UiO-66/AgNPs Coating for Dental Implants in Preventing Bacterial Infections.

Titanium (Ti)-based biomaterials lack inherent antimicrobial activities, and the dental plaque formed on the implant surface is one of the main risk factors for implant infections. Construction of an antibacterial surface can effectively prevent implant infections and enhance implant success. Silver nanoparticles (AgNPs) exhibit broad antibacterial activity and a low tendency to induce drug resistance, but AgNPs easily self-aggregate in the aqueous environment, which significantly impairs their antibacterial activity. In this study, UiO-66/AgNP (U/A) nanocomposite was prepared, where zirconium metal-organic frameworks (UiO-66) were employed as the confinement matrix to control the particle size and prevent aggregation of AgNPs. The bactericidal activity of U/A against methicillin-resistant Staphylococcus aureus and Escherichia coli increased nearly 75.51 and 484.50 times compared with individually synthesized Ag. The antibacterial mechanism can be attributed to the enhanced membrane rupture caused by the ultrafine AgNPs on UiO-66, leading to protein leakage and generation of intracellular reactive oxygen species. Then, U/A was loaded onto Ti substrates (Ti-U/A) by using self-assembly deposition methods to construct an antibacterial surface coating. Ti-U/A exhibited excellent antibacterial activities and desired biocompatibility both in vitro and in vivo. The U/A nanocomposite coating technique is thus expected to be used as a promising surface modification strategy for Ti-based dental implants for preventing dental implant infections.

Bioisosteric replacement strategy leads to novel DNA gyrase B inhibitors with improved potencies and properties.

The identification of novel 4-hydroxy-2-quinolone-3-carboxamide antibacterials with improved properties is of great value for the control of antibiotic resistance. In this study, a series of N-heteroaryl-substituted 4-hydroxy-2-quinolone-3-carboxamides were developed using the bioisosteric replacement strategy. As a result of our research, we discovered the two most potent GyrB inhibitors (WBX7 and WBX18), with IC50 values of 0.816 µM and 0.137 µM, respectively. Additional antibacterial activity screening indicated that WBX18 possesses the best antibacterial activity against MRSA, VISA, and VRE strains, with MIC values rangingbetween0.5and 2 µg/mL, which was 2 to over 32 times more potent than that of vancomycin. In vitro safety and metabolic stability, as well as in vivo pharmacokinetics assessments revealed that WBX18 is non-toxic to HUVEC and HepG2, metabolically stable in plasma and liver microsomes (mouse), and displays favorable in vivo pharmacokinetic properties. Finally, docking studies combined with molecular dynamic simulation showed that WBX18 could stably fit in the active site cavity of GyrB.

Alginate and Chitosan-Based Hydrogel Enhance Antibacterial Agent Activity on Topical Application.

Untreated topical infections can become chronic, posing serious health issues. Optimal skin adherence is crucial in addressing such infections. In this context, chitosan and alginate emerge as promising candidates for use as a foundation in the development of topical hydrogels. The aim of this review is to examine the literature on topical hydrogel formulations that use chitosan and alginate as foundations, specifically in the context of topical antibacterial agents. The research methodology involves a literature review by examining articles published in databases such as PubMed, Scopus, ScienceDirect, and Google Scholar. The keywords employed during the research were "Alginate", "Chitosan", "Hydrogel", and "Antibacterial". Chitosan and alginate serve as bases in topical hydrogels to deliver various active ingredients, particularly antibacterial agents, as indicated by the search results. Both have demonstrated significant antibacterial effectiveness, as evidenced by a reduction in bacterial colony counts and an increase in inhibition zones. This strongly supports the idea that chitosan and alginate could be used together to make topical hydrogels that kill bacteria that work well. In conclusion, chitosan and alginate-based hydrogels show great potential in treating bacterial infections on the skin surface. The incorporation of chitosan and alginate into hydrogel formulations aids in retaining antibacterial agents, allowing for their gradual release over an optimal period. Therefore, hydrogels specifically formulated with chitosan and alginate have the potential to serve as a solution to address challenges in the treatment of topical bacterial infections.

Comparative evaluation of antimicrobial efficacy of triple antibiotic paste and amoxicillin clavulanate paste as an intracanal medicament against Enterococcus faecalis: An in vitro study.

Background: Triple antibiotic paste (TAP) is the commonly used intracanal medicament against Enterococcus faecalis. Amoxicillin clavulanate paste (ACP) is recommended as a "fall-back" antibiotic when traditional dental antibiotics fail. Literature comparing the antimicrobial efficacy of TAP and ACP in eradicating E. faecalis from the root canal system is sparse; hence, this in vitro study was conducted to evaluate and compare the antimicrobial efficacy of TAP and ACP as an intracanal medicament for endodontic treatment of single-rooted permanent teeth against E. faecalis. Materials and Methods: This in vitro, experimental study evaluated 60 root samples obtained from extracted single-rooted human permanent teeth. The canal diameter was enlarged and subsequently infected with E. faecalis for 21 days. Four groups of the contaminated samples were treated with TAP, ACP, calcium hydroxide (positive control), and saline (negative control), respectively. Dentinal shavings were collected at the end of the 1st, 7th, and 10th day and inoculated in agar plates. The number of colony-forming units was determined, and the data were statistically analyzed using the Kolmogorov-Smirnov and Shapiro-Wilks test. P <0.05 was considered statistically significant. Results: The mean number of E. faecalis colony counts across all 3 test days demonstrated that TAP exhibited the highest inhibition of bacterial growth, followed by ACP which is not statistically significant (P = 1.00). Conclusion: Considering the limitations of this in vitro study, the findings suggest that ACP could be an effective alternative intracanal medicament to TAP for endodontic therapy.

Untargeted metabolomics uncovers prime pathways linked to antibacterial action of citral against bacterial vaginosis-causing Gardnerella vaginalis: An in vitro and in vivo study.

Global increase in recurrence of bacterial vaginosis (BV) and worrisome rise in antimicrobial resistance pose an urgent call for new/novel antibacterial agents. In light of the circumstance, the present study demonstrates the in vitro and in vivo antibacterial activity of a phytochemical citral, with a particular emphasis to elucidate its mechanistic action against Gardnerella vaginalis -a potential cause of BV. Out of 21 phytochemicals screened initially against G. vaginalis, citral was envisaged to be a phenomenal antibacterial agent showing MIC and MBC at 128 µg/mL. Citral's rapid killing ability was revealed by a time-killing kinetics assay supported by CFU, signifying that it completely killed the given inoculum of planktonic G. vaginalis cells within 60 min. Further, citral was found to exhibit 1 min contact-killing efficacy together with mature-biofilm disintegrating ability at increasing MICs. To further understand the molecular action of citral, in vitro investigations such as ROS estimation, PI staining and intracellular protein release assay were performed, which demonstrated that citral deteriorated the membrane integrity of G. vaginalis. Galleria mellonella, a simple invertebrate model used to evaluate citral's non-toxic and antibacterial activity in vivo, demonstrates that citral completely restored the larvae from G. vaginalis infection. The metabolite level investigation using LC-MS revealed that citral had negative impact on biotin metabolism (via., biotin), spermidine metabolism (via., 5'-methylthioadenosine and spermidine) and nucleotide metabolism (via., guanine, adenine and uridine). Since that biotin is associated with seven different metabolic pathways, it is conceivable that citral could target biotin biosynthesis or its metabolism and as a result, disrupt other metabolic pathways, such as lipid and fatty acid synthesis, which is essential for the creation of cell membranes. Thus, the current study is the first of its kind to delineate the promising in vitro and in vivo antibacterial efficacy of citral and decipher its plausible antibacterial action mechanism through metabolomic approach, which concomitantly emphasizes citral as a viable natural therapeutic alternative to manage and control BV.

Isolation and Characterization of a Novel Virulent Phage ASG01 of Aeromonas salmonicida and Its Cell Wall Hydrolase Activity.

Aeromonas salmonicida is an important pathogen that causes furunculosis in trout and salmon with high morbidity and mortality, resulting in significant economic losses in aquaculture. Overuse of antibiotics has led to the continuous emergence of drug-resistant strains. Hence, there is an urgent need to find an alternative environmentally friendly antimicrobial agent. In this study, we isolated a virulent phage of A. salmonicida, named ASG01, which belongs to the Myoviridae family and maintains lytic activity at a pH value range from 4 to 12 and in the temperature range from 30 °C to 60 °C. The whole genomic sequence of ASG01 showed 82% similarity to Aeromonas phage pAh6-C. The cell wall hydrolase (Cwh)-encoding gene from the genome of ASG01 was predicted and heterologously expressed. Notably, in the absence of additional phage genes, endogenous expression of Cwh could lyse E. coli cells and greatly inhibit the growth of tested fish pathogenic bacteria. The lytic activity of Cwh was eliminated when the predicted active site was mutated. These results indicate that Cwh of ASG01 possessed excellent lytic activity and a wide antibacterial spectrum, suggesting its potential as an effective enzybiotic.

Xenomyrothecium tongaense PTS8: a rare endophyte of Polianthes tuberosa with salient antagonism against multidrug-resistant pathogens.

Introduction: Endophytes refer to microorganisms residing within the endosphere of plants, particularly perennials, without inflicting noticeable injury or inducing obvious morphological variations to their host plant or host organism. Endophytic fungi, although often overlooked microorganisms, have garnered interest due to their significant biological diversity and ability to produce novel pharmacological substances. Methods: In this study, fourteen endophytic fungi retrieved were from the stem of the perennial plant Polianthes tuberosa of the Asparagaceae family. These fungal crude metabolites were tested for antagonistic susceptibility to Multi-Drug Resistant (MDR) pathogens using agar well diffusion, Minimum Inhibitory Concentration (MIC), and Minimum Bactericidal Concentration (MBC) assays. The chequerboard test was used to assess the synergistic impact of active extract. Results and discussion: In early antibacterial screening using the Agar plug diffusion test, three of fourteen endophytes demonstrated antagonism against Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococcus (VRE). Three isolates were grown in liquid medium and their secondary metabolites were recovered using various organic solvents. Eight extracts from three endophytic fungi displayed antagonism against one or more human pathogens with diameters ranging from 11 to 24 mm. The highest antagonistic effect was obtained in ethyl acetate extract for PTS8 isolate against two MRSA (ATCC 43300, 700699) with 20 ± 0.27 and 22 ± 0.47 mm zones of inhibition, respectively, among different solvent extracts. The extract had MICs of 3.12 ± 0.05 and 1.56 ± 0.05 µg/mL, and MBCs of 50 ± 0.01 and 12.5 ± 0.04 µg/mL, respectively. Antagonism against VRE was 18 ± 0.23 mm Zone of Inhibition (ZOI) with MIC and MBC of 6.25 ± 0.25 and 25 ± 0.01 µg/mL. When ethyl acetate extract was coupled with antibiotics, the chequerboard assay demonstrated a synergistic impact against MDR bacteria. In an antioxidant test, it had an inhibitory impact of 87 ± 0.5% and 88.5 ± 0.5% in 2,2-Diphenyl-1-Picrylhydrazyl and reducing power assay, respectively, at 150 µg/mL concentration. PTS8 was identified as a Xenomyrothecium tongaense strain by 18S rRNA internal transcribed spacer (ITS) sequencing. To our insight, it is the foremost study to demonstrate the presence of an X. tongaense endophyte in the stem of P. tuberosa and the first report to study the antibacterial efficacy of X. tongaense which might serve as a powerful antibacterial source against antibiotic-resistant human infections.

Antimicrobial cetylpyridinium chloride causes functional inhibition of mitochondria as potently as canonical mitotoxicants, nanostructural disruption of mitochondria, and mitochondrial Ca2+ efflux in living rodent and primary human cells.

People are exposed to high concentrations of antibacterial agent cetylpyridinium chloride (CPC) via food and personal care products, despite little published information regarding CPC effects on eukaryotes. Here, we show that low-micromolar CPC exposure, which does not cause cell death, inhibits mitochondrial ATP production in primary human keratinocytes, mouse NIH-3T3 fibroblasts, and rat RBL-2H3 immune mast cells. ATP inhibition via CPC (EC50 1.7 µM) is nearly as potent as that caused by canonical mitotoxicant CCCP (EC50 1.2 µM). CPC inhibition of oxygen consumption rate (OCR) tracks with that of ATP: OCR is halved due to 1.75 µM CPC in RBL-2H3 cells and 1.25 µM in primary human keratinocytes. Mitochondrial [Ca2+] changes can cause mitochondrial dysfunction. Here we show that CPC causes mitochondrial Ca2+ efflux from mast cells via an ATP-inhibition mechanism. Using super-resolution microscopy (fluorescence photoactivation localization) in live cells, we have discovered that CPC causes mitochondrial nanostructural defects in live cells within 60 min, including the formation of spherical structures with donut-like cross section. This work reveals CPC as a mitotoxicant despite widespread use, highlighting the importance of further research into its toxicological safety.

[Research progress of antibacterial hydrogel in treatment of infected wounds].

Objective: To review the research progress of new antibacterial hydrogels in the treatment of infected wounds in the field of biomedicine, in order to provide new methods and ideas for clinical treatment of infected wounds. Methods: The research literature on antibacterial hydrogels at home and abroad was extensively reviewed in recent years, and the antibacterial hydrogels for the treatment of infected wounds were classified and summarized. Results: Antibacterial hydrogels can be divided into three categories: inherent antibacterial hydrogels, antibacterial agent release hydrogels, and environmental response antibacterial hydrogels. The advantages and disadvantages of antibacterial materials, antibacterial mechanism, antibacterial ability, and biocompatibility were discussed respectively. Inherent antibacterial hydrogels have the characteristics of wide source, low cost, and simple preparation, but their antibacterial ability is relatively weak. New antimicrobial substances are added to antibacterial agent release hydrogels, such as antimicrobial peptides, metal ions, graphene materials, etc., providing a new therapeutic strategy for alternative antibiotic therapy. On the basis of the antibacterial material, environmental promoting factors such as photothermal effect, pH value, and magnetic force are added to the environmental response antibacterial hydrogels, which synergically enhances the antibacterial ability of the hydrogel, improves the precise regulation function and bionic effect of the hydrogel. Conclusion: The selection of a variety of materials, the addition of a variety of antibacterial agents, and the effect of various promoting factors make composite hydrogels show multiple characteristics. The development of antibacterial hydrogels that can effectively address practical clinical applications remains a significant challenge. In the future, expanding the application range of antibacterial hydrogels, constructing drug-loaded hydrogels, and developing intelligent hydrogels are still new areas that need to be explored and studied.

Antibacterial activity of plant-derived compounds and cream formulations against canine skin bacteria.

An urgent need to find alternative antimicrobial compounds effective in the prevention and treatment of skin infections led us to study the inhibitory activity of eight plant-derived bioactive compounds (betulin, curcumin, glycyrrhizic acid, guaiazulene, piperine, quercetin, quinine, tannic acid) against 14 canine skin isolates (11 Gram-positive and three Gram-negative bacteria) selected based on antibiotic resistance and virulence features. The minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) were determined using the broth microdilution method. In detail, the results for the eight different plant compounds showed their inhibitory activity in the concentration range from 0.04 to more than 16 mg/ml (MIC) and from 0.25 to more than 16 mg/ml (MBC). The most potent compounds appear to be tannic acid, followed by quinine and curcumin (MIC 0.04-16.0 mg/ml). The most susceptible strain to the tested agents in general was Bacillus cereus AE13, while Enterococcus faecium AA14 was the most resistant strain (the highest MICs) among the tested bacteria. The two most potent plant-derived compounds (tannic acid and quinine) were tested in mixture in different ratios (1:1, 1:2, 2:1). The lowest MIC and MBC values were observed for the 1:2 ratio, which was used for preparation of creams with different cream bases. One of the cream formulations (cream F) was effective up to 63.0 mg/ml (MIC) with a microbial inactivation time of 1-6 h according to the tested strain. This study provides evidence that some plant-derived compounds could have an antimicrobial effect against canine skin bacteria, the strength of which is bacterial strain dependent.

Green synthesis of tellurium-doped SnO2 nanoparticles with sulfurized g-C3 N4 : Insights into methylene blue photodegradation and antibacterial capability.

The construction of SnO2 nanoparticles (NPs), specifically Te-doped SnO2 NPs, using a simple and economical co-precipitation technique has been thoroughly described in this work. NH3 served as the reducing agent in this procedure, whilst polyethylene glycol served as the capping agent. The primary goals of our work were to investigate the physicochemical properties of the synthesized SnO2 NPs and assess their potential use as antibacterial agents and photocatalysts. Scanning electron microscopy-energy dispersive X-ray, ultraviolet light, Fourier transform infrared spectroscopy, X-ray diffraction (XRD), and other analytical techniques were used to thoroughly analyze the NPs. Based on the full width at half maximum of the most noticeable peaks in the XRD spectrum, the Debye-Scherrer equation was used to calculate the crystallite sizes, which indicated the presence of a single tetragonal SnO2 phase. Particularly noteworthy was the exceptional photocatalytic activity of graphene-assisted Te-doped SnO2 NPs, achieving an impressive decomposition efficiency of up to 98% in the photo-oxidation of methylene blue. Furthermore, our investigation delved into the antibacterial attributes of the synthesized SnO2 NPs against Escherichia coli and Staphylococcus aureus, demonstrating inhibitory effects on both bacteria strains. This suggests potential applications for these NPs in various environmental and medical contexts.

Antibacterial and Anti-Biofilm Efficacy of Endolysin LysAB1245 against a Panel of Important Pathogens.

Infections caused by antibiotic-resistant bacteria pose a significant global challenge. This study explores the antibacterial effects of a bacteriophage-derived endolysin, LysAB1245, against important pathogens, including Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. We determined the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) for all tested isolates. A time-kill study was conducted to evaluate the reduction in bacterial survival following treatment with LysAB1245. Additionally, the effects of LysAB1245 on P. aeruginosa K1455 and methicillin-resistant S. aureus (MRSA) NPRC 001R-formed biofilms were investigated. The MIC and MBC of LysAB1245 against all the tested isolates ranged from 4.68 to 9.36 µg/mL and 4.68 to 18.72 µg/mL, respectively. The time-kill study demonstrated more than a 4 log CFU/mL (99.99%) reduction in bacterial survival within 6 h of LysAB1245 treatment at 2MIC. LysAB1245 (1/8-1/2MIC) treatment significantly reduced biofilms formed by P. aeruginosa and MRSA in a concentration-dependent manner. Furthermore, scanning electron and confocal laser scanning microscopy confirmed the potential inhibition effects on 3-day established biofilms formed on abiotic surfaces upon treatment with LysAB1245 at 2MIC. The findings indicate that endolysin LysAB1245 could be employed as a new alternative therapeutic antibacterial and anti-biofilm agent for combating biofilm-related infections.

Effective ciprofloxacin cationic antibacterial agent against persister bacteria with low hemolytic toxicity.

With the widespread use of antibiotics, bacterial resistance has developed rapidly. To make matters worse, infections caused by persistent bacteria and biofilms often cannot be completely eliminated, which brings great difficulties to clinical medication. In this work, three series of quinolone pyridinium quaternary ammonium small molecules were designed and synthesized. Most of the compounds showed good antibacterial activity against Gram-positive bacteria (S. aureus and E. faecalis) and Gram-negative bacteria (E. coli and S. maltophilia). The activity of the para-pyridine quaternary ammonium salt was better than that of the meta-pyridine. 3f was the optimal compound with good stability in body fluids and was unlikely to induce bacterial resistance. The hemolysis rate of erythrocytes at 1280 µg/mL for 3f was only 5.1%. Encouragingly, 3f rapidly killed bacteria within 4 h at 4 × MIC concentration and was effective in killing persistent bacteria in biofilms. The antibacterial mechanism experiments showed that 3f could cause disorder of bacterial membrane potential, increase bacterial membrane permeability, dissolve and destroy the membrane. Incomplete bacterial membranes lead to leakage of bacterial genetic material, concomitant production of ROS, and bacterial death due to these multiple effects.

Nanozyme-based inulin@nanogold for adhesive and antibacterial agent with enhanced biosafety.

Nanozymes with oxidase or peroxidase-mimicking activity have emerged as a promising alternative for disinfecting resistant pathogens. However, further research and clinical applications of nanozymes are hampered by their low in vivo biosafety and biocompatibility. In this study, inulin-confined gold nanoparticles (IN@AuNP) are synthesized as an antibacterial agent via a straightforward in situ reduction of Au3+ ions by the hydroxyl groups in inulin. The IN@AuNP exhibits both peroxidase-mimicking and oxidase-mimicking catalytic activities, of which the maximum reaction velocity (Vmax) for H2O2 is 2.66 times higher than that of horseradish peroxidase. IN@AuNP can catalyze the production of reactive oxygen species (ROS), resulting in effective antibacterial behavior against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria. Abundant hydroxyl groups retained in inulin endow the nanozyme with high adhesion to bacteria, reducing the distance between the captured bacteria and ROS, achieving an antibacterial ratio of 100 % within 1 h. Importantly, due to the natural biosafety and non-absorption of the dietary fiber inulin, as well as the inability of inulin-trapped AuNP to diffuse, the IN@AuNP exhibits high biosafety and biocompatibility under physiological conditions. This work is expected to open a new avenue for nanozymes with great clinical application value.

Computational Design of Novel Griseofulvin Derivatives Demonstrating Potential Antibacterial Activity: Insights from Molecular Docking and Molecular Dynamics Simulation.

In response to the urgent demand for innovative antibiotics, theoretical investigations have been employed to design novel analogs. Because griseofulvin is a potential antibacterial agent, we have designed novel derivatives of griseofulvin to enhance its antibacterial efficacy and to evaluate their interactions with bacterial targets using in silico analysis. The results of this study reveal that the newly designed derivatives displayed the most robust binding affinities towards PBP2, tyrosine phosphatase, and FtsZ proteins. Additionally, molecular dynamics (MD) simulations underscored the notable stability of these derivatives when engaged with the FtsZ protein, as evidenced by root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and solvent-accessible surface area (SASA). Importantly, this observation aligns with expectations, considering that griseofulvin primarily targets microtubules in eukaryotic cells, and FtsZ functions as the prokaryotic counterpart to microtubules. These findings collectively suggest the promising potential of griseofulvin and its designed derivatives as effective antibacterial agents, particularly concerning their interaction with the FtsZ protein. This research contributes to the ongoing exploration of novel antibiotics and may serve as a foundation for future drug development efforts.

Scirpusin B isolated from Passiflora edulis Var. flavicarpa attenuates carbohydrate digestive enzymes, pathogenic bacteria and oral squamous cell carcinoma.

Passiflora edulis Var. flavicarpa (passion fruit) generates vast waste (60-70%) in the form of peel and seed after the juice extraction. The study aimed to isolate Scirpusin B (SB) from passion fruit (PF) seed waste collected from Northeast India and to analyse its anti-radical, antibacterial, anti-diabetic, and anti-oral cancer activities. Scirpusin B was isolated following hydro-alcoholic extraction, fractionation, and column chromatography. The isolated fraction was further identified through NMR and mass spectroscopy. SB exhibited significant antiradical activity against six standard antioxidant compounds, indicating its commercial application. SB inhibited α-amylase (IC50 Value: 76.38 ± 0.25 µg/mL) and α-glucosidase digestive enzymes (IC50 Value: 2.32 ± 0.04 µg/mL), signifying its antidiabetic properties. In addition, SB showed profound antibacterial activity against eight gram-positive and gram-negative bacteria reported for the first time. Furthermore, SB inhibited SAS and TTN oral cancer cell proliferation up to 95% and 83%, respectively. SB significantly inhibited colonies of SAS and TTn cells in the clonogenic assay, attributing to its anticancer properties. The PI-FACS assay confirmed the ability of SB (75 µM) to kill SAS and TTn cells by 40.26 and 44.3% in 72 h. The mechanism of SB inhibiting oral cancer cell proliferation was understood through western blot analysis, where SB significantly suppressed different cancer hallmark proteins, such as TNF-α, survivin, COX-2, cyclin D1, and VEGF-A. The present study suggests that SB isolated from PF seed can add noteworthy value to the waste biomass for various industrial and medical applications. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03876-6.

Perillaldehyde: A promising antibacterial agent for the treatment of pneumonia caused by Acinetobacter baumannii infection.

Perillaldehyde is a monoterpene compound mainly from the medicinal plant Perilla frutescens (L.) Britt., which has hypolipidemic, antioxidant, antibacterial and anti-inflammatory functions. In this investigation, we discovered that Perillaldehyde had powerful antimicrobial activity against Acinetobacter baumannii 5F1, and its minimum inhibitory concentration was 287.08 µg/mL. A. baumannii is a conditionally pathogenic bacterium with a high clinical resistance rate and is a major source of hospital infections, especially in intensive care units, which is one of the main causes of pneumonia. Inflammatory immune response is characteristic of pneumonia caused by A. baumannii infection. The results of our in vitro experiments indicate that Perillaldehyde disrupts the cell membrane of A. baumannii 5F1 and inhibits its quorum sensing to inhibit biofilm formation, among other effects. With an experimental model of murine pneumonia, we investigated that Perillaldehyde decreased NLRP3 inflammasome activation and TNF-α expression in lung tissues by inhibiting the NF-κB pathway, and also impacted MAPKs protein signaling pathway through the activation of TLR4. Notably, the use of high doses of Perillaldehyde for the treatment of pneumonia caused by A. baumannii 5F1 infection resulted in a survival rate of up to 80 % in mice. In summary, we demonstrated that Perillaldehyde is promising as a new drug for the treatment of pneumonia caused by A. baumannii 5F1 infection.

Therapeutic potential of low-molecular weight lignin model polymer fractions for treating skin lesions in animals: a pilot study.

Bacterial infections and resistance to antibiotics are increasingly severe problems. In recent years, Staphylococcus species have emerged as important pathogens in animals and humans. Current therapeutic methods against these species have serious disadvantages; therefore new agents with antibacterial potential, such as plant-based substances, are very important in therapy. We report a pilot study with new method of fractioning the dehydrogenate polymer DHP obtained from coniferyl alcohol and application of the low-MW fractions of 200-3000 Da for antibacterial activity in healing animal lesions. In vivo experiments were conducted on the dogs having a skin lesion. Dogs were treated with the suspension containing the low-MW DHP fractions as the active ingredient, in combination with alginate for 7 days. Cytological smears and microbiological analyses of the affected area were performed. Staphylococcus spp. was isolated from lesions in all dogs from our research. The results show that the low-MW DHP suspension in alginate promotes skin healing and reduction of the infection of the lesions in the affected animals. Pharmaceutical composition containing the low-MW DHP fractions exerts a soothing effect on the subject in wound treatment. Reduction in the number of bacteria by 30% and more were noticed in 6 dogs, while in 4 dogs this percentage is above 50%. No side effects were noticed. Synthesized lignin oligomers may have a significant place as antimicrobial and skin healing agents, especially since an increasing number of multidrug-resistant staphylococci are found on the skin lesions in animals.

Target identification, and optimization of dioxygenated amide derivatives as potent antibacterial agents with FabH inhibitory activity.

The enzyme FabH plays a critical role in the initial step of fatty acid biosynthesis, which is vital for the survival of bacteria. As a result, FabH has emerged as an appealing target for the development of novel antibacterial agents. In this study, employing the chemical proteomics method, we validated the previously identified skeleton amide derivatives bearing dioxygenated rings, potentially formed through metabolic processes. Building upon the proteomics findings, we then synthesized and evaluated 32 compounds containing N-heterocyclic amides for their antimicrobial activity for future optimizing the deoxygenated amides. Several compounds demonstrated potent antimicrobial properties with low toxicity, particularly compound 25, which exhibited remarkable potential as an agent with an MIC range of 1.25-3.13 µg/mL against the tested bacterial strains and an IC50 of 2.0 µM against E. coli-derived FabH. Furthermore, we evaluated nine analogues with relatively low MIC values through cytotoxicity and hemolytic activity assessments, Lipinski's rule-of-five criteria, and in silico ADMET predictions to ascertain their druggability potential. Notably, a detailed docking simulation was performed to investigate the binding interactions of compound 25 within the binding pocket of E. coli FabH, which encouragingly revealed strong binding interactions. Based on our findings, compound 25 emerges as the optimal candidate for in vivo therapy aimed at treating infected skin defects. Remarkably, the application of compound 25 demonstrated a significant reduction in the duration of wound infection and notably accelerated the healing process of infected wounds, achieving an impressive 94 % healing rate by day 10.

Towards Antibacterial Agents: Synthesis and Biological Activity of Multivalent Amide Derivatives of Thiacalix[4]arene with Hydroxyl and Amine Groups.

Antimicrobial resistance to modern antibiotics stimulates the search for new ways to synthesize and modify antimicrobial drugs. The development of synthetic approaches that can easily change different fragments of the molecule is a promising solution to this problem. In this work, a synthetic approach was developed to obtain multivalent thiacalix[4]arene derivatives containing different number of amine and hydroxyl groups. A series of macrocyclic compounds in cone, partial cone, and 1,3-alternate stereoisomeric forms containing -NHCH2CH2R (R = NH2, N(CH3)2, and OH) and -N(CH2CH2OH)2 terminal fragments, and their model non-macrocyclic analogues were obtained. The antibacterial activity against Gram-positive (Staphylococcus aureus, Bacillus cereus, and Enterococcus faecalis) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacterial strains and cytotoxicity of the obtained compounds were studied. Structure-activity relationships were established: (1) the macrocyclic compounds had high antibacterial activity, while the monomeric compounds had low activity; (2) the compounds in cone and partial cone conformations had better antibacterial activity compared to the compounds in 1,3-alternate stereoisomeric form; (3) the macrocyclic compounds containing -NHCH2CH2N(CH3)2 terminal fragments had the highest antibacterial activity; (4) introduction of additional terminal hydroxyl groups led to a significant decrease in antibacterial activity; (5) the compounds in partial cone conformation had significant bactericidal activity against all studied cell strains; the best selectivity was observed for the compounds in cone conformation. The mechanism of antibacterial activity of lead compounds with terminal fragments -NHCH2CH2N(CH3)2 was proved using model negatively charged POPG vesicles, i.e., the addition of these compounds led to an increase in the size and zeta potential of the vesicles. The obtained results open up the possibility of using the synthesized macrocyclic compounds as promising antibacterial agents.