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Abstract Methotrexate (MTX), an efficient chemotherapy medication is used in treating various malignancies. However, the breast cancer cell line MDA-MB-231 has developed resistance to it due to low levels of the MTX transport protein, and reduced folate carrier (RFC), making it less effective against these cancer cells. Here we designed a very simple, biocompatible, and non-toxic amine-capped ZnO quantum dots to overcome the MTX resistance on the MDA-MB-231 breast cancer cell line. The QD was characterized by HRTEM, DLS EDX, FT-IR, UV–Vis, and Fluorescence spectroscopy. MTX loading onto the QD was confirmed through fluorescence and UV–Vis spectroscopy. Additionally, extensive confocal microscopic investigations were carried out to determine whether the MTX was successfully released on the MDA-MB-231 cell line. It was discovered that QD is a better pH-responsive delivery system than the previous ones because it successfully delivers MTX to the MDA-MB-231 at a higher rate on an acidic pH than it does at a physiological pH. QD also has anticancer activity and can eradicate cancer cells on its own. These factors make the QD to be an effective pH-responsive delivery system that can improve the efficacy of the medication in therapeutic diagnosis.

The rapid evolution of drug resistance is one of the greatest health issues of the 21st century. There is an alarming situation to find new therapeutic strategies or candidate drugs to tackle ongoing multi-drug resistance development. The marine environment is one of the prime natural ecosystems on Earth, the majority of which is still unexplored, especially when it comes to the microbes. A wide variety of bioactive compounds have been obtained from a varied range of marine organisms; however, marine bacteria-produced bacteriocins are still undermined. Owing to the distinct environmental stresses that marine bacterial communities encounter, their bioactive compounds frequently undergo distinct adaptations that confer on them a variety of shapes and functions, setting them apart from their terrestrial counterparts. Bacterially produced ribosomally synthesized and posttranslationally modified peptides (RiPPs), known as bacteriocins, are one of the special interests to be considered as an alternative to conventional antibiotics because of their variety in structure and diverse potential biological activities. Additionally, the gut microbiome of marine creatures are a largely unexplored source of new bacteriocins with promising activities. There is a huge possibility of novel bacteriocins from marine bacterial communities that might come out as efficient candidates to fight against antibiotic resistance, especially in light of the growing pressure from antibiotic-resistant diseases and industrial desire for innovative treatments. The present review summarizes known and fully characterized marine bacteriocins, their evolutionary aspects, challenges, and the huge possibilities of unexplored novel bacteriocins from marine bacterial communities present in diverse marine ecosystems.

Antimicrobial peptides (AMPs) are considered a promising alternative to conventional antibiotics to fight against the rapid evolution of antibiotic resistance. Other than their potent antimicrobial properties, AMP-based vesicles can be used as efficient drug-delivery vehicles. In the present study, we synthesized and characterized a new cyclic AMP, consisting of all-hydrophobic cores with antimicrobial activity against S. aureus. Interestingly, CycP undergoes supramolecular self-assembly, and self-assembled CycP (sCycP) vesicles are characterized under an electron microscope; however, these vesicles do not display antimicrobial activity. Next, sCycP vesicles are used in combination with SXT (sulfamethoxazole–trimethoprim) vesicles to check the drug loading and delivery capacity of sCycP vesicles to bacterial cell membranes. Interestingly, sCycP vesicles showed synergistic action with SXT vesicles and resulted in a significant reduction in MIC against S. aureus. Further, electron microscopy confirmed the membrane-specific killing mechanism of SXT-loaded sCycP vesicles. Additionally, CycP showed high binding affinities with the β-lactamase of S. aureus, which was one of its possible antimicrobial mechanisms of action. Overall, the results suggested that CycP is a novel self-assembled dual-action cyclic AMP with non-cytotoxic properties that can be used alone as an AMP or a self-assembled drug delivery vehicle for antibiotics to combat S. aureus infections.

Hospital-acquired antibiotic-resistant pneumonia is one of the major causes of mortality around the world that pose a catastrophic threat. Pseudomonas aeruginosa is one of the most significant opportunistic pathogens responsible for hospital-acquired pneumonia and gained resistance to the majority of conventional antibiotics. There is an urgent need for antibiotic alternatives to control drug-resistant pneumonia and other related respiratory infections. In the present study, we explored the antibacterial potential of cineole in combination with homeopathic medicines against biofilm-forming drug-resistant P. aeruginosa. Out of 26 selected and screened homeopathic medicines, Hypericum Perforatum (HyPer) was found to eradicate biofilm-forming drug-resistant P. aeruginosa most effectively when used in combination with cineole. Interestingly, the synergistic action of HyPer and cineole was also found to be similarly effective against planktonic cells of P. aeruginosa. Further, the potential synergistic killing mechanisms of cineole and HyPer were determined by analyzing zeta membrane potential, outer membrane permeability, and DNA release from P. aeruginosa cells upon treatment with cineole and HyPer. Additionally, molecular docking analysis revealed strong binding affinities of hypericin (an active ingredient of HyPer) with the PqsA (a quorum sensing protein) of P. aeruginosa. Overall, our findings revealed the potential synergistic action of cineole and HyPer against biofilm-forming drug-resistant P. aeruginosa. Cineole and HyPer could be used in combination with other bronchodilators as inhalers to control the biofilm-forming drug-resistant P. aeruginosa.

The involvement of multiple antibiotic-resistant gastrointestinal pathogens in diarrhea aggravates the disease condition uncontrollably. The current study aimed to find and develop a suitable formulation utilizing multiple natural components from known plant sources to augment the current therapeutic outcomes. The hydroethanolic extraction method was applied through boiling and fermentation on ancient observation-based efficacious plant parts for developing the antidiarrheal polyherbal formulation AP-01. An animal study model of diarrhea was used to evaluate the safety and efficacy of the formulation. The formulation was tested in vitro on four different multiple antibiotic-resistant gastrointestinal pathogens collected from the national repository. The formulation depicted no cytotoxicity on normal gut cells and was efficacious at 10 ml/kg single dose in relieving symptoms of diarrhea by 79.71%, compared with the standard drug showing a reduction of symptoms by 83.01%. AP-01 exhibited delayed gastric motility. The symptoms of diarrhea ceased to occur within 320.66 ± 5.05 minutes with AP-01, whereas the standard drug took 308 ± 6.63 minutes. AP-01 was found successful at a viable dosage regimen of 75 μl/ml v/v to 100 μl/ml v/v in inhibiting the growth of different pathogens from the Enterobacteriaceae family possessing resistance against several classes of antibiotics in culture media. Chemical analysis revealed different alkaloids, flavonoids, and polyphenols that probably work in unison through multiple modes of action to arrest diarrhea and inhibit pathogens simultaneously. These promising results shown by AP-01 should evoke an effort to dive deep into research and development for better therapeutic formulations for infectious diarrhea by harvesting nature’s arsenal.

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.

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.

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.

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.

Abstract Since the birth of Christ, in these 2019 years, the man on earth has never experienced a survival challenge from any acellular protist compared to SARS-CoV-2. No specific drugs yet been approved. The host immunity is the only alternative to prevent and or reduce the infection and mortality rate as well. Here, a novel mechanism of melanin mediated host immunity is proposed having potent biotechnological prospects in health care management of COVID-19. Vitamin D is known to enhance the rate of melanin synthesis; and this may concurrently regulate the expression of furin expression. In silico analyses have revealed that the intermediates of melanin are capable of binding strongly with the active site of furin protease. On the other hand, furin expression is negatively regulated via 1-α-hydroxylase (CYP27B1), that belongs to vitamin-D pathway and controls cellular calcium levels. Here, we have envisaged the availability of biological melanin and elucidated the bio-medical potential. Thus, we propose a possible synergistic application of melanin and the enzyme CYP27B1 (regulates vitamin D biosynthesis) as a novel strategy to prevent viral entry through the inactivation of furin protease and aid in boosting our immunity at the cellular and humoral levels.

Secondary bacterial infections are commonly associated with prior or concomitant respiratory viral infections. Viral infections damage respiratory airways and simultaneously defects both innate and acquired immune response that provides a favorable environment for bacterial growth, adherence, and facilitates invasion into healthy sites of the respiratory tract. Understanding the molecular mechanism of viral-induced secondary bacterial infections will provide us a chance to develop novel and effective therapeutic approaches for disease prevention. The present study describes details about the secondary bacterial infection during viral infections and their immunological changes.The outcome of discussion avails an opportunity to understand possible secondary bacterial infections associated with novel SARS-CoV-2, presently causing pandemic outbreak COVID-19.

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.

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.

The search for a bioactive natural antibacterial agent with wound healing properties is a common practice for the development of new-generation molecules. Antimicrobial peptides are a good alternative to antibiotics and easy-to-form hydrogels under self-assembled conditions without pH adjustment. With this in mind, the peptide pool was extracted from a formulated curd composed of a blend of probiotic bacteria such as Streptococcus thermophilus, Lactobacillus casei, and Bifidobacterium bifidum at an optimized ratio of 7:1:2. The water content of curd was collected by the drainage column, centrifuged, filtered through a 0.45-μM filter, and used for hydrogel preparation. Matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry (MS) analysis confirmed the presence of peptide pool in the extracted water. The prepared hydrogel was freeze dried, and its effect on biofilm formation, swarming mortality, antimicrobials, wound healing, and biocompatibility was subsequently verified. Transmission electron microscope (TEM) and scanning electron microscope (SEM) images revealed the fibrous network of peptides after self-assembly with non-polar n-hexane solvent and a porous structure after drying, respectively. The observed biocompatibility, antimicrobial activity, and strong wound healing activity of the developed curd-based hydrogel have opened a new platform for antibacterial ointment formulation.

Urinary tract infection (UTI) is one of the most common infectious diseases at the community level. In order to assess the adequacy of empirical therapy, the susceptibility of antibiotics and resistance pattern of bacteria responsible for UTI in West Bengal, India, were evaluated throughout the period of 2008-2013. The infection reports belonging to all age groups and both sexes were considered. E. coli was the most abundant uropathogen with a prevalence rate of 67.1%, followed by Klebsiella spp. (22%) and Pseudomonas spp. (6%). Penicillin was least effective against UTI-causing E. coli and maximum susceptibility was recorded for the drugs belonging to fourth generation cephalosporins. Other abundant uropathogens, Klebsiella spp., were maximally resistant to broad-spectrum penicillin, followed by aminoglycosides and third generation cephalosporin. The antibiotic resistance pattern of two principal UTI pathogens, E. coli and Klebsiella spp. in West Bengal, appears in general to be similar to that found in other parts of the Globe. Higher than 50% resistance were observed for broad-spectrum penicillin. Fourth generation cephalosporin and macrolides seems to be the choice of drug in treating UTIs in Eastern India. Furthermore, improved maintenance of infection incident logs is needed in Eastern Indian hospitals in order to facilitate regular surveillance of the occurrence of antibiotic resistance patterns, since such levels continue to change.

Bacterial infections are raising serious concern across the globe. The effectiveness of conventional antibiotics is decreasing due to global emergence of multi-drug-resistant (MDR) bacterial pathogens. This process seems to be primarily caused by an indiscriminate and inappropriate use of antibiotics in non-infected patients and in the food industry. New classes of antibiotics with different actions against MDR pathogens need to be developed urgently. In this context, this review focuses on several ways and future directions to search for the next generation of safe and effective antibiotics compounds including antimicrobial peptides, phage therapy, phytochemicals, metalloantibiotics, LPS and efflux pump inhibitors to control the infections caused by MDR pathogens.

An antifungal lipopeptide fengycin, producing strain SM1 was isolated from farm land soil sample and identified as Bacillus thuringienesis strain SM1 by using 16S rDNA analysis. Fengycin detected in the culture extract was further purified using HPLC and showed a molecular mass of 1492.8 Da by MALDI-TOF-MS analysis. Purified fengycin was allowed to construct their self-assembled structure onto a hydrophobic surface showing a clear improvement of antibacterial activity. In self-assembly, fengycin adapts a spherical micelle core shell like structure. Self-assembled fengycin may be a successful antimicrobial compound modifying its action from confined antifungal function. Besides it can open up a new area of research in supramolecullar lipopeptide based compound making. This can revealed the mode of action of this unique self-assembled structure to fully evaluate its potential for use as an antimicrobial drug to control the emergence of bacterial infection.