confirmation should always be sought in patients where disease is suspected. It is strongly recommended that any non–Pseudomonas aeruginosa, oxidase-positive, Gram-negative bacillus isolated from any clinical specimen from a patient in an endemic area should be suspected to be Burkholderia pseudomallei (BP). In addition, based on antibiogram, any Gramnegative bacilli that are oxidase-positive, typically resistant to aminoglycosides (e.g., gentamicin), colistin, and polymyxin but sensitive to amoxicillin/clavulanic acid should be considered as BP. This bacteria is inherently resistant to penicillin, ampicillin, first generation and second-generation cephalosporins, gentamicin, tobramycin, streptomycin, and polymyxin. For intensive phase (10 to 14 days), ceftazidime or carbapenem is the drug of choice. For eradication phase (3 to 6 months), oral trimethoprim/ sulfamethoxazole is the drug of choice. Surgery (drainage of abscess) has an important role in the management of melioidosis. Preventive measures through protective gears could be useful particularly for the risk groups.

The Burden of Tuberculosis as a Permanent Medical and Legal Challenge for Mankind through Centuries

Tuberculosis (TB) is a contagious disease, and throughout human history, it has been permanently opening numerous medical and legal questions, for which the answers are implied by the current social circumstances. In ancient times, insufficient knowledge of the etiopathogenesis of TB resulted in discrimination and isolation of patients. In the Middle Ages, kings used TB as a disease to secure their political power over the citizens, while TB culturally took a romanticized form during the 19th and 20th centuries, together with a great social phobia of contagion, disease, and dying on the other hand. Stereotypes were formed around all TB victims, while society tried to understand the nature of the disease and establish a civilizational relationship with it as a health problem having numerous social implications. Modern public health measures for the control of the TB pandemic were established after the discovery of the Koch bacillus in the 19th century. The invention and mass use of the BCG vaccine, the discovery of streptomycin and isoniazid, and the new era of TB treatment, with the consequent emergence of drug resistance, co epidemic with AIDS, neglect of public health facilities and the current COVID-19 pandemics threaten many legal rights of the infected and the sick and pose new challenges in its global elimination. Numerous attempts by society over the centuries to devise preventive and therapeutic measures for TB, through different levels of social obligations and activities, have had and continue to have a profound impact on the human race, shaping its further response to the victims of this deadly disease.