Treatment Of Infectious Diseases Research Articles

A bacteriophage-based validation of a personal protective equipment doffing procedure to be used with high-consequence pathogens.

To determine if the high-level personal protective equipment used in the treatment of high-consequence infectious diseases is effective at stopping the spread of pathogens to healthcare personnel (HCP) while doffing. Personal protective equipment (PPE) is fundamental to the safety of HCPs. HCPs treating patients with high-consequence infectious diseases use several layers of PPE, forming complex protective ensembles. With high-containment PPE, step-by-step procedures are often used for donning and doffing to minimize contamination risk to the HCP, but these procedures are rarely empirically validated and instead rely on following infection prevention best practices. A doffing protocol video for a high-containment PPE ensemble was evaluated to determine potential contamination pathways. These potential pathways were tested using fluorescence and genetically marked bacteriophages. The experiments revealed existing protocols permit contamination pathways allowing for transmission of bacteriophages to HCPs. Updates to the doffing protocols were generated based on the discovered contamination pathways. This updated doffing protocol eliminated the movement of viable bacteriophages from the outside of the PPE to the skin of the HCP. Our results illustrate the need for quantitative, scientific investigations of infection prevention practices, such as doffing PPE.

Identification of Microorganism in Infected Wounds by Positively Charged Selective Sensor Array and Deep Learning Algorithm.

Microorganism are ubiquitous and intimately connected with human health and disease management. The accurate and fast identification of pathogenic microorganisms is especially important for diagnosing infections. Herein, three tetraphenylethylene derivatives (S-TDs: TBN, TPN, and TPI) featuring different cationic groups, charge numbers, emission wavelengths, and hydrophobicities were successfully synthesized. Benefiting from distinct cell wall binding properties, S-TDs were collectively utilized to create a sensor array capable of imaging various microorganisms through their characteristic fluorescent signatures. Furthermore, the interaction mechanism between S-TDs and different microorganisms was explored by calculating the binding energy between S-TDs and cell membrane/wall constituents, including phospholipid bilayer and peptidoglycan. Using a combination of the fluorescence sensor array and a deep learning model of residual network (ResNet), readily differentiation of Gram-negative bacteria (G-), Gram-positive bacteria (G+), fungi, and their mixtures was achieved. Specifically, by extensive training of two ResNet models with large quantities of images data from 14 kinds of microorganism stained with S-TDs, identification of microorganism was achieved at high-level accuracy: over 92.8% for both Gram species and antibiotic-resistant species, with 90.35% accuracy for the detection of mixed microorganism in infected wound. This novel method provides a rapid and accurate method for microbial classification, potentially aiding in the diagnosis and treatment of infectious diseases.

[Accepted, unedited version] The dark side of drug repurposing, from clinical trial challenges to antimicrobial resistance: analysis based on three major fields

Drug repurposing is a strategic endeavor that entails the identification of novel therapeutic applications for pharmaceuticals that are already available in the market. Despite the advantageous nature of implement- ing this particular strategy owing to its cost-effectiveness and efficiency in reducing the time required for the drug discovery process, it is essential to bear in mind that there are various factors that must be meticulously considered and taken into account. Up to this point, there has been a noticeable absence of comprehensive analyses that shed light on the limitations of repurposing drugs. The primary aim of this review is to con- duct a thorough illustration of the various challenges that arise when contemplating drug repurposing from a clinical perspective in three major fields cardiovascular, cancer and diabetes and to further underscore the potential risks associated with the emergence of antimicrobial resistance when employing repurposed antibiotics for the treatment of noninfectious and infectious diseases. The process of developing repurposed medications necessitates the application of creativity and innovation in designing the development program, as the body of evidence may differ for each specific case. In order to effectively repurpose drugs, it is crucial to consider the clinical implications and potential drawbacks that may arise during this process. By com- prehensively analyzing these challenges, we can attain a deeper comprehension of the intricacies involved in drug repurposing, which will ultimately lead to the development of more efficacious and safe therapeutic approaches.

Chemically engineered mTOR-nanoparticle blockers enhance antitumour efficacy

Hepatocellular carcinoma (HCC) is a highly prevalent and deadly type of cancer, and although pharmacotherapy remains the cornerstone of treatment, therapeutic outcomes are often unsatisfactory. Pharmacological inhibition of mammalian target of rapamycin (mTOR) has been closely associated with HCC regression. Herein, we covalently conjugated AZD8055, a potent mTORC1/2 blocker, with a small panel of unsaturated fatty acids via a dynamically activating linkage to enable aqueous self-assembly of prodrug conjugates to form mTOR nanoblockers. Cell-based experiments were carried out to evaluate the effects of the nanoblocker against hepatocellular carcinoma (HCC) cells. The orthotopic and subcutaneous HCC mouse models were established to examine its antitumour activity. Among several fatty acids as promoieties, linoleic acid-conjugated self-assembling nanoblocker exhibited optimal size distribution and superior physiochemical properties. Compared with free agents, PEGylated AZD8055 nanoblocker (termed AZD NB) was pharmacokinetically optimized after intravenous administration. Invivo investigations confirmed that AZD NB significantly suppressed tumour outgrowth in subcutaneous HCCLM3 xenograft, Hepatoma-22, and orthotopic Hepa1-6 liver tumour models. Strikingly, treatment with AZD NB, but not free agent, increased intratumour infiltration of IFN-γ+CD8+ T cells and CD8+ memory T cells, suggesting a potential role of the mTOR nanoblocker to remodel the tumour microenvironment. Overall, a single conjugation with fatty acid transformed a hydrophobic mTOR blocker into a systemically injectable nanomedicine, representing a facile and generalizable strategy for improving the therapeutic index of mTOR inhibition-based cancer therapy. The mTOR inhibition by chemically engineered nanoblocker presented here had enhanced efficacy against tumours compared with the pristine drug and thus has the potential to improve the survival outcomes of patients with HCC. Additionally, this new nanosystem derived from co-assembling of small-molecule prodrug entities can serve as a delivery platform for the synergistic co-administration of distinct pharmaceutical agents. This work was supported by the National Natural Science Foundation of China (32171368,81721091), the Zhejiang Provincial Natural Science Foundation of China (LZ21H180001), the Jinan Provincial Laboratory Research Project of Microecological Biomedicine (JNL-2022039c and JNL-2022010B), State Key Laboratory for Diagnosis and Treatment of Infectious Diseases (zz202310), and Natural Science Foundation of Shandong Province (ZR2023ZD59).

CHRFAM7A diversifies human immune adaption through Ca2+ signalling and actin cytoskeleton reorganization

Human restricted genes contribute to human specific traits in the immune system. CHRFAM7A, a uniquely human fusion gene, is a negative regulator of the α7 nicotinic acetylcholine receptor (α7 nAChR), the highest Ca2+ conductor of the ACh receptors implicated in innate immunity. Understanding the mechanism of how CHRFAM7A affects the immune system remains unexplored. Two model systems are used, human induced pluripotent stem cells (iPSC) and human primary monocytes, to characterize α7 nAChR function, Ca2+ dynamics and decoders to elucidate the pathway from receptor to phenotype. CHRFAM7A/α7 nAChR is identified as a hypomorphic receptor with mitigated Ca2+ influx and prolonged channel closed state. This shifts the Ca2+ reservoir from the extracellular space to the endoplasmic reticulum (ER) leading to Ca2+ dynamic changes. Ca2+ decoder small GTPase Rac1 is then activated, reorganizing the actin cytoskeleton. Observed actin mediated phenotypes include cellular adhesion, motility, phagocytosis and tissue mechanosensation. CHRFAM7A introduces an additional, human specific, layer to Ca2+ regulation leading to an innate immune gain of function. Through the actin cytoskeleton it drives adaptation to the mechanical properties of the tissue environment leading to an ability to invade previously immune restricted niches. Human genetic diversity predicts profound translational significance as its understanding builds the foundation for successful treatments for infectious diseases, sepsis, and cancer metastasis. This work is supported in part by the Community Foundation for Greater Buffalo (Kinga Szigeti) and in part by NIH grant R01HL163168 (Yongho Bae).

Implementing antimicrobial stewardship: lessons and perspectives from a university-affiliated tertiary hospital in Korea

Antimicrobial stewardship programs (ASPs) can lower antibiotic use, decrease medical expenses, prevent the emergence of resistant bacteria, and enhance treatment for infectious diseases. This study summarizes the stepwise implementation and effects of ASPs in a single university-affiliated tertiary care hospital in Korea; it also presents future directions and challenges in resource-limited settings. At the study hospital, the core elements of the ASP such as leadership commitment, accountability, and operating system were established in 2000, then strengthened by the formation of the Antimicrobial Stewardship (AMS) Team in 2018. The actions of ASPs entail key components including a computerized restrictive antibiotic prescription system, prospective audit, post-prescription review through quantitative and qualitative intervention, and pharmacy-based interventions to optimize antibiotic usage. The AMS Team regularly tracked antibiotic use, the effects of interventions, and the resistance patterns of pathogens in the hospital. The reporting system was enhanced and standardized by participation in the Korea National Antimicrobial Use Analysis System, and educational efforts are ongoing. Stepwise implementation of the ASP and the efforts of the AMS Team have led to a substantial reduction in the overall consumption of antibiotics, particularly regarding injectables, and optimization of antibiotic use. Our experience highlights the importance of leadership, accountability, institution-specific interventions, and the AMS Team.

A Brief History of Antimicrobial Resistance.

Despite mounting attention in recent years, health threats posed by antimicrobial resistance are not new. Antimicrobial resistance has dogged infectious disease treatment processes since the first modern antimicrobials were discovered.

T Cell and Natural Killer Cell Membrane-Camouflaged Nanoparticles for Cancer and Viral Therapies.

Extensive research has been conducted on the application of nanoparticles in the treatment of cancer and infectious diseases. Due to their exceptional characteristics and flexible structure, they are classified as highly efficient drug delivery systems, ensuring both safety and targeted delivery. Nevertheless, nanoparticles still encounter obstacles, such as biological instability, absence of selectivity, recognition as unfamiliar elements, and quick elimination, which restrict their remedial capacity. To surmount these drawbacks, biomimetic nanotechnology has been developed that utilizes T cell and natural killer (NK) cell membrane-encased nanoparticles as sophisticated methods of administering drugs. These nanoparticles can extend the duration of drug circulation and avoid immune system clearance. During the membrane extraction and coating procedure, the surface proteins of immunological cells are transferred to the biomimetic nanoparticles. Such proteins present on the surface of cells confer several benefits to nanoparticles, including prolonged circulation, enhanced targeting, controlled release, specific cellular contact, and reduced in vivo toxicity. This review focuses on biomimetic nanosystems that are derived from the membranes of T cells and NK cells and their comprehensive extraction procedure, manufacture, and applications in cancer treatment and viral infections. Furthermore, potential applications, prospects, and existing challenges in their medical implementation are highlighted.

Impact of medical bloggers’ activities on the prevention of disease risk, public, population and individual health: the opinion of social media users

Due to the high information and communication importance and potential of the medical blogosphere in the formation of health literacy of the population, there is the increased need to study the opinions of Russian social media users on the impact of the content of medical blogs on personal and public health. Aim of the study was to find out the opinion of social media users on the extent to which the activities of bloggers specializing in public health and health care topics influence the prevention of major non-communicable and infectious diseases, public and personal health, within the changing boundaries of medical knowledge broadcasting (using sociological methods). Material and methods. The authors conducted a quantitative sociological survey of 178 respondents - users of social media: 55 (30.9 %) women and 123 (69.1 %) men about visiting blogs specializing in public health and healthcare. The collection of information was carried out by e-mailing a questionnaire developed by the authors, and analyzed the answers to questions from active blog users through a Google form in April – May 2023. Results. The study results of the impact of bloggers’ activities on personal and public health, including those related to the quality of medical information disseminated in social media, are described. Respondents believe that medical bloggers have a greater impact on public health than personal health. At the same time, according to the respondents, the spheres of influence in the field of public health do not coincide with the spheres of influence in the field of personal health. Thus, 74.7 % of respondents believe that medical bloggers have an impact on maintaining a healthy lifestyle of the population, prevention (61.8 % of all respondents think so) and treatment of infectious diseases (61.2 %). The requirements for the quality of information provided by bloggers are considered. Based on the analysis of Russian and foreign scientific literature, the authors developed a graphical diagram of the effect of dissemination through the blogosphere of information in the field of health care and disease prevention. Conclusions. The content published on medical blogs affects the health literacy of the population. That is why, medical blogs can be seen as a social determinant of health, because health blogs can be the key to the success of disease prevention and control efforts for public health maintaining. For organizing a communication intervention of medical personnel in social media to inform the population about methods for preventing the risk of developing major non-communicable and infectious diseases and increasing the level of health literacy of the population, medical blogs can and should be used to inform and educate patients as part of general or targeted multimodal educational practices or as a means of delivering electronic content. The risks of publishing inaccurate information in the blogosphere must be considered, whereby patients can easily become misinformed, which can have serious consequences for their health, and even increase their risk of mortality. To make the best use of the blogosphere, it is necessary to solve the problems of content accuracy and increase the level of professionalism of bloggers who write on medical topics. They need to be professionally trained to work for health, contributing to the prevention of the risk of developing major non-communicable and communicable diseases, improving the health of the population through education, and raising the level of health literacy. It makes sense to assess the success of the communicative intervention of doctors in social media and their management of the training of medical bloggers as a personnel determinant of public health, since it will depend on the personnel potential of the healthcare sector.

Research Progress on Liposome Pulmonary Delivery of Mycobacterium tuberculosis Nucleic Acid Vaccine and Its Mechanism of Action.

Traditional vaccines have played an important role in the prevention and treatment of infectious diseases, but they still have problems such as low immunogenicity, poor stability, and difficulty in inducing lasting immune responses. In recent years, the nucleic acid vaccine has emerged as a relatively cheap and safe new vaccine. Compared with traditional vaccines, nucleic acid vaccine has some unique advantages, such as easy production and storage, scalability, and consistency between batches. However, the direct administration of naked nucleic acid vaccine is not ideal, and safer and more effective vaccine delivery systems are needed. With the rapid development of nanocarrier technology, the combination of gene therapy and nanodelivery systems has broadened the therapeutic application of molecular biology and the medical application of biological nanomaterials. Nanoparticles can be used as potential drug-delivery vehicles for the treatment of hereditary and infectious diseases. In addition, due to the advantages of lung immunity, such as rapid onset of action, good efficacy, and reduced adverse reactions, pulmonary delivery of nucleic acid vaccine has become a hot spot in the field of research. In recent years, lipid nanocarriers have become safe, efficient, and ideal materials for vaccine delivery due to their unique physical and chemical properties, which can effectively reduce the toxic side effects of drugs and achieve the effect of slow release and controlled release, and there have been a large number of studies using lipid nanocarriers to efficiently deliver target components into the body. Based on the delivery of tuberculosis (TB) nucleic acid vaccine by lipid carrier, this article systematically reviews the advantages and mechanism of liposomes as a nucleic acid vaccine delivery carrier, so as to lay a solid foundation for the faster and more effective development of new anti-TB vaccine delivery systems in the future.

[Silencing of Resistance Mechanism in Vancomycin-Resistance Enterococci Using Antisense RNA of vanA Gene].

The World Health Organization has included the problem of antibiotic resistance among the top 10 important health problems in the world. Treatment of infectious diseases has become more difficult due to the spread of antibiotic resistance between bacteria via transposable elements. Vancomycin-resistant enterococci (VRE) are of critical medical and public health importance due to their association with serious nosocomial infections and high risk of death. One of the most important features of VREs is that they have multiple antibiotic resistance and treatment options are reduced. Therefore, new treatment methods are needed. The vanA gene constitutes the building block of the vancomycin resistance mechanism and causes high resistance to vancomycin. In this study, it was aimed to investigate the neutralization of the vancomycin resistance mechanism by creating vanA antisense RNA (asRNA). The vanA positive VRE50 strain in our culture collection which was isolated from the clinical sample, was used to amplify the vanA gene by polymerase chain reaction (PCR). The amplified vanA amplicon was inserted inversely into the pUC19 plasmid by means of the enzyme cutting sites in the primers used. The resulting plasmid was combined with the pAT392 plasmid which can replicate in gram-positive bacteria and a fusion plasmid was created. The fusion plasmid whose orientation was confirmed, was transferred to the wild strain VRE50 by electroporation method. Minimum inhibitory concentration (MIC) values of transformed VRE (tVRE50) and wild type VRE50 strains used as control were determined by the E-Test method. The vancomycin MIC value of the wild type VRE50 strain was determined as 1024 µg/mL and that of the tVRE50 strain was 32 µg/mL and it was determined that the vancomycin resistance of the tVRE50 strain decreased with asRNA (antisense RNA). Antisense RNA technology is an important method for neutralizing the expression of genes. This study showed that neutralization of the vancomycin resistance gene may provide a lower MIC value in a vancomycin-resistant enterococcus strain and lead to increased susceptibility. This new approach provides a new method for VRE treatment by neutralizing the vancomycin resistance mechanism. The result obtained in this study needs to be supported by in vivo tests.

Intranasal neomycin evokes broad-spectrum antiviral immunity in the upper respiratory tract

Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that are accessible and effective are urgently needed, especially in countries that are disproportionately affected. Repurposing generic medicine has the potential to bring new treatments for infectious diseases to patients efficiently and equitably. In this study, we found that intranasal delivery of neomycin, a generic aminoglycoside antibiotic, induces the expression of interferon-stimulated genes (ISGs) in the nasal mucosa that is independent of the commensal microbiota. Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19. Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants. These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections.

New perspectives on the role of vitamin D in the mucosal barrier system of fish gills infected with Flavobacterium columnare

The mucosal barrier of vertebrates comprises a unique array of physical elements and bioactive molecules that act in concert to protect the host against pathogens. Vitamin D (VD), an essential nutrient for animals, along with its receptor (VDR), plays a major role in immunity. However, the correlation between VD/VDR and the mucosal barrier system remains unclear. Here, we employed the fish gill as a model and evaluated the role of VD as a dietary supplement in modifying this typical mucosal barrier system. Varies levels of VD (15.2, 364.3, 782.5, 1167.9, 1573.8, and 1980.1 IU/kg) were formulated and fed to grass carp (Ctenopharyngodon idella) for 70 d. Subsequently, fish were challenged with Flavobacterium columnare, a pathogen in epithelial tissues. Following infection, dietary VD alleviated gill rot and damage caused by F. columnare. Further investigations demonstrated that VD improved physical barrier function by elevating the antioxidant capacity and tight junction barriers, and moderated excessive apoptosis. The promoted physical barrier function was related to nuclear factor E2-related factor 2 and myosin light-chain kinase signaling. Additionally, VD treatment enhanced the immune barrier function by boosting disease resistance, producing antibacterial compounds and immunoglobulins, downregulating pro-inflammatory cytokines, and upregulating the gene expression of anti-inflammatory cytokines, which correlated with nuclear factor kappa B and the target of rapamycin signaling pathways. Thus, VD strengthened pathogen defenses in the gill mucosal barrier system. This finding supports the rationale for VD intervention in infectious diseases and will be critical for the viability of sustainable practices in aquaculture.

Antimicrobial of Ethanolic Extract from Marpuyan Stem Bark (Rhodamnia cinerea Jack)

The Bark of Marpuyan Tree (Rhodamnia cinerea Jack) is a plant that has been empirically used by communities in Indonesia for the treatment of infectious diseases caused by bacteria and fungi. The bark of Marpuyan contains flavonoids, phenolics, and saponins. This study aimed to evaluate the antibacterial and antifungal activities of the ethanol extract of the bark of Marpuyan using the disc diffusion method at various extract concentrations, namely 30%, 25%, 15%, 10%, and 5%. The results of the antibacterial activity test against Gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermidis, and Bacillus subtilis) showed inhibitory zones with respective diameters of 11.67±0.21 mm, 12.29±0.43 mm, and 12.78±0.14 mm. These results indicate weak antibacterial activity. In the antibacterial activity test against Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Salmonella typhi), inhibitory zones were found with respective diameters of 13.05±0.05 mm, 12.58±1.78 mm, and 10.98±0.21 mm. These results also indicate weak antibacterial activity. However, in the antifungal activity test, no activity was found against Candida albicans and Malassezia furfur. Nevertheless, the ethanol extract of Marpuyan bark showed moderate antifungal activity against Trichophyton mentagrophytes, with an inhibitory zone diameter of 15.44±2.02 mm.

Blue-Light-Activated Water-Soluble Sn(IV)-Porphyrins for Antibacterial Photodynamic Therapy (aPDT) against Drug-Resistant Bacterial Pathogens.

Antimicrobial resistance has emerged as a global threat to the treatment of infectious diseases. Antibacterial photodynamic therapy (aPDT) is a promising alternative approach and is highly suitable for the treatment of cutaneous bacterial infections through topical applications. aPDT relies on light-responsive compounds called photosensitizer (PS) dyes, which generate reactive oxygen species (ROS) when induced by light, thereby killing bacterial cells. Despite several previous studies in this area, the molecular details of targeting and cell death mediated by PS dyes are poorly understood. In this study, we further investigate the antibacterial properties of two water-soluble Sn(IV) tetrapyridylporphyrins that were quaternized with methyl and hexyl groups (1 and 2). In this follow-up study, we demonstrate that Sn(IV)-porphyrins can be photoexcited by blue light (a 427 nm LED) and exhibit various levels of bactericidal activity against both Gram-(+) and Gram-(-) strains of bacteria. Using localization studies through fluorescence microscopy, we show that 2 targets the bacterial membrane more effectively than 1 and exhibits comparatively higher aPDT activity. Using multiple fluorescence reporters, we demonstrate that photoactivation of 1 and 2 results in extensive collateral damage to the bacterial cells including DNA cleavage, membrane damage, and delocalization of central systems necessary for bacterial growth and division. In summary, this investigation provides deep insights into the mechanism of bacterial killing mediated by the Sn(IV)-porphyrins. Moreover, our approach offers a new method for evaluating the activity of PS, which may inspire the discovery of new PS with enhanced aPDT activity.

Evaluation of bacteriostatic and antioxidant activities of various extracts from aerial part of Piper nigrum grown in Gulf countries traditionally used for the treatment of various infectious diseases

AbstractPiper nigrum (P. nigrum) is a tropical medicinal plant widely available in Southeast Asian countries including Oman. In Asian It has a long history of usage in places such as Oman for treating of rheumatism, colds, and various infections. Based on the medicinal uses, the purpose of this research is to create diverse fractions using increasing solvent polarity from the aerial part of the collected plant species and evaluate their antibacterial and antioxidant activities by using established bioassays. The aerial part was collected from the Southern part of Oman and processed using the standard method. The processed materials were recovered using the maceration method using methanol, and the methanol raw extracts was further fractionated with water extraction, butanol, ethyl acetate (ETA), hexane, and dichloromethane are produced using different liquid polarities. Each of the six plant extracts was tested for antioxidant and antibacterial potential at different concentrations against DPPH (1, 1-diphenyl-2-picrylhydrazyl) and agar diffusion methods. All of the fractions at varied concentrations shown promising antioxidant activity with DPPH against the gallic acid. The maximum activity was observed in hexane extract, while the smallest potential was noticed in butanol extract, in the following order: hexane > chloroform > water > methanol > ethyl acetate > butanol extract. The antibacterial efficacy of six different polarities extracts gives moderate activity against two Gram-positive bacteria strains namely S. saprophyticus and S. aureus and three Gram-negative namely P. vulgaris, K. senegalensis and E. coli. Among the six extracts, hexane extract had the most antibacterial activity, whereas butanol extract had the smallest activity. The remaining four extracts, chloroform, ethyl acetate, methanol, and water, all had comparable activity. In conclusion, the extracts with the greatest activity from the chosen plant types might be employed as natural antioxidants to treat infectious disorders.

Acute liver failure caused by high-dose tigecycline: A case report.

High-dose tigecycline is gradually being introduced for the treatment of serious infectious diseases due to the increasing difficulty in treating pan-resistant bacterial infections. However, the safety of high-dose tigecycline is controversial. We report the case of a 76-year-old female patient with cerebral hemorrhage who received high-dose tigecycline (100 mg q12h) with other drugs for ventilator-associated pneumonia. 25 days after admission, she developed acute liver failure, mainly manifested by abnormally high bilirubin, coagulation dysfunction, and gastrointestinal hemorrhage with hemorrhagic shock. According to the updated Roussel Uclaf causality assessment method, the patient's acute liver injury was most likely caused by tigecycline.

In vitro study of the bactericidal activity for new derivatives of quaternary ammonium salts based on pyridoxine against gram-positive/gram-negative bacteria

Background: preventive care and successful treatment of infectious diseases (including hospital-acquired infections) are among the most important tasks of modern healthcare. There are not many effective antiseptics and disinfectants to solve this problem. Quaternary ammonium salts are currently one of the promising classes of disinfectants but their use is limited by the ability of microorganisms to develop resistance to these compounds. Modification of QAS with substituents of various natures is a possible way to solve this problem.
 Aims: in this work a bactericidal activity comparative analysis for two original quaternary ammonium compounds based on pyridoxine was carried out in comparison with benzalkonium chloride.
 Materials and methods: the bactericidal activity of 0.1% and 0.2% aqueous solutions of original QACs based on pyridoxine were studied against two widespread pathogens: S. aureus and E. coli. Antibacterial activity data were obtained using a standard in vitro test (bactericidal activity test on a metal surface, exposure time 1, 5 and 15 minutes). In addition to standard conditions, antibacterial efficacy was also studied under protein loading conditions (adding BSA solution to the surface).
 Results: for the studied compounds the RF (reduction factor - reduction lgCFU of microorganisms) was on average ≥ 3. Complicating the model conditions in the form of protein load led to a decrease in efficiency by 1-3 orders. We have also observed an interesting effect of exposure time-dependent specificity reversal to the S. aureus and E. coli.
 Conclusions: The obtained results showed high activity of the studied compounds (corresponding to the effectiveness criterion RF≥3 for commercial compounds used in this field).

Antibiotics daptomycin interacts with S protein of SARS-CoV-2 to promote cell invasion of Omicron (B1.1.529) pseudovirus

ABSTRACT The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has posed enormous challenges to global public health. The use of antibiotics has greatly increased during the SARS-CoV-2 epidemic owing to the presence of bacterial co-infection and secondary bacterial infections. The antibiotics daptomycin (DAP) is widely used in the treatment of infectious diseases caused by gram-positive bacteria owing to its highly efficient antibacterial activity. It is pivotal to study the antibiotics usage options for patients of coronavirus infectious disease (COVID-19) with pneumonia those need admission to receive antibiotics treatment for bacterial co-infection in managing COVID-19 disease. Herein, we have revealed the interactions of DAP with the S protein of SARS-CoV-2 and the variant Omicron (B1.1.529) using the molecular docking approach and Omicron (B1.1.529) pseudovirus (PsV) mimic invasion. Molecular docking analysis shows that DAP has a certain degree of binding ability to the S protein of SARS-CoV-2 and several derived virus variants, and co-incubation of 1–100 μM DAP with cells promotes the entry of the PsV into human angiotensin-converting enzyme 2 (hACE2)-expressing HEK-293T cells (HEK-293T-hACE2), and this effect is related to the concentration of extracellular calcium ions (Ca2+). The PsV invasion rate in the HEK-293T-hACE2 cells concurrently with DAP incubation was 1.7 times of PsV infection alone. In general, our findings demonstrate that DAP promotes the infection of PsV into cells, which provides certain reference of antibiotics selection and usage optimization for clinicians to treat bacterial coinfection or secondary infection during SARS-CoV-2 infection.

The Ca2+-dependent phosphatase calcineurin dephosphorylates TBK1 to suppress antiviral innate immunity.

Tumor necrosis factor receptor-associated factor family member-associated NF-κB activator-binding kinase 1 (TBK1) plays a key role in the induction of the type 1 interferon (IFN-I) response, which is an important component of innate antiviral defense. Viruses target calcium (Ca2+) signaling networks, which participate in the regulation of the viral life cycle, as well as mediate the host antiviral response. Although many studies have focused on the role of Ca2+ signaling in the regulation of IFN-I, the relationship between Ca2+ and TBK1 in different infection models requires further elucidation. Here, we examined the effects of the Newcastle disease virus (NDV)-induced increase in intracellular Ca2+ levels on the suppression of host antiviral responses. We demonstrated that intracellular Ca2+ increased significantly during NDV infection, leading to impaired IFN-I production and antiviral immunity through the activation of calcineurin (CaN). Depletion of Ca²+ was found to lead to a significant increase in virus-induced IFN-I production resulting in the inhibition of viral replication. Mechanistically, the accumulation of Ca2+ in response to viral infection increases the phosphatase activity of CaN, which in turn dephosphorylates and inactivates TBK1 in a Ca2+-dependent manner. Furthermore, the inhibition of CaN on viral replication was counteracted in TBK1 knockout cells. Together, our data demonstrate that NDV hijacks Ca2+ signaling networks to negatively regulate innate immunity via the CaN-TBK1 signaling axis. Thus, our findings not only identify the mechanism by which viruses exploit Ca2+ signaling to evade the host antiviral response but also, more importantly, highlight the potential role of Ca2+ homeostasis in the viral innate immune response.IMPORTANCEViral infections disrupt intracellular Ca2+ homeostasis, which affects the regulation of various host processes to create conditions that are conducive for their own proliferation, including the host immune response. The mechanism by which viruses trigger TBK1 activation and IFN-I induction through viral pathogen-associated molecular patterns has been well defined. However, the effects of virus-mediated Ca2+ imbalance on the IFN-I pathway requires further elucidation, especially with respect to TBK1 activation. Herein, we report that NDV infection causes an increase in intracellular free Ca2+ that leads to activation of the serine/threonine phosphatase CaN, which subsequently dephosphorylates TBK1 and negatively regulates IFN-I production. Furthermore, depletion of Ca2+ or inhibition of CaN activity exerts antiviral effects by promoting the production of IFN-I and inhibiting viral replication. Thus, our results reveal the potential role of Ca2+ in the innate immune response to viruses and provide a theoretical reference for the treatment of viral infectious diseases.