Broad-spectrum Antibacterial Activity Research Articles

Novel biaryloxazolidinone derivatives with broad-spectrum antibacterial activity, favorable drug-like profiles and in vivo efficacy against linezolid-resistant Staphylococcusaureus

The emergence of multidrug-resistant bacteria along with a declining pipeline of clinically useful antibiotics has led to the urgent need for the development of more effective antibacterial agents to treat drug-resistant bacteria. We previously discovered compound OB-158 with potent antibacterial activity but exhibited poor oral bioavailability. Herein, a systematic structural optimization of OB-158 to improve pharmacokinetic profiles yielded 26 novel biaryloxazolidinone analogues, and their activities against Gram-positive S. aureus, multidrug resistant S. aureus and Enterococcus faecalis were evaluated. Remarkably, compound 8b was identified with potent antibacterial activity against S. aureus (MIC=0.06μg/mL), MSSA (MIC=0.125μg/mL), MRSA (MIC=0.06μg/mL), LRSA (MIC=0.125μg/mL) and LREFa (MIC=0.5μg/mL). Compound 8b was demonstrated as a promising candidate through druglikeness evaluation including metabolism in microsomes and plasma, Caco-2cell permeability, plasma protein binding, cytotoxicity, and inhibition of CYP450 and human monoamine oxidase. Notably, compound 8b displayed excellent PK profile with appropriate T1/2 of 1.49h, high peak plasma concentration (Cmax=2320ng/mL), high plasma exposure (AUC0-t=8310hng/mL), and superior oral bioavailability (F=68.1%) in Sprague-Dawley rats. Ultimately, in vivo efficacy of compound 8b in a mouse model of LRSA systemic infection was also demonstrated. Taken together, compound 8b represents a promising drug candidate for the treatment of linezolid-resistant Gram-positive bacterial strains infection.

Testing of Anti-EMT, Anti-Inflammatory and Antibacterial Activities of 2',4'-Dimethoxychalcone.

Chalcone (1,3-diaryl-2-propen-1-one) is an α, β-unsaturated ketone that serves as an active constituent or precursor of numerous natural substances, exhibiting a broad spectrum of pharmacological effects. In this study, the classical Claisen-Schmidt condensation method was used to synthesize the chalcone derivative 2',4'-dimethoxychalcone (DTC) and evaluate its pharmacological activity. By upregulating the expression of the epithelial cell marker E-cadherin and downregulating the expression of the mesenchymal cell marker vimentin, DTC was found to inhibit transforming growth factor-β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) process in A549 cells, maintaining the cells' epithelial-like morphology and reducing the ability of the cells to migrate. Additionally, DTC demonstrated the ability to decrease the expression levels of nitric oxide (NO), tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in RAW264.7 cells, suggesting a possible anti-inflammatory effect. Furthermore, DTC was found to exhibit bacteriostatic activity against Staphylococcus aureus (S. aureus), Proteus vulgaris (P. vulgaris), methicillin-resistant Staphylococcus aureus (MRSA), and Candida albicans (C. albicans), indicating that this chemical may possess broad-spectrum antibacterial activity.

Discovery and Structure-Activity Relationship of Cadazolid: A First-In-Class Quinoxolidinone Antibiotic for the Treatment of Clostridioides difficile Infection.

Clostridioides difficile (C. difficile) is one of the leading causes of healthcare-associated infections worldwide. The increasing incidence of strains resistant to currently available therapies highlights the need for alternative treatment options with a novel mode of action. Oxazolidinones that are connected to a quinolone moiety with a pyrrolidine linker, such as compound 1, are reported to exhibit potent broadspectrum antibacterial activity. In an effort to optimize this class of compounds for the treatment of C. difficile infection (CDI), we have identified cadazolid (9), a first-in-class quinoxolidinone antibiotic, which is a potent inhibitor of C. difficile protein synthesis. In order to achieve narrow-spectrum coverage of clinically most relevant strains without affecting the gut microbiota, an emphasis was placed on abolishing activity against commensals of the intestinal microbiome while retaining good coverage of pathogenic C. difficile, including hypervirulent and epidemic strains.

Antibacterial Activity by Diffusion and Dilution Methods of Liquid Smoke Cocos nucifera L.

Introduction: Liquid smoke is a product that obtained industrially from coconut shell through pyrolysis process at 400°C for 2,5 hours and redestillation to obtain grade 1 liquid smoke. Coconut shell liquid smoke contains chemical compounds, namely phenol, which has been researched to act as a disinfectant that has broad spectrum antibacterial activity against gram positive and gram negative bacteria. Method: This study aims to determine the potential of cocos nucifera L. liquid smoke as an antibacterial against Staphylococcus aureus and Methicillin-resistant staphylococcus aureus (MRSA) bacteria using diffusion and dilution methods. The concentrations used were 100%, 80%, 60%, 40%, 35%, 30%, 15%, 10%, 7%, 5%. As positive control was used Tetracycline 25 ppm. Results: Liquid smoke has the potential to inhibit the growth of both bacteria. The effective concentration to inhibit the growth of S. aureus at 40% concentration and MRSA at 80% concentration. The MIC value of liquid smoke against S. aureus is 0,78%, while on MRSA 3,12%. The MBC of S. aureus and MRSA bacteria at concentrations 1,56% and 6,25%. Staphylococcus aureus has higher sensitivity to Cocos nucifera L. grade 1 liquid smoke than MRSA bacteria. Conclusion: Cocos nucifera L. liquid smoke has antibacterial activity against Staphylococcus aureus and MRSA at effective concentrations of 40% and 80%. The MIC value of S. aureus is 0,78%, while MRSA is 3,12%. The MBC of S. aureus and MRSA bacteria at concentrations 1,56% and 6,25%. Keywords: antibacterial, liquid smoke, phenol, Cocos nucifera L.

Systematic alanine and stapling mutational analysis of antimicrobial peptide Chem-KVL

Chem-KVL is a tandem repeating peptide, with 14 amino acids that was modified based on a short peptide from a fragment of the human host defense protein chemerin. Chem-KVL increases cationicity and hydrophobicity and shows broad-spectrum antibacterial activity. To determine the molecular determinants of Chem-KVL and whether staple-modified Chem-KVL would improve antibacterial activity and protease stability or decrease cytotoxicity, we combined alanine and stapling scanning, and designed a series of alanine and staple-derived Chem-KVL peptides, termed Chem-A1 to Chem-A14 and SCL-1 to SCL-7. We next examined their antibacterial activity against several gram-positive and gram-negative bacteria, their proteolytic stability, and their cytotoxicity. Ala scanning of Chem-KVL suggested that both the positively charged residues (Lys and Arg) and the hydrophobic residues (Lue and Val) were critical for the antibacterial activities of Chem-KVL peptide. Of note, Chem-A4 was able to remarkably inhibit the growth of gram-positive and gram-negative bacteria when compared to the original peptide. And the antibacterial activities of stapled SCL-4 and SCL-7 were several times higher than those of the linear peptide against gram-positive and gram-negative bacteria. Stapling modification of peptides resulted in increased helicity and protein stability when compared with the linear peptide. These stapled peptides, especially SCL-4 and SCL-7, may serve as the leading compounds for further optimization and antimicrobial therapy.

Acorus calamus L. rhizome extract and its bioactive fraction exhibits antibacterial effect by modulating membrane permeability and fatty acid composition.

Ethnopharmacological relevanceIndia's ancient texts, the Charak Samhita and Sushruta Samhita, make reference to the traditional medicinal usage of Acorus calamus L. In India and China, it has long been used to cure stomach aches, cuts, diarrhea, and skin conditions. This ability of the rhizome is attributed to its antimicrobial properties. Research studies to date have shown its antimicrobial properties. However, scientific evidence on its mode of action is still lacking. Aim of the studyAcorus calamus L. rhizome extract and its bioactive fraction exhibits antibacterial effect by modulating membrane permeability and fatty acid composition. Material and methodThe secondary metabolites in the rhizome of A. calamus L. were extracted in hexane using Soxhlet apparatus. The ability of the extract to inhibit multidrug resistant bacterial isolates, namely Bacillus cereus, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa were evaluated using checkerboard assay. Further, the extract was purified using thin layer chromatography, gravity column chromatography, and combiflash chromatography. Structure elucidation of the active compound was done using GC-MS, FT-IR, and UV–Vis spectral scan. The mode of action of the bioactive fraction was determined. Bacterial membrane damage was analyzed using SEM, membrane permeability was determined using SYBR green I and PI dye, leakage of cytoplasmic contents were analyzed using Bradford assay and Fehling’s reagent. The ability to inhibit efflux pump of A. baumannii was determined using EtBr accumulation assay and β-lactamase inhibition was analyzed using nitrocefin as substrate. Also, the biofilm inhibition of B. cereus was determined using crystal violet dye. Moreover, the effect of the bioactive fraction on the fatty acid profile of the bacterial membrane was determined by GC-FAME analysis using 37 component FAME mix as standard. ResultsAcorus calamus L. rhizome hexane extract (AC-R-H) demonstrated broad-spectrum antibacterial activity against all the isolates tested. AC-R-H extract also significantly reduced the MIC of ampicillin against all tested bacteria, indicating its bacterial resistance modulating properties. The assay guided purification determined Asarone as the major compound present in the bioactive fraction (S-III-BAF). S-III-BAF was found to reduce the MIC of ampicillin against Escherichia coli (100–25 mg/mL), Pseudomonas aeruginosa (15–3.25 mg/mL), Acinetobacter baumannii (12.5–1.56 mg/ml), and Bacillus cereus (10–1.25 mg/mL). Further, it recorded synergistic activity with ampicillin against B. cereus (FICI = 0.365), P. aeruginosa (FICI = 0.456), and A. baumannii (FICI = 0.245). The mode of action of S-III-BAF can be attributed to its ability to disturb the membrane integrity, enhance membrane permeability, reduce biofilm formation, and possibly alter the fatty acid composition of the bacterial cell membranes. ConclusionThe bioactive fraction of AC-R-H extract containing Asarone as the active compound showed antibacterial activity and synergistic interactions with ampicillin against the tested bacterial isolates. Such activity can be attributed to the modulation of fatty acids present in bacterial membranes, which enhances membrane permeability and causes membrane damage.

AMP-Mimetic Antimicrobial Polymer-Involved Synergic Therapy with Various Coagents for Improved Efficiency.

The misuse of antibiotics contributes to the emergence of multidrug-resistant (MDR) bacteria. Infections caused by MDR bacteria are rapidly evolving into a significant threat to global healthcare due to the lack of effective and safe treatments. Antimicrobial peptides (AMPs) with broad-spectrum antibacterial activity kill bacteria generally through a membrane disruption mechanism; hence, they tend not to induce resistance readily. However, AMPs exhibit disadvantages, such as high cost and susceptibility to proteolytic degradation, which limit their clinical application. AMP-mimetic antimicrobial polymers, with low cost, stability to proteolysis, broad-spectrum antimicrobial activity, negligible antimicrobial resistance, and rapid bactericidal effect, have received extensive attention as a new type of antibacterial drugs. Lately, AMP-mimetic polymer-involved synergic therapy provides a superior alternative to combat MDR bacteria by distinct mechanisms. In this Review, we summarize the AMP-mimetic antimicrobial polymers involved in synergic therapy, particularly focusing on the different combinations between the polymers with commercially available antimicrobials, organic small molecule photosensitizers, inorganic nanomaterials, and nitric oxide.

Development of a Selective and Stable Antimicrobial Peptide.

Antimicrobial peptides (AMPs) are presented as potential scaffolds for antibiotic development due to their desirable qualities including broad-spectrum activity, rapid action, and general lack of susceptibility to current resistance mechanisms. However, they often lose antibacterial activity under physiological conditions and/or display mammalian cell toxicity, which limits their potential use. Identification of AMPs that overcome these barriers will help develop rules for how this antibacterial class can be developed to treat infection. Here we describe the development of our novel synthetic AMP, from discovery through in vivo application. Our evolved AMP, DTr18-dab, has broad-spectrum antibacterial activity and is nonhemolytic. It is active against planktonic bacteria and biofilm, is unaffected by colistin resistance, and importantly is active in both human serum and a Galleria mellonella infection model. Several modifications, including the incorporation of noncanonical amino acids, were used to arrive at this robust sequence. We observed that the impact on antibacterial activity with noncanonical amino acids was dependent on assay conditions and therefore not entirely predictable. Overall, our results demonstrate how a relatively weak lead can be developed into a robust AMP with qualities important for potential therapeutic translation.

Metagenomic nanopore sequencing for exploring the nature of antimicrobial metabolites of Bacillus haynesii

Multidrug-resistant (MDR) pathogens are a rising global health worry that imposes an urgent need for the discovery of novel antibiotics particularly those of natural origin. In this context, we aimed to use the metagenomic nanopore sequence analysis of soil microbiota coupled with the conventional phenotypic screening and genomic analysis for identifying the antimicrobial metabolites produced by promising soil isolate(s). In this study, whole metagenome analysis of the soil sample(s) was performed using MinION™ (Oxford Nanopore Technologies). Aligning and analysis of sequences for probable secondary metabolite gene clusters were extracted and analyzed using the antiSMASH version 2 and DeepBGC. Results of the metagenomic analysis showed the most abundant taxa were Bifidobacterium, Burkholderia, and Nocardiaceae (99.21%, followed by Sphingomonadaceae (82.03%) and B. haynesii (34%). Phenotypic screening of the respective soil samples has resulted in a promising Bacillus isolate that exhibited broad-spectrum antibacterial activities against various MDR pathogens. It was identified using microscopical, cultural, and molecular methods as Bacillus (B.) haynesii isolate MZ922052. The secondary metabolite gene analysis revealed the conservation of seven biosynthetic gene clusters of antibacterial metabolites namely, siderophore lichenicidin VK21-A1/A2 (95% identity), lichenysin (100%), fengycin (53%), terpenes (100%), bacteriocin (100%), Lasso peptide (95%) and bacillibactin (53%). In conclusion, metagenomic nanopore sequence analysis of soil samples coupled with conventional screening helped identify B. haynesii isolate MZ922052 harboring seven biosynthetic gene clusters of promising antimicrobial metabolites. This is the first report for identifying the bacteriocin, lichenysin, and fengycin biosynthetic gene clusters in B. haynesii MZ922052.

Nonphytotoxic and pH-responsive ZnO-ZIF‑8 loaded with honokiol as a “nanoweapon” effectively controls the soil-borne bacterial pathogen Ralstonia solanacearum

The development of intelligently released and environmentally safe nanocarriers not only aligns with the sustainable agricultural strategy but also offers a potential solution for controlling severe soil-borne bacterial diseases. Herein, the core-shell structured nanocarrier loaded with honokiol bactericide (honokiol@ZnO-ZIF-8) was synthesized via a one-pot method for the targeted control of Ralstonia solanacearum, the causative agent of tobacco bacterial wilt disease. Results indicated that honokiol@ZnO-ZIF-8 nanoparticles induced bacterial cell membrane and DNA damage through the production of excessive reactive oxygen species (ROS), thereby reducing bacterial cell viability and ultimately leading to bacterial death. Additionally, the dissociation mechanism of the nanocarriers was elucidated for the first time through thermodynamic computational simulation. The nanocarriers dissociate primarily due to H+ attacking the N atom on imidazole, causing the rupture of the Zn-N bond under acidic conditions and at room temperature. Furthermore, honokiol@ZnO-ZIF-8 exhibited potent inhibitory effects against other prominent Solanaceae pathogenic bacteria (Pseudomonas syringae pv. tabaci), demonstrating its broad-spectrum antibacterial activity. Biosafety assessment results indicated that honokiol@ZnO-ZIF-8 exhibited non-phytotoxicity towards tobacco and tomato plants, with its predominant accumulation in the roots and no translocation to aboveground tissues within a short period. This study provides potential application value for the intelligent release of green pesticides. Environment implicationThe indiscriminate use of agrochemicals poses a significant threat to environmental, ecological security, and sustainable development. Slow-release pesticides offer a green and durable strategy for crop disease control. In this study, we developed a non-phytotoxic and pH-responsive honokiol@ZnO-ZIF-8 nano-bactericide based on the pathogenesis of Ralstonia solanacearum. Thermodynamic simulation revealed the dissociation mechanism of ZIF-8, with different acidity controlling the dissociation rate. This provides a theoretical basis for on-demand pesticide release while reducing residue in the. Our findings provide strong evidence for effective soil-borne bacterial disease control and on-demand pesticide release.

A novel antimicrobial peptide Spasin141-165 identified from Scylla paramamosain exhibiting protection against Aeromonas hydrophila infection

Aeromonas hydrophila is a widely distributed Gram-negative waterborne pathogen responsible for large-scale outbreaks of hemorrhagic septicemia in fish, causing severe economic losses to the global aquaculture industry. In view of few therapeutic drugs currently available for use in aquaculture and the emergence of multidrug-resistant A. hydrophila, there is an urgent need to develop new antimicrobial agents as an alternative to antibiotics. Antimicrobial peptides (AMPs) have strong antimicrobial effects and unique machanisms of action, and are not easy to induce bacterial resistance, making them an ideal alternative to antibiotics. In this study, we identified a new functional gene from marine crab Scylla paramamosain, named Spasin, which encodes a mature peptide of 240 amino acids and expressed widely in various tissues of crabs. Notably, a truncated peptide Spasin141–165 derived from Spasin, showed potent and broad-spectrum antibacterial and antifungal activity at minimum inhibitory concentrations (MICs) ranged from 0.75 μM–48 μM, which is a novel AMP. It effectively killed S. aureus and A. baumannii within 2 h and 90 min, respectively. Importantly, it is not toxic to HEK-293 T, RAW 264.7, and ZF4 cell lines. Mechanistic studies showed that addition of 8 μg mL−1 lipoteichoic acid or lipopolysaccharides decreased bacterial susceptibility to Spasin141–165. In addition, Spasin141–165 altered the permeability of the inner and outer cell membranes, and resulted in the release of ATP and the accumulation of intracellular reactive oxygen species. Notably, Spasin141–165 significantly increased the survival rate of zebrafish infected with A. hydrophila, redcued the bacterial load in the spleen, and effectively inhibited the expression of inflammation-associated factors (e.g., IL-1β, TNF-α, etc.). Taken together, Spasin141–165 is a potential antibacterial agent for the treatment of A. hydrophila infections in aquaculture and a promising antibiotic alternative.

Antibacterial, Phytochemical and Toxicological Activities of Garcinia kola Extracts against Multidrug Resistant Clinical Bacteria

Objective: The rise in multiple antibiotic resistant microorganisms has led to a decline in the efficacy of many antibiotics, prompting the investigation of alternative solutions such as medicinal plants. To tackle this concerning issue, this study was undertaken to evaluate the phytochemical composition, antibacterial activity, and toxicological characteristics of Garcinia kola extracts against multidrug-resistant bacteria commonly found in clinical settings. Material-Method: The cold maceration technique was employed to extract the root and leaf of Garcinia kola using water and methanol. The extracts were then subjected to phytochemical screening. To evaluate the extracts' potential to inhibit bacterial growth, five multidrug-resistant isolates were utilized in this study. Agar well assay was used to determine the zones of inhibition. The Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) were determined using the broth macro dilution technique. Additionally, Brine shrimp lethality assay was conducted to determine the lethal concentration (LC50) of the extracts. The extracts were also combined for synergism. Results: The investigation found that the root extract in methanol had the highest yield at 25.58%. All four extracts contained ten out of the fourteen tested phytochemicals. The methanol leaf and root extracts exhibited the highest and lowest inhibition zones of 20mm and 9mm against Staphylococcus aureus, respectively. The MIC values ranged from 250 to 600 mg/ml, indicating broad-spectrum antibacterial activity. The cytotoxicity test showed a range of 33.03 to 126.3µg/mL for the aqueous and methanol extracts. Conclusion: Although Garcinia kola shows potential as a source of antibacterial compounds, caution should be exercised due to its toxic effects.

Sprayable biogenic Ag-collagen nanocomposites with potent antibacterial and antibiofilm activity for Acinetobacter baumannii infected wound healing under hyperglycemic condition

Owing to their susceptibility to infection by drug-resistant bacteria, refractory wounds pose a formidable risk to the well-being of patients with diabetes and other immune-compromised conditions, and their management poses significant economic distress to the healthcare system, particularly in low and middle-income countries. Therefore, deployable interventions for rapid and effective management of such wounds are needed. In the present study, we report the processing of sprayable biogenic Ag-collagen nanocomposites (Ag-Col NCs) with cogent antibacterial and healing activity in Acinetobacter baumannii infected wounds under hyperglycemic conditions. Silver nanoparticles (Ag NPs) has been synthesized by using the plant extract of Urginea indica (U. indica), which was further used for the processing of Ag-Col NCs. Synthesized NCs were found to have notable broad spectrum antibacterial activity against clinically significant strains (Acinetobacter baumannii, Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus) and appreciable biocompatibility towards RAW 264.7 and 3 T3 mouse fibroblast cell lines. The sprayable NC system was found to promote the wound healing activity in mouse model (Balb/c) not only in normal but also in hyperglycemic conditions. Our experimental findings suggest the potential of the Ag-Col NC spray in chronic wound management and an exploitable option in both clinical and personalized settings.

Antibacterial Polyketides from the Deep-Sea Cold-Seep-Derived Fungus Talaromyces sp. CS-258.

Thirty-two fungal polyketide derivatives, including eleven new compounds, namely (3R,5'R)-5-hydroxytalaroflavone (1), talaroisochromenols A-C (3, 5, and 11), (8R,9R,10aR)-5-hydroxyaltenuene (13), (8R,9R,10aS)-5-hydroxyaltenuene (14), (8R,9S,10aR)-5-hydroxyaltenuene (15), nemanecins D and E (25 and 26), 2,5-dimethyl-8-iodochromone (27), and talarofurolactone A (29), together with one new naturally occurring but previously synthesized metabolite, 6-hydroxy-4-methoxycoumarin (28), were isolated and identified from the deep-sea cold-seep-derived fungus Talaromyces sp. CS-258. Among them, racemic ((±)-11) or epimeric (13-15, 25, and 26) mixtures were successfully separated by chiral or gradient elution HPLC. Meanwhile, compound 27 represents a rarely reported naturally occurring iodinated compound. Their planar structures as well as absolute configurations were determined by extensive analysis via NMR, MS, single-crystal X-ray diffraction, Mosher's method, and ECD or NMR calculation (with DP4+ probability analysis). Possible biosynthetic routes of some isolated compounds, which are related to chromone or isochromone biosynthetic pathways, were put forward. The biological analysis results revealed that compounds 7, 9, 10, 18-22, 24, 30, and 31 showed broad-spectrum antibacterial activities against several human and aquatic pathogens with MIC ranges of 0.5-64 μg/mL.

Membrane-Active All-Hydrocarbon-Stapled α-Helical Amphiphilic Tat Peptides: Broad-Spectrum Antibacterial Activity and Low Incidence of Drug Resistance.

Multidrug resistance against conventional antibiotics has dramatically increased the difficulty of treatment and accelerated the need for novel antibacterial agents. The peptide Tat (47-57) is derived from the transactivating transcriptional activator of human immunodeficiency virus 1, which is well-known as a cell-penetrating peptide in mammalian cells. However, it is also reported that the Tat peptide (47-57) has antifungal activity. In this study, a series of membrane-active hydrocarbon-stapled α-helical amphiphilic peptides were synthesized and evaluated as antibacterial agents against Gram-positive and Gram-negative bacteria, including multidrug-resistant strains. The impact of hydrocarbon staple, the position of aromatic amino acid residue in the hydrophobic face, the various types of aromatic amino acids, and the hydrophobicity on bioactivity were also investigated and discussed in this study. Among those synthesized peptides, analogues P3 and P10 bearing a l-2-naphthylalanine (Φ) residue at the first position and a Tyr residue at the eighth position demonstrated the highest antimicrobial activity and negligible hemolytic toxicity. Notably, P3 and P10 showed obviously enhanced antimicrobial activity against multidrug-resistant bacteria, low drug resistance, high cell selectivity, extended half-life in plasma, and excellent performance against biofilm. The antibacterial mechanisms of P3 and P10 were also preliminarily investigated in this effort. In conclusion, P3 and P10 are promising antimicrobial alternatives for the treatment of the antimicrobial-resistance crisis.

Enzyme-Triggered Polyelectrolyte Complex for Responsive Delivery of α-Helical Polypeptides to Optimize Antibacterial Therapy.

Responsive nanomaterials hold significant promise in the treatment of bacterial infections by recognizing internal or external stimuli to achieve stimuli-responsive behavior. In this study, we present an enzyme-responsive polyelectrolyte complex micelles (PTPMN) with α-helical cationic polypeptide as a coacervate-core for the treatment of Escherichia coli (E. coli) infection. The complex was constructed through electrostatic interaction between cationic poly(glutamic acid) derivatives and phosphorylation-modified poly(ethylene glycol)-b-poly(tyrosine) (PEG-b-PPTyr) by directly dissolving them in aqueous solution. The cationic polypeptide adopted α-helical structure and demonstrated excellent broad-spectrum antibacterial activity against both Gram-negative and Gram-positive bacteria, with a minimum inhibitory concentration (MIC) as low as 12.5 μg mL-1 against E. coli. By complexing with anionic PEG-b-PPTyr, the obtained complex formed β-sheet structures and exhibited good biocompatibility and low hemolysis. When incubated in a bacterial environment, the complex cleaved its phosphate groups triggered by phosphatases secreted by bacteria, exposing the highly α-helical conformation and restoring its effective bactericidal ability. In vivo experiments confirmed accelerated healing in E. coli-infected wounds.

Zinc oxide nanoparticles mediate bacterial toxicity in Mueller-Hinton Broth via Zn2.

As antibiotic resistance increases and antibiotic development dwindles, new antimicrobial agents are needed. Recent advances in nanoscale engineering have increased interest in metal oxide nanoparticles, particularly zinc oxide nanoparticles, as antimicrobial agents. Zinc oxide nanoparticles are promising due to their broad-spectrum antibacterial activity and low production cost. Despite many studies demonstrating the effectiveness of zinc oxide nanoparticles, the antibacterial mechanism is still unknown. Previous work has implicated the role of reactive oxygen species such as hydrogen peroxide, physical damage of the cell envelope, and/or release of toxic Zn2+ ions as possible mechanisms of action. To evaluate the role of these proposed methods, we assessed the susceptibility of S. aureus mutant strains, ΔkatA and ΔmprF, to zinc oxide nanoparticles of approximately 50 nm in size. These assays demonstrated that hydrogen peroxide and electrostatic interactions are not crucial for mediating zinc oxide nanoparticle toxicity. Instead, we found that Zn2+ accumulates in Mueller-Hinton Broth over time and that removal of Zn2+ through chelation reverses this toxicity. Furthermore, we found that the physical separation of zinc oxide nanoparticles and bacterial cells using a semi-permeable membrane still allows for growth inhibition. We concluded that soluble Zn2+ is the primary mechanism by which zinc oxide nanoparticles mediate toxicity in Mueller-Hinton Broth. Future work investigating how factors such as particle morphology (e.g., size, polarity, surface defects) and media contribute to Zn2+ dissolution could allow for the synthesis of zinc oxide nanoparticles that possess chemical and morphological properties best suited for antibacterial efficacy.

Fabrication and antimicrobial properties of novel meropenem-honey encapsulated chitosan nanoparticles against multiresistant and biofilm-forming Staphylococcus aureus as a new antimicrobial agent.

Honey exhibits a broad spectrum of antibacterial activity against Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) ones. Chitosan (Cs) is a mucoadhesive polymer that also has antibacterial properties. Special attention has been paid to the design of polymeric nanoparticles (NPs) as new nano drug delivery systems to overcome bacterial resistance and its problems. The aim of the present study is to synthesize Cs-meropenem NPs with/without honey as an antibiofilm and antibacterial agent to inhibit Staphylococcus aureus. This study synthesized meropenem and honey-loaded Cs nanogels and subsequently characterized them by Field Emission Scanning Electron Microscopy (FESEM), Fourier Transform Infrared Spectroscopy (FTIR), and DLS-zeta potential. Using the broth microdilution and crystal violet assays, the antibacterial and antibiofilm activity of meropenem and honey-loaded Cs nanogel, free meropenem, free honey, and free Cs NPs were investigated in vitro against MRSA strains. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) was also used to test the cytotoxicity of several Cs-NPs compound against the HEK-293 regular cell line. The average size of meropenem and honey-Cs-NPs was reported to be 119.885nm, and encapsulation efficiency was 88.33 ± 0.97 with stability up to 60 days at 4°C. The NPs showed enhanced antibiofilm efficacy against S. aureus at sub-minimum inhibitory concentrations. Additionally, the cytotoxicity of meropenem and honey-encapsulated Cs against the HEK-293 normal cell line was insignificant. Our findings suggested that meropenem and honey-Cs-NPs might be potential antibacterial and antibiofilm materials.

Bactericidal Permeability-Increasing Protein (BPI) Inhibits Mycobacterium tuberculosis Growth.

Bactericidal permeability-increasing protein (BPI) is a multifunctional cationic protein produced by neutrophils, eosinophils, fibroblasts, and macrophages with antibacterial anti-inflammatory properties. In the context of Gram-negative infection, BPI kills bacteria, neutralizes the endotoxic activity of lipopolysaccharides (LPSs), and, thus, avoids immune hyperactivation. Interestingly, BPI increases in patients with Gram-positive meningitis, interacts with lipopeptides and lipoteichoic acids of Gram-positive bacteria, and significantly enhances the immune response in peripheral blood mononuclear cells. We evaluated the antimycobacterial and immunoregulatory properties of BPI in human macrophages infected with Mycobacterium tuberculosis. Our results showed that recombinant BPI entered macrophages, significantly reduced the intracellular growth of M. tuberculosis, and inhibited the production of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Furthermore, BPI decreased bacterial growth directly in vitro. These data suggest that BPI has direct and indirect bactericidal effects inhibiting bacterial growth and potentiating the immune response in human macrophages and support that this new protein's broad-spectrum antibacterial activity has the potential for fighting tuberculosis.

Antimicrobial and Probiotic Potential of Lactobacilli Associated with Traditional Fermented Beverages.

Fermented foods have been recognized as a source of probiotic bacteria which can have a positive effect when administered to humans and animals. Discovering new probiotics in fermented food products poses a global economic and health importance. In this study, we investigated the antimicrobial and probiotic potential of lactobacilli isolated from fermented beverages produced traditionally by ethnic groups in Northeast India. Out of thirty Lactobacilli, fifteen exhibited strong antimicrobial activity against Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter aerogenes with significant anti-biofilm and anti-quorum sensing activity. These isolates also showed characteristics associated with probiotic properties, such as tolerance to low pH and bile salts, survival in the gastric tract, auto-aggregation, and hydrophobicity without exhibiting hemolysis formation or resistance to certain antibiotics. The isolates were identified using gram staining, biochemical tests, and 16S rDNA sequencing. They exhibited probiotic potential, broad-spectrum of antibacterial activity, promising anti-biofilm, anti-quorum sensing activity, non-hemolytic, and tolerance to acidic pH and bile salts. Overall, four specific Lactobacillus isolates, Lactiplantibacillus plantarum BRD3A and Lacticaseibacillus paracasei RB10OW from fermented rice-based beverage, and Lactiplantibacillus plantarum RB30Y and Lacticaseibacillus paracasei MP11A from traditional local curd demonstrated potent antimicrobial and probiotic properties. These findings suggest that these lactobacilli isolates from fermented beverages have the potential to be used as probiotics with therapeutic benefits, highlighting the importance of traditional fermented foods for promoting gut health and infectious disease management.