Synthesis of a tetralone derivative of ampicillin to control ampicillin-resistant Staphylococcusaureus.

Due to the rapid emergence of antibiotic resistant new bacterial strains and new infections, there is an urgent need for novel or newly modified and efficient alternatives of treatment. However, conventional antibiotics are still used in therapeutic settings but their efficacy is uncertain due to the rapid evolution of drug resistance. In the present study, we have synthesized a new derivative of conventional antibiotic ampicillin using SN2-type substitution reaction. NMR and mass analysis of the newly synthesized derivative of ampicillin confirmed it as ampicillin-bromo-methoxy-tetralone (ABMT). Importantly, ABMT is revealed to have efficient activity against Staphylococcus aureus (S. aureus) with a MIC value of 32 µg ml-1 while ampicillin was not effective, even at 64 µg ml-1 of concentration. Electron microscopy results confirmed the membrane-specific killing of S. aureus at 1 h of treatment. Additionally, molecular docking analysis revealed a strong binding affinity of ABMT with ß-lactamase via the formation of a closed compact bridge. Our findings, avail a new derivative of ampicillin that could be a potential alternative to fight ampicillin-resistant bacteria possibly by neutralizing the ß-lactamase action.

Targeting interleukin-17 in radiation-induced toxicity and cancer progression.

Recent strategies to combine chemoradiation with immunotherapy to treat locally advanced lung cancer have improved five-year survival outcomes. However, collateral toxicity to healthy lungs, esophagus, cardiac, and vascular tissue continues to limit the effectiveness of curative-intent thoracic radiation (tRT). It is necessary to gain a deeper comprehension of the fundamental mechanisms underlying inflammation-mediated radiation-induced damage to normal cells. Several cells have been linked in published studies to the release of cytokines and chemokines after radiation therapy. Several inflammatory mediators, such as IL-1, IL-6, TNF-α, and TGF-ß, also cause the production of Interleukin-17 (IL-17), a cytokine that is essential for maintaining immunological homeostasis and plays a role in the toxicity caused by radiation therapy. However, currently, the role of IL-17 in RT-induced toxicity in conjunction with cancer progression remains poorly understood. This review provides an overview of the most recent data from the literature implicating IL-17 in radiation-mediated tissue injuries and the efficacy of tRT in lung cancer, as well as its potential as a therapeutic target for interventions to reduce the side effects of tRT with curative intent and to boost an anti-tumor immune response to improve treatment outcomes. IL-17 may also act as a biomarker for predicting the effectiveness of a given treatment as well as the toxicity caused by tRT.

Differential Regulation of TFEB-Induced Autophagy during Mtb Infection and Starvation.

Through the promotion of phagolysosome formation, autophagy has emerged as a crucial mechanism to eradicate intracellular Mycobacterium tuberculosis (Mtb). A cell-autonomous host defense mechanism called lysosome biogenesis and autophagy transports cytoplasmic cargos and bacterial phagosomes to lysosomes for destruction during infection. Similar occurrences occurred in stressful or starvation circumstances and led to autophagy, which is harmful to the cell. It is interesting to note that under both hunger and infection states, the transcription factor EB (TFEB) acts as a master regulator of lysosomal activities and autophagy. This review highlighted recent research on the multitier regulation of TFEB-induced autophagy by a variety of host effectors and Mtb sulfolipid during Mtb infection and starvation. In general, the research presented here sheds light on how lysosome biogenesis and autophagy are differentially regulated by the TFEB during Mtb infection and starvation.

Gut-Antimicrobial Peptides: Synergistic Co-Evolution with Antibiotics to Combat Multi-Antibiotic Resistance.

Due to huge diversity and dynamic competition, the human gut microbiome produces a diverse array of antimicrobial peptides (AMPs) that play an important role in human health. The gut microbiome has an important role in maintaining gut homeostasis by the AMPs and by interacting with other human organs via established connections such as the gut-lung, and gut-brain axis. Additionally, gut AMPs play a synergistic role with other gut microbiota and antimicrobials to maintain gut homeostasis by fighting against multi-antibiotic resistance (MAR) bacteria. Further, conventional antibiotics intake creates a synergistic evolutionary pressure for gut AMPs, where antibiotics and gut AMPs fight synergistically against MAR. Overall, gut AMPs are evolving under a complex and highly synergistic co-evolutionary pressure created by the various interactions between gut microbiota, gut AMPs, and antibiotics; however, the complete mechanism is not well understood. The current review explores the synergistic action of gut AMPs and antibiotics along with possibilities to fight against MAR bacteria.

Laterosporulin25: A probiotically produced, novel defensin-like bacteriocin and its immunogenic properties.

Although multiple vaccines have been developed against infectious diseases, the rapid emergence of new pathogens develops an urgent need for novel strategies to combat infectious diseases. Antimicrobial peptides (AMPs) are excellent agents to fight against infectious diseases having unique multiple mechanisms of action against various pathogens. Apart from the direct applications, AMPs can also be developed as subunit vaccines or could be used as a highly immunogenic carrier protein with highly antigenic but non-immunogenic antigens. Here in the present study, we have identified a novel defensin-like bacteriocin, laterosporulin25 (LS25) upon genome mining of Brevibacillus laterosporus DSM25, a probiotic bacterial strain. By using immunoinformatic tools, we have studied the immunogenic and physiochemical properties of LS25. LS25 is characterized as defensin-like bacteriocin, having 51 amino acids and a molecular weight of 5862.7 Da. The modeled tertiary structure of LS25 is docked with TLR3 and TLR4-MD2 complex to confirm the facilitation of induced immune response that is further validated using molecular dynamics simulations and In-silico immune stimulations. Overall, detailed immunoinformatics analysis suggested LS25 as a potential candidate to be used as an adjuvant or carrier protein for subunit vaccine development, however, further in-vitro and in-vivo experiments are essential to validate its potential.

Surfactin-like lipopeptides from Bacillus clausii efficiently bind to spike glycoprotein of SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) rapidly spread across the globe, infecting millions and causing hundreds of deaths. It has been now around three years but still, it remained a serious threat worldwide, even after the availability of some vaccines. Bio-surfactants are known to have antiviral activities and might be a potential alternative for the treatment of SARS-CoV-2 infection. In the present study, we have isolated and purified, a surfactin-like lipopeptide produced by a probiotic bacterial strain Bacillus clausii TS. Upon purification and characterization with MALDI analysis, the molecular weight of the lipopeptide is confirmed as 1037 Da (similar to surfactin C) which is known to have antiviral activities against various enveloped viruses. Purified surfactin-like lipopeptide showed efficient binding and inhibition of SARS-CoV-2 spike (S1) protein, revealed by competitive ELISA assay. Further, we have explored the complete thermodynamics of the inhibitory binding of surfactin-like lipopeptide with S1 protein using isothermal titration calorimetric (ITC) assay. ITC results are in agreement with ELISA with a binding constant of 1.78 × 10-4 M-1. For further validation of the inhibitory binding of surfactin-like lipopeptide with S1 protein and its receptor binding domain (RBD), we performed molecular docking, dynamics, and simulation experiments. Our results suggested that surfactin could be a promising drug agent for the spike protein targeting drug development strategy against SARS-CoV-2 and other emerging variants.Communicated by Ramaswamy H. Sarma.

Preventing Respiratory Viral Diseases with Antimicrobial Peptide Master Regulators in the Lung Airway Habitat.

The vast surface area of the respiratory system acts as an initial site of contact for microbes and foreign particles. The whole respiratory epithelium is covered with a thin layer of the airway and alveolar secretions. Respiratory secretions contain host defense peptides (HDPs), such as defensins and cathelicidins, which are the best-studied antimicrobial components expressed in the respiratory tract. HDPs have an important role in the human body's initial line of defense against pathogenic microbes. Epithelial and immunological cells produce HDPs in the surface fluids of the lungs, which act as endogenous antibiotics in the respiratory tract. The production and action of these antimicrobial peptides (AMPs) are critical in the host's defense against respiratory infections. In this study, we have described all the HDPs secreted in the respiratory tract as well as how their expression is regulated during respiratory disorders. We focused on the transcriptional expression and regulation mechanisms of respiratory tract HDPs. Understanding how HDPs are controlled throughout infections might provide an alternative to relying on the host's innate immunity to combat respiratory viral infections.

Bacteria-derived chimeric toxins as potential anticancer agents.

Cancer is one of the major causes of death globally, requiring everlasting efforts to develop novel, specific, effective, and safe treatment strategies. Despite advances in recent years, chemotherapy, as the primary treatment for cancer, still faces limitations such as the lack of specificity, drug resistance, and treatment failure. Bacterial toxins have great potential to be used as anticancer agents and can boost the effectiveness of cancer chemotherapeutics. Bacterial toxins exert anticancer effects by affecting the cell cycle and apoptotic pathways and regulating tumorigenesis. Chimeric toxins, which are recombinant derivatives of bacterial toxins, have been developed to address the low specificity of their conventional peers. Through their targeting moieties, chimeric toxins can specifically and effectively detect and kill cancer cells. This review takes a comprehensive look at the anticancer properties of bacteria-derived toxins and discusses their potential applications as therapeutic options for integrative cancer treatment.

Plant-Derived Antimicrobial Peptides: Novel Preservatives for the Food Industry.

Food spoilage is a widespread issue brought on by the undesired growth of microbes in food products. Thousands of tons of usable food or food products are wasted every day due to rotting in different parts of the world. Several food preservation techniques are employed to prevent food from rotting, including the use of natural or manufactured chemicals or substances; however, the issue persists. One strategy for halting food deterioration is the use of plant-derived antimicrobial peptides (AMPs), which have been investigated for possible bioactivities against a range of human, plant, and food pathogens. The food industry may be able to benefit from the development of synthetic AMPs, produced from plants that have higher bioactivity, better stability, and decreased cytotoxicity as a means of food preservation. In order to exploit plant-derived AMPs in various food preservation techniques, in this review, we also outline the difficulties in developing AMPs for use as commercial food preservatives. Nevertheless, as technology advances, it will soon be possible to fully explore the promise of plant-derived AMPs as food preservatives.

NOTCH signaling in COVID-19: a central hub controlling genes, proteins, and cells that mediate SARS-CoV-2 entry, the inflammatory response, and lung regeneration.

In the lungs of infected individuals, the downstream molecular signaling pathways induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are incompletely understood. Here, we describe and examine predictions of a model in which NOTCH may represent a central signaling axis in lung infection in Coronavirus Disease 2019 (COVID-19). A pathway involving NOTCH signaling, furin, ADAM17, and ACE2 may be capable of increasing SARS-CoV-2 viral entry and infection. NOTCH signaling can also upregulate IL-6 and pro-inflammatory mediators induced to hyperactivation in COVID-19. Furthermore, if NOTCH signaling fails to turn down properly and stays elevated, airway regeneration during lung healing can be inhibited-a process that may be at play in COVID-19. With specific NOTCH inhibitor drugs in development and clinical trials for other diseases being conducted, the roles of NOTCH in all of these processes central to both infection and healing merit contemplation if such drugs might be applied to COVID-19 patients.

Conservation and Enhanced Binding of SARS-CoV-2 Omicron Spike Protein to Coreceptor Neuropilin-1 Predicted by Docking Analysis.

The Omicron variant of SARS-CoV-2 bears peptide sequence alterations that correlate with a higher infectivity than was observed in the original SARS-CoV-2 isolated from Wuhan, China. We analyzed the CendR motif of spike protein and performed in silico molecular docking with neuropilin-1 (Nrp1), a receptor-ligand interaction known to support infection by the original variant. Our analysis predicts conserved and slightly increased energetic favorability of binding for Omicron CendR:Nrp1. We propose that the viral spike:Nrp1 coreceptor pathway may contribute to the infectivity of the Omicron variant of SARS-CoV-2.

Thermostable vaccines: an innovative concept in vaccine development.

INTRODUCTION: Vaccines represent he most common and safer ways of combating infectious diseases. Loss of potency owing to thermal denaturation or degradation of almost all the vaccines necessitates their storage, transportation, and final dissemination under refrigerated conditions. However, maintenance of a continuous cold chain raises the costs of vaccines significantly. A large number of life-saving vaccines are discarded before their application owing to exposure to sub-optimum temperatures. Therefore, there is a pressing need for the development of a thermostable vaccine with a long shelf life at ambient temperature. AREAS COVERED: A literature search was performed to compile a list of different vaccines, and their storage and handling conditions. Similarly, a separate list was prepared for different coronavirus vaccines. A literature survey was also performed to look at different approaches undertaken globally to address the issue of the cold-chain problem. We emphasized the importance of yeast cells in the development of thermostable vaccines. In the end, we discussed why thermostable vaccines are required, not only in resource-poor countries but also for resource-rich countries . EXPERT OPINION: Temperature change can severely impact the stability of various life-saving vaccines. Therefore, there is a pressing need for the development of thermostable vaccines with a long shelf lives.

Host-directed therapies for malaria and tuberculosis: common infection strategies and repurposed drugs.

INTRODUCTION: Malaria and tuberculosis are highly infectious diseases declared a global health emergency by the World Health Organization, and together they account for more than 1.5 million deaths worldwide each year. In the case of both malaria and tuberculosis, emergence of multidrug resistance towards frontline drugs has been reported in the recent past. Therefore, an urgent need exists for the discovery and development of novel drugs or therapies to fight these diseases. AREAS COVERED: We provide a detailed overview of major infection strategies, commonly used by both the parasite Plasmodium and by Mycobacterium tuberculosis (Mtb) during disease development. We also describe selected host-directed drugs which can be repurposed to treat both malaria and tuberculosis, and co-infections. EXPERT OPINION: Investigation of common infection strategies used by both Plasmodium and Mtb, during the development of disease in humans, suggests that they are potential host targets for which to develop host-directed therapies. By taking advantage of these common infection strategies, there is a chance that a number of available drugs can be repurposed to fight both malaria and tuberculosis, and their co-infections.

Characterization and Antimicrobial Studies of Iturin-Like and Bogorol-Like Lipopeptides From Brevibacillus spp. Strains GI9 and SKDU10.

Accession numbers for whole-genome sequence of Brevibacillus sp. strain GI9 and SKDU10 are CAGD01000001 to CAGD01000061 and LSSO00000000, respectively. Members of the genus Brevibacillus have been demonstrated to produce a variety of bioactive compounds including polyketides, lipopeptides and bacteriocins. Lipopeptides are non-ribosomally synthesized surface-active compounds with antimicrobial, antitumor, and immune-stimulatory activities. They usually exhibit strong antifungal and antibacterial activities and are considered as promising compounds in controlling fungal diseases. In this study, we have characterized two lipopeptides from Brevibacillus sp. strains GI9 and SKDU10. The corresponding lipopeptides were purified by reverse-phase high-performance liquid chromatography. Mass analysis and characterization by MALDI-TOF-MS (Matrix-assisted laser desorption ionization time-of-flight mass spectrometry) analysis revealed production of an iturin-like lipopeptide by strain GI9 and bogorol-like lipopeptide by strain SKDU10. Both lipopeptides exhibited broad spectrum antibacterial activity and inhibited the growth of various fungi. They showed minimum inhibitory concentration (MIC) values between 90 and 300 µg/ml against indicator strains of bacteria and drug-resistant Candida indicator strains. The lipopeptides did not show phytotoxic effect in seed germination experiments but caused hemolysis. Further, both lipopeptides inhibited the growth of fungi on fruits and vegetables in in vitro experiments, thereby exhibited potential use in biotechnological industry as effective biocontrol agents.

LPD-12: a promising lipopeptide to control COVID-19.

INTRODUCTION: The recent pandemic outbreak of SARS-CoV-2 has been associated with a lethal atypical pneumonia, making COVID-19 an urgent public health issue with an increasing rate of mortality and morbidity. There are currently no vaccines or therapeutics available for COVID-19, which is causing an urgent search for a new drug to combat the COVID-19 pandemic. The lipid membrane alternation efficiency of small antimicrobial lipopeptides enables them to block viral membrane fusion to the host cell. Lipopeptides could serve as potential antiviral agents, by interacting or competing with viral fusion proteins. METHODS: This study screened seven different lipopeptides (tsushimycin, daptomycin, surfactin, bacillomycin, iturin, srfTE, and LPD-12) and docked them individually against the spike (S)-glycoprotein of SARS-CoV-2. RESULTS: Based on the maximum docked score and minimum atomic contact energy, LPD-12 (-1137.38 kcal) was the appropriate molecule for proper binding with the S-glycoprotein of SARS-CoV-2 and thus significantly interrupted its affinity of binding with angiotensin-converting enzyme-2 (ACE2), which is the only receptor molecule found to be facilitating disease development. The results confirmed a strong binding affinity of LPD-12 with ACE2, with a binding free energy of -1621.62 kcal, which could also reciprocally prevent the binding of S-protein. CONCLUSTION: It can be concluded that LPD-12 may act as a potential therapeutic drug, by reducing the entry of SARS-CoV-2 to the human cells via the ACE2 receptor and related infections.

Fusion Protein Targeted Antiviral Peptides: Fragment-Based Drug Design (FBDD) Guided Rational Design of Dipeptides Against SARS-CoV-2.

Infectious diseases caused by viruses have become a serious public health issue in the recent past, including the current pandemic situation of COVID-19. Enveloped viruses are most commonly known to cause emerging and recurring infectious diseases. Viral and cell membrane fusion is the major key event in the case of enveloped viruses that is required for their entry into the cell. Viral fusion proteins play an important role in the fusion process and in infection establishment. Because of this, the fusion process targeting antivirals become an interest to fight against viral diseases caused by the enveloped virus. Lower respiratory tract infections casing viruses like influenza, respiratory syncytial virus (RSV), and severe acute respiratory syndrome coronavirus (SARS-CoV) are examples of such enveloped viruses that are at the top in public health issues. Here, we summarized the viral fusion protein targeted antiviral peptides along with their mechanism and specific design to combat the viral fusion process. The pandemic COVID-19, severe respiratory syndrome disease is an outbreak worldwide. There are no definitive drugs yet, but few are in on-going trials. Here, an approach of fragmentbased drug design (FBDD) methodology is used to identify the broad spectrum agent target to the conserved region of fusion protein of SARS CoV-2. Three dipeptides (DL, LQ and ID) were chosen from the library and designed by the systematic combination along with their possible modifications of amino acids to the target sites. Designed peptides were docked with targeted fusion protein after energy minimization. Results show strong and significant binding affinity (DL = -60.1 kcal/mol; LQ = - 62.8 kcal/mol; ID= -71.5 kcal/mol) during interaction. Anyone of the active peptides from the developed libraries may help to block the target sites competitively to successfully control COVID-19.

Electrochemical communication in biofilm of bacterial community.

Electrochemical communication during biofilm formation has recently been identified. Bacteria within biofilm-adopt different strategies for electrochemical communication such as direct contact via membrane-bound molecules, diffusive electron transfer via soluble redox-active molecules, and ion channel-mediated long-range electrochemical signaling. Long-range electrical signals are important to communicate with distant members within the biofilm, which function through spatially propagating waves of potassium ion (K+ ) that depolarizes neighboring cells. During propagation, these waves coordinate between the metabolic states of interior and peripheral cells of the biofilm. The understanding of electrochemical communication within the biofilm may provide new strategies to control biofilm-mediated drug resistance. Here, we summarized the different mechanisms of electrochemical communication among bacterial populations and suggested its possible role in the development of high level of antibiotic resistance. Thus, electrochemical signaling opens a new avenue concerning the electrophysiology of bacterial biofilm and may help to control the biofilm-mediated infection by developing future antimicrobials.

Host-directed therapies: a potential solution to combat COVID-19.

Coronavirus disease 2019 (COVID-19) characterized by immuno-pathological host responses including pneumonia, lymphopenia, and cytokine storm that leads to severe lung inflammation, developed in acute respiratory distress syndrome (ARDS). In the absence of an effective vaccine or any definitive cure, the use of host-directed therapies is an effective alternative and demanding treatment option in the current pandemic outbreak of COVID-19.