Broad-spectrum Antibacterial Activity Research Articles

Lentil Extract-Mediated Ag QD Synthesis: Predilection for Albumin Protein Interaction, Antibacterial Activity, and Its Cytotoxicity for Wi-38 and PC-3 Cell Lines.

Recent focus has been directed toward semiconductor nanocrystals owing to their unique physicochemical properties. Nevertheless, the synthesis and characterization of quantum dots (QDs) pose considerable challenges, limiting our understanding of their interactions within a biological environment. This research offers valuable insights into the environmentally friendly production of silver quantum dots (Ag QDs) using lentil extract and clarifies their distinct physicochemical characteristics, previously unexplored to our knowledge. These findings pave the path for potential practical applications. The investigation of the phytochemical-assisted Ag QDs' affinity for BSA demonstrated modest interactions, as shown by the enthalpy and entropy changes as well as the associated Gibbs free energy during their association. Steady-state and time-resolved fluorescence spectroscopy further demonstrated a transient effect involving dynamic quenching, predominantly driven by Forster resonance energy transfer. Additionally, the study highlights the potential broad-spectrum antibacterial activity of Ag QDs (<5 nm, a zeta potential of -3.04 mV), exhibiting a remarkable MIC value of 1 μg/mL against Gram-negative bacteria (E. coli) and 1.65 μg/mL against Gram-positive bacteria (S. aureus). They can readily enter cells and tissues due to their minuscule size and the right chemical environment. They cause intracellular pathway disruption, which leads to cell death. This outcome emphasizes the distinctive biocompatibility of the green-synthesized Ag QDs, which has been confirmed by their MTT assay-based cytotoxicity against the PC-3 and Wi-38 cell lines.

Detection of antibacterial peptides in artisanal rennet and evaluation of their antibacterial activity

This study assessed the antimicrobial effectiveness of artisanal lamb and goat rennet compared to industrial calf rennet against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus. Results showed all three rennets were more effective against E. coli than S. aureus. Only lamb rennet achieved complete inhibition of both bacteria at a minimum inhibitory concentration of 7000 ppm. An extensive peptidomics analysis was conducted to characterize these rennet samples and correlate their antimicrobial activity with the data on endogenous peptides. Moreover, a prediction of the potential antimicrobial activity of the peptides was carried out with specific bioinformatic tools available online, proving that the isolated peptides did have the tested biological activity. Lamb rennet was found to contain 73 antimicrobial peptides with bioactivity scores between 1 and 0.52, including casocidin-I, known for its broad-spectrum antibacterial activity. Further research is ongoing to explore the applications of artisanal rennet in cheese production.

Thanatin: A Promising Antimicrobial Peptide Targeting the Achilles' Heel of Multidrug-Resistant Bacteria.

Antimicrobial resistance poses an escalating threat to human health, necessitating the development of novel antimicrobial agents capable of addressing challenges posed by antibiotic-resistant bacteria. Thanatin, a 21-amino acid β-hairpin insect antimicrobial peptide featuring a single disulfide bond, exhibits broad-spectrum antibacterial activity, particularly effective against multidrug-resistant strains. The outer membrane biosynthesis system is recognized as a critical vulnerability in antibiotic-resistant bacteria, which thanatin targets to exert its antimicrobial effects. This peptide holds significant promise for diverse applications. This review begins with an examination of the structure-activity relationship and synthesis methods of thanatin. Subsequently, it explores thanatin's antimicrobial activity, detailing its various mechanisms of action. Finally, it discusses prospective clinical, environmental, food, and agricultural applications of thanatin, offering valuable insights for future research endeavors.

Mussel-inspired adhesive drug-loaded hydrogels for oral ulcers treatment

Oral aphthous ulcers are common mucosal lesions that cause pain and discomfort. There are diverse biomaterials and drug treatments for oral ulcers used in both research and clinical settings. However, the complex oral environment often results in low adhesion and short drug retention times, which lead to poor drug availability and treatment outcomes. In this study, a mussel-inspired adhesive hydrogel was developed by grafting catechol onto hyaluronic acid (C-HA), and dopamine was added for oxidative pre-polymerization to form modified hyaluronic acid (M-HA), which remarkably increased the adhesion of the hydrogels. Then, M-HA was interpenetrated into the gelatin methacryloyl (GelMA) network. Chlorhexidine gluconate (CHG) was then incorporated into the hydrogel to enhance its availability and therapeutic effect through its sustained-release capability. The GelMA/M-HA hydrogel demonstrated strong adhesion to wet tissues, antibacterial and anti-inflammatory properties, and good biocompatibility. In both rat oral ulcers and infected wounds, the adhesive hydrogel significantly accelerated the healing of the ulcers and infected wounds. These results indicated that this adhesive hydrogel offers a promising new strategy for the treatment of oral ulcers in clinical practice. Statement of significanceOral ulcers are a common and high-incidence mucosal condition that seriously affect people's daily lives, often making it difficult for patients to chew and speak. However, a dynamic oral environment with various types of bacteria influences drug availability and treatment effects in clinical settings. To address this challenge, an adhesive, mussel-inspired, drug-loaded hydrogel was constructed using natural macromolecules (hyaluronic acid and gelatin) with good biocompatibility. Chlorhexidine gluconate (CHG), with its broad-spectrum antibacterial activity, has been incorporated to synergistically promote oral ulcer healing. The splendid adhesion, antibacterial, and therapeutic effects of this hydrogel demonstrated a new strategy for treating oral ulcers.

Antioxidant, antibacterial, and anti-biofilm activities of selected indigenous plant species against nosocomial bacterial pathogens.

Biofilms are responsible for over 60% of nosocomial infections. The focus of this study was to investigate the antioxidant, antibacterial, antibiofilm, and anti-motility activities of Gardenia volkensii, Carissa bispinosa, Peltophorum africanum, and Senna petersiana. Antioxidant activity was evaluated using free radical (DPPH) scavenging and ferric reducing power assays. Antibacterial and antibiofilm activities were evaluated using the broth micro-dilution and the crystal violet assays, respectively. Anti-motility was evaluated using anti-swarming activities, and the brine shrimp lethality assay was used for cytotoxicity. Gardenia volkensii and C. bispinosa acetone extracts had low EC50 values of 9.59 and 9.99μg ml-1on the free-radical scavenging activity, respectively. All the plant extracts demonstrated broad-spectrum antibacterial activity against Klebsiella pneumoniae, Pseudomonasa aeruginosa, Escherichia coli, Enterococcus faecalis, and Staphylococcus aureus [minimum inhibitory concentration (MIC)<0.63mg ml-1]. The initial cell adherence stage of P. aeruginosa and E. coli was the most susceptible stage where sub-MICs resulted in inhibitions>50%. Peltophorum africanum had the least cytotoxic effects. All extracts had anti-motility activity against P. aeruginosa and E. coli. This study showed that not only do the plants have strong antibacterial activity but had noteworthy inhibition (>50%) of initial cell adherence and may be suitable candidates for the treatment of nosocomial pathogens.

Gold nanoparticle decorated bismuth vanadate casting on screen-printed electrode for chlortetracycline detection

Chlortetracycline is one of the tetracyclines with broad-spectrum antibacterial activity (CTC). Humans rarely use CTC, but farm animals consume vast quantities of it, which causes the growth of antibiotic-resistant bacteria and environmental contamination. There is no report on the AuNPs and BiVO4 nanocomposite being dropped cast on SPCE for electrochemical monitoring of the CTC, and the most expensive, time-consuming, and expensively equipped method is conventional chromatography. Here, we report a simple method for preparing gold nanoparticle decorated bismuth vanadate (AuNPs@BiVO4), which was dropped cast on a screen-printed carbon electrode (SPCE). The AuNPs@BiVO4 and AuNPs@BiVO4/SPCE materials were characterized using TEM, SEM-EDX, XPS, DLS, ELS, EIS, and CV, showing a consistent nanocomposite and its electrode. The as-prepared AuNPs@BiVO4/SPCE was used to detect and determine chlortetracycline (CTC) by different pulse potentials in phosphate buffer pH 7.0. The electrode possessed a wide linear range of 0.99–19.06 µM, with obtained LOD = 0.15 µM, LOQ = 0.49 µM, and sensitivity = 0.059 μA μM−1 cm−2. It also exhibited good selectivity, stability, and repeatability, recovering 87.14 %–100 % for detecting CTC in Mili Q and tap water. The findings show that the straightforward approach for making AuNPs@BiVO4 nanocomposite and an AuNPs@BiVO4/SPCE electrode is consistent with electrochemical CTC monitoring. Thus, the proposed electrode could be applied for the detection and determination of CTC in water sources and has the potential to be used for real sample analysis.

Multi-Hydrogen Bonding on Quaternized-Oligourea Receptor Facilitated Its Interaction with Bacterial Cell Membranes and DNA for Broad-Spectrum Bacteria Killing.

Herein, we report a new strategy for the design of antibiotic agents based on the electrostatic interaction and hydrogen bonding, highlighting the significance of hydrogen bonding and the increased recognition sites in facilitating the interaction with bacterial cell membranes and DNA. A series of quaternary ammonium functionalized urea-based anion receptors were studied. While the monodentate mono-urea M1, bisurea M2, and trisurea M3 failed to break through the cell membrane barrier and thus could not kill bacteria, the extended bidentate dimers D1-D3 presented gradually increased membrane penetrating capabilities, DNA conformation perturbation abilities, and broad-spectrum antibacterial activities against E. coli, P. aeruginosa, S. aureus, E. faecalis, and S. epidermidis.

CRP and IHF act as host regulators in Royal Jelly's antibacterial activity

Royal Jelly (RJ) is a natural substance produced by honeybees, serving not only as nutrition for bee brood and queens but also as a functional food due to its health-promoting properties. Despite its well-known broad-spectrum antibacterial activity, the precise molecular mechanism underlying its antibacterial action has remained elusive. In this study, we investigated the impact of RJ on the bacteria model MG1655 at its half-maximal inhibitory concentration, employing LC–MS/MS to analyze proteomic changes. The differentially expressed proteins were found to primarily contribute to the suppression of gene expression processes, specifically transcription and translation, disrupting nutrition and energy metabolism, and inducing oxidative stress. Notably, RJ treatment led to a marked inhibition of superoxide dismutase and catalase activities, resulting in heightened oxidative damage and lipid peroxidation. Furthermore, through a protein–protein interaction network analysis using the STRING database, we identified CRP and IHF as crucial host regulators responsive to RJ. These regulators were found to play a pivotal role in suppressing essential hub genes associated with energy production and antioxidant capabilities. Our findings significantly contribute to the understanding of RJ's antibacterial mechanism, highlighting its potential as a natural alternative to conventional antibiotics. The identification of CRP and IHF as central players highlights the intricate regulatory networks involved in RJ's action, offering new targets for developing innovative antimicrobial strategies.

Biological and phytochemical analysis of fractionated extracts of Ziziphus nummularia against pathogenic bacteria, oxidative stress and cytotoxicity

In modern medicine, synthetic drugs are predominant, yet they often pose health hazards. So, there is a need to find natural alternatives. Ziziphus nummularia (Burm. F.) Wight &amp; Arn., belongs to family Rhamnaceae, is well known for its traditional value such as its fruits have been used as natural appetizer and orally consumed around the world. This study investigated the phytochemical composition and bioactivity of crude and fractionated extracts from the stem bark of Ziziphus nummularia. Crude extracts were prepared using cold maceration, followed by partitioning based on polarity into n-hexane, chloroform, and ethyl acetate fractions. These extracts were subjected to phytochemical analysis and evaluated for antioxidant, antibacterial, and cytotoxic activities. The crude methanolic extract exhibited the highest antioxidant activity, with IC50 values of 136.49 μg/mL in DPPH and 78.9 μg/mL in ABTS assays. Antibacterial tests using the agar well diffusion method revealed that the methanolic extract, ethyl acetate, and chloroform fractions demonstrated broad-spectrum antibacterial activity against E. coli, K. pneumoniae, S. aureus, and S. epidermidis, with inhibition zones ranging from 0 to 8.43 ± 0.23 mm at 400 mg/mL. The brine shrimp lethality assay indicated significant cytotoxicity in the methanolic, ethyl acetate, and chloroform extracts, compared to the negligible effect of the n-hexane fraction. These findings highlight the potential of Z. nummularia as a source of bioactive compounds with therapeutic applications against infectious diseases, toxins, and oxidative stress. Further isolation of pure compounds and animal trials are recommended to explore its potential in drug discovery.

Biomass extract-mediated preparation of magnesium-doped nickel oxide nanoparticles and their in vitro bioactivities assessment

Biomass extract-mediated fabrication of metal oxide nanoparticles received significant attention in material research because it is eco-friendly, cost-effective, and easy to scalability. Here, the fabrication of Boerhavia diffusa leaf extract (BDE)-mediated magnesium-doped nickel oxide nanoparticles (Mg-doped-NiO-BDE) and their in vitro bioactivities are reported. Several characterization procedures are used to characterize the prepared NiO nanoparticles. Field emission scanning electron microscopy and transmission electron microscopy images exhibit that the Mg-doped-NiO-BDE are distorted spherical. The X-ray diffraction showed that the average crystallite sizes of the nanoparticles are around 51–55 nm. X-ray diffraction, X-ray photoelectron spectroscopy, and energy-dispersive X-ray spectroscopy analysis results confirm that the NiO is produced, and Mg-doping has occurred in the adopted reaction condition. The doped NiO NPs exhibit broad-spectrum antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), as well as antifungal action against Aspergillus niger (A. nigar). The antioxidant, anti-inflammatory, and anti-diabetic efficiencies of doped-NiO NPs (concentration = 400 μg/mL) are around 65 %, 89 %, and 87 %, respectively. The Mg-doped-NiO-BDE nanoparticles show around 75 % viability against the human lung cancer cell line (A459) with a concentration of up to 100 μg/mL, while the IC50 value is 185.6 μg/mL. The scratch test is executed with the mouse fibroblast cells (L929) in which doped-NiO NPs exhibit around 36 % wound-closing ability. The above results signify that the fabricated Mg-doped-NiO-BDE is a potent bioactive material that could be used for biomedical applications.

A promising eco-friendly and cost-effective photocatalytic rolled graphene oxide/poly(m-methylaniline) core-shell nanocomposite for antimicrobial action.

A new and innovative rolled graphene oxide (roll-GO)/poly-m-methylaniline (PmMA) core-shell nanocomposite has been successfully synthesized using an in situ polymerization technique. This eco-friendly and cost-effective material shows great promise due to its antimicrobial properties. The characterization of the nanocomposite involved X-ray diffraction and Fourier transform infrared spectroscopy to analyze its structure and functional groups, whereas scanning electron microscopy and transmission electron microscopy (TEM) were utilized to examine its morphology. TEM analysis revealed the formation of roll-GO, forming multi-walled tubes with inner and outer diameters of 50 and 70nm, respectively. Optical analysis demonstrated an enhanced bandgap in the nanocomposite, with bandgap values of 2.38eV for PmMA, 2.67eV for roll-GO, and 1.65eV for roll-GO/PmMA. The antibacterial efficacy of the nanocomposite was tested against Gram-positive bacteria, including Bacillus subtilis and Staphylococcus aureus, as well as Gram-negative bacteria such as Escherichia coli and Salmonella sp. The well diffusion method was used to determine the inhibition zones, revealing that the nanocomposite demonstrated broad-spectrum antibacterial activity against all the pathogens tested. The largest inhibition zones were observed for B. subtilis, followed by S. aureus, E. coli, and Salmonella sp. Notably, the inhibition zones increased when the samples were exposed to light compared to dark conditions, with increases of 33 and 18mm noted for B. subtilis. This enhanced activity under light exposure is attributed to the photocatalytic properties of the nanocomposite. The antibacterial mechanism is based on both adsorption and degradation processes. Moreover, antibacterial activity was found to increase with increasing concentrations of nanoparticles, ranging from 100 to 500ppm. This suggests that the nanocomposite has potential as an alternative to antibiotics, especially considering the growing issue of bacterial resistance. The promising results obtained from the inhibition zones make these nanocomposites suitable for various applications. Currently, the research team is working on the development of a prototype utilizing these antimicrobial particles within commercial bottles for sterilization purposes in factories and companies.

Design of biphasic Fe and Zn doped hydroxyapatite: Novel strategy for combating osteomyelitis infections

Hydroxyapatite (HA) bioceramics are widely used materials for orthopaedic applications, offering enhanced cellular adhesion and differentiation. However, the lack of antibacterial features makes the HA biomaterials prone to bacterial infections in in-vivo conditions. The osteomyelitis-like conditions are often treated with prolonged doses of antibiotics and may require surgical removal. Such problems can be tackled by inducing the antibacterial characteristics in the biomaterials which prevent such infections. Various research studies have been conducted to improve the mechanical and antibacterial characteristics of biomaterials like HA through doping. The present study focuses on the synthesis, characterization, and antibacterial study of Zn and Fe doped HA (ZFHAp) for application in the treatment of osteomyelitis. Response Surface Methodology (RSM) based Central Composite Design (CCD) approach was used to optimize the process parameters using the Design Expert software. The analyses indicated the presence of Calcium Iron Hydrogen Phosphate (CIHP) and Parascholzite (PS) as major phases. The optimized experimental conditions were estimated as 0.09 M Zn and 0.04 M Fe at 65 °C, corresponding to 71.29 % and 28.71 % of the CIHP and PS phases, respectively. The synthesized nanopowder showed mixed morphology comprising spherical and rod-shaped particles due to biphasic composition. The ZFHAp sample showed a broad-spectrum antibacterial activity, with IC50 values of 4.02 mg/ml and 4.79 mg/ml against E. coli and S. aureus, respectively. The optimized sample showed excellent biocompatibility with the osteoblast-like cells (MG-63) with improved biomineralization properties. The antibacterial and osteoinductive characteristics of the synthesized biphasic Fe and Zn doped HA suggest its potential application against osteomyelitis-related conditions.

Alginate Cryogels for Rapid Hemostasis and Toluidine Blue-Mediated Photodynamic Inactivation of Bacteria.

The development of new wound dressings with fast hemostatic and bactericidal properties for prehospital care is critical. Antibacterial photodynamic therapy (aPDT) has attracted attention due to its broad-spectrum antibacterial activity and minimal bacterial resistance. However, photosensitizers used in aPDT often face issues such as poor water solubility, short-lived singlet oxygen (1O2), and limited 1O2 diffusion range. In this study, sodium alginate was covalently modified with the photosensitizer toluidine blue O (TBO) and phenylboronic acid (PBA). The modified alginate was then cross-linked with Ca(II) ions and lyophilized to form a cryogel, named SA@Ca(II)@TBO@PBA (SCTP). This cryogel functions as an antibacterial photodynamic wound dressing. The chemical immobilization of TBO and PBA enhanced the cryogel's targeting ability. PBA formed reversible covalent bonds with diol groups on bacterial cell surfaces, allowing the cryogel to capture bacteria effectively and enhance aPDT. The bactericidal efficiency of the cryogel was tested through in vitro antibacterial assays, and its hemostatic properties were confirmed in vivo. The results indicate that this cryogel has excellent hemostatic and antibacterial capabilities, showing great promise as a wound dressing for clinical applications.

Concise Synthesis of Pseudane IX, Its N-Oxide, and Novel Carboxamide Analogs with Antibacterial Activity.

A four-step synthesis of the natural product pseudane IX, starting from 3-oxododecanoic acid phenylamide and including only one chromatographic purification, was accomplished with an overall yield of 52%. The same synthetic sequence, but with a controlled partial reduction of a nitro group in the penultimate intermediate, led to the N-oxide of pseudane IX (NQNO). A shortened three-step variation of the synthesis allowed for the preparation of novel carboxamide analogs of the natural product. An agar diffusion assay against six different bacterial strains revealed significant antibacterial activity of the novel analogs against S. aureus at a concentration of 100 µg/mL. One of the novel compounds showed a remarkably broad spectrum of antibacterial activity, comparable to that of the positive control NQNO.

Discovery of aminopiperidine based potent & novel topoisomerase inhibitor with broad spectrum anti-bacterial activity

Bacterial DNA gyrase and topoisomerase IV inhibition has emerged as a promising strategy for the cure of infections caused by antibiotic-resistant bacteria. The Novel Bacterial Topoisomerase Inhibitors (NBTIs) bind to a different site from that of the quinolones with novel mechanism of action. This evades the existing target-mediated bacterial resistance associated with quinolones. This article presents our efforts to identify in vitro potent and broad-spectrum antibacterial agent 4l.

AI-guided few-shot inverse design of HDP-mimicking polymers against drug-resistant bacteria

Host defense peptide (HDP)-mimicking polymers are promising therapeutic alternatives to antibiotics and have large-scale untapped potential. Artificial intelligence (AI) exhibits promising performance on large-scale chemical-content design, however, existing AI methods face difficulties on scarcity data in each family of HDP-mimicking polymers (<102), much smaller than public polymer datasets (>105), and multi-constraints on properties and structures when exploring high-dimensional polymer space. Herein, we develop a universal AI-guided few-shot inverse design framework by designing multi-modal representations to enrich polymer information for predictions and creating a graph grammar distillation for chemical space restriction to improve the efficiency of multi-constrained polymer generation with reinforcement learning. Exampled with HDP-mimicking β-amino acid polymers, we successfully simulate predictions of over 105 polymers and identify 83 optimal polymers. Furthermore, we synthesize an optimal polymer DM0.8iPen0.2 and find that this polymer exhibits broad-spectrum and potent antibacterial activity against multiple clinically isolated antibiotic-resistant pathogens, validating the effectiveness of AI-guided design strategy.

Antibacterial characteristics and mechanistic insights of combined tea polyphenols, Nisin, and epsilon-polylysine against feline oral pathogens: a comprehensive transcriptomic and metabolomic analysis.

This study evaluates the antibacterial characteristics and mechanisms of combined tea polyphenols (TPs), Nisin, and ε-polylysine (PL) against Streptococcus canis, Streptococcus minor, Streptococcus mutans, and Actinomyces oris, common zoonotic pathogens in companion animals. Pathogenic strains were isolated from feline oral cavities and assessed using minimum inhibitory concentration (MIC) tests, inhibition zone assays, growth kinetics, and biofilm inhibition studies. Among single agents, PL exhibited the lowest MIC values against all four pathogens. TP showed significant resistance against S. minor, and Nisin against S. mutans. The combination treatment (Comb) of TP, Nisin, and PL in a ratio of 13:5:1 demonstrated broad-spectrum antibacterial activity, maintaining low MIC values, forming large inhibition zones, prolonging the bacterial lag phase, reducing growth rates, and inhibiting biofilm formation. RNA sequencing and metabolomic analysis indicated that TP, Nisin, and PL inhibited various membrane-bound carbohydrate-specific transferases through the phosphoenolpyruvate-dependent phosphotransferase system in S. canis, disrupting carbohydrate uptake. They also downregulated glycolysis and the citric acid cycle, inhibiting cellular energy metabolism. Additionally, they modulated the activities of peptidoglycan glycosyltransferases and d-alanyl-d-alanine carboxypeptidase, interfering with peptidoglycan cross-linking and bacterial cell wall stability. The Comb therapy significantly enhances antibacterial efficacy by targeting multiple bacterial pathways, offering potential applications in food and pharmaceutical antimicrobials.

Carbon Dots with Integrated Photothermal Antibacterial and Heat-Enhanced Antioxidant Properties for Diabetic Wound Healing.

Diabetic wounds pose a persistent challenge due to their slow healing nature, primarily caused by bacterial infection and excessive reactive oxygen species (ROS)-induced inflammation. In this study, carbon dots with synergistic antibacterial and antioxidant properties, referred to as AA-CDs, are developed specifically for diabetic wound healing using a straightforward solvothermal method. By utilizing cost-effective precursors like citric acid and ascorbic acid, AA-CDs are engineered to possess tailored functions of photothermal sterilization and ROS scavenging. The resulting AA-CDs demonstrats broad-spectrum antibacterial activity, particularly against multidrug-resistant strains, along with efficient ROS scavenging both in solution and within cells. Additionally, AA-CDs exhibits a protective effect against oxidative stress-induced damage. Notably, with a high photothermal conversion efficiency (41.18%), AA-CDs displays heat-enhanced antioxidant performance, providing not only augmented ROS scavenging but also additional protection against oxidative stress, yielding a true "1 + 1 > 2" effect. To facilitate their use in vivo, AA-CDs are incorporated into a thermally responsive hydrogel, which exhibits evident anti-inflammatory properties by modulating inflammatory factors and significantly promots the healing of diabetic wounds. This study underscores the value of integrated platforms for diabetic wound healing and highlights the potential of versatile CDs as promising therapeutic agents in biomedical applications.

Total Synthesis Facilitates In Vitro Reconstitution of the C-S Bond-Forming P450 in Griseoviridin Biosynthesis.

Griseoviridin is a group A streptogramin natural product from Streptomyces with broad-spectrum antibacterial activity. A hybrid polyketide-nonribosomal peptide, it comprises a 23-membered macrocycle, an embedded oxazole motif, and a macrolactone with a unique ene-thiol linkage. Recent analysis of the griseoviridin biosynthetic gene cluster implicated SgvP, a cytochrome P450 monooxygenase, in late-stage installation of the critical C-S bond. While genetic and crystallographic experiments provided indirect evidence to support this hypothesis, the exact function of SgvP has never been confirmed biochemically. Herein, we report a convergent total synthesis of pre-griseoviridin, the putative substrate of P450 SgvP and precursor to griseoviridin. Our strategy features concise and rapid assembly of two fragments joined via sequential peptide coupling and Stille macrocyclization. Access to pre-griseoviridin then enabled in vitro validation of SgvP as the C-S bond-forming P450 during griseoviridin biosynthesis, culminating in a nine-step chemoenzymatic synthesis of griseoviridin.

Trans-Cinnamaldehyde Inhibition of Pyruvate Dehydrogenase: Effects on Streptococcus mutans Carbohydrate Metabolism.

Dental caries is a chronic oral infectious disease, and Streptococcus mutans (S. mutans) plays an important role in the formation of dental caries. Trans-cinnamaldehyde (CA) exhibits broad-spectrum antibacterial activity; however, its target and mechanism of action of CA on S. mutans needs to be further explored. In this study, it was verified that CA could inhibit the growth and biofilm formation of S. mutans. Further proteomic analysis identified 33, 55, and 78 differentially expressed proteins (DEPs) in S. mutans treated with CA for 1, 2, and 4 h, respectively. Bioinformatics analysis showed that CA interfered with carbohydrate metabolism, glycolysis, pyruvate metabolism, and the TCA cycle, as well as amino acid metabolism of S. mutans. Protein interactions suggested that pyruvate dehydrogenase (PDH) plays an important role in the antibacterial effect of CA. Moreover, the upstream and downstream pathways related to PDH were verified by various assays, and the results proved that CA not only suppressed the glucose and sucrose consumption and inhibited glucosyltransferase (GTF) and lactate dehydrogenase (LDH) activities but also decreased the ATP production. Interestingly, the protein interaction, qRT-PCR, and molecular docking analysis showed that PDH might be the target of CA to fight S. mutans. In summary, the study shows that CA interferes with the carbohydrate metabolism of bacteria by inhibiting glycolysis and the tricarboxylic acid (TCA) cycle via binding to PDH, which verifies that PDH is a potential target for the development of new drugs against S. mutans.