Antimicrobial Peptides Research Articles

Antibiofilm Mechanisms of the Helical G3 Peptide against Staphylococcus epidermidis.

Antibacterial peptides (ABPs) have been recognized as promising alternatives to conventional antibiotics due to their broad antibacterial spectrum, high antibacterial activity, and low possibility of inducing bacterial resistance. However, their antibiofilm mechanisms have not yet reached a consensus. In this study, we investigated the antibiofilm activity of a short helical peptide G3 against Staphylococcus epidermidis, one of the most important strains of medical device contamination. Studies show that G3 inhibits S. epidermidis biofilm formation in a variety of ways. In the initial adhesion stage, G3 changes the properties of bacterial surfaces, such as charges, hydrophobicity, and permeability, by rapidly binding to them, thus interfering with their initial adhesion. In the mature stage, G3 prefers to target extracellular polysaccharides, leading to the death of outside bacteria and the disruption of the three-dimensional (3D) architecture of the bacterial biofilm. Such efficient antibiofilm activity of G3 endows it with great potential in the treatment of infections induced by the S. epidermidis biofilm.

Dermaseptin B2 bioactive gene's potential for anticancer and anti-proliferative effect is linked to the regulation of the BAX/BBC3/AKT pathway.

Dermaseptin B2 (DrsB2) is an antimicrobial peptide with anticancer and angiostatic properties. We aimed to assess the in vitro inhibitory effect of pDNA/DrsB2 on the growth of breast cancer cells and its impact on the expression of genes involved in the BAX/BBC3/AKT pathway. The nucleic acid sequence of DrsB2 was artificially synthesized and inserted into the pcDNA3.1( +) Mammalian Expression Plasmid. PCR testing and enzyme digesting procedures evaluated the accuracy of cloning. The vectors were introduced into cells using LipofectamineTM2000 transfection reagent. The breast cancer cells were assessed by flow cytometry, MTT assessment, soft agar colony method, and wound healing investigation. The gene's transcription was evaluated using real-time PCR with a significance level of P < 0.05. The recombinant plasmid harboring the pDNA/DrsB2 vector was effectively produced, and the gene sequence showed absolute homogeneity (100% similarity) with the DrsB2 gene. The transfection effectiveness of MCF-7 and MCF-10A cells was 79% and 68%, respectively. The findings are measured using the growth inhibition 50% (GI50) metric, which indicates the concentration of pDNA/DrsB2 that stops 50% of cell growth. The proportions of early apoptosis, late apoptosis, necrosis, and viable MCF-7 cells in the pDNA/DrsB2 group were 40.50%, 2.31%, 1.69%, and 55.50%, respectively. The results showed a 100% increase in gene expression in programmed cell death following treatment with pDNA/DrsB2 (**P < 0.01). To summarize, the results described in this work offer new possibilities for treating cancer by targeting malignancies via pDNA/DrsB2 and activating the BAX/BBC3/AKT signaling pathways.

Maize Kernel-Associated Metagenomes Reveal Potential Microbe–Microbe Interactions that Underlie Fusarium Ear Rot Disease

As an alternative to host resistance, transgenic expression of entomocidal and antimicrobial proteins from Bacillus thuringiensis ( Bt) in maize can mitigate Fusarium ear rot (FER). This study evaluated FER in Bt and conventional maize and the role of microbes in the kernel-associated metagenome using quantitative reduced representation sequencing. Our results revealed significant differences in FER severity across environments and varieties and between inoculation treatments. The lower FER scores of conventional maize Spectrum 6416 relative to other varieties highlighted resistant alleles in maize germplasm, whereas strong correlations indicated FER-induced yield loss. Mitigation of FER by transgenes was validated by about threefold enrichment of Fusarium verticillioides ( Fv) postinoculation compared with nonsignificant Fv enrichment in conventional maize. Although the major causal pathogen of FER, Fv, was the most abundant species in the metagenomes ( r = 0.41 to 0.49), a similar degree of correlation was observed between FER and several Fusarium spp. ( r = 0.2 to 0.56). The potential FER-suppressing properties of Talaromyces stipitatus and Ustilago maydis were indicated by negative correlations with FER ( r = –0.22 to –0.42), Fv, and some Fusarium spp. The more FER-resistant varieties consistently enriched for potential FER-suppressing Burkholderia cenocepacia (negatively correlated with Fv). This suggests host genetic background-dependent recruitment of beneficial microbes that suppress pathogens and that microbe–microbe interactions play a role in FER severity. Quantitative and species/strain-level metagenomic profiles hold promise for identifying robust disease-suppressing microbes and microbes that act in synergy with pathogens and for developing holobiont-aware breeding strategies that account for host–microbiome coevolution and host genotype, microbiome/metagenome, and environment interactions. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .

Queuosine biosynthetic enzyme, QueE moonlights as a cell division regulator.

In many organisms, stress responses to adverse environments can trigger secondary functions of certain proteins by altering protein levels, localization, activity, or interaction partners. Escherichia coli cells respond to the presence of specific cationic antimicrobial peptides by strongly activating the PhoQ/PhoP two-component signaling system, which regulates genes important for growth under this stress. As part of this pathway, a biosynthetic enzyme called QueE, which catalyzes a step in the formation of queuosine (Q) tRNA modification is upregulated. When cellular QueE levels are high, it co-localizes with the central cell division protein FtsZ at the septal site, blocking division and resulting in filamentous growth. Here we show that QueE affects cell size in a dose-dependent manner. Using alanine scanning mutagenesis of amino acids in the catalytic active site, we pinpoint residues in QueE that contribute distinctly to each of its functions-Q biosynthesis or regulation of cell division, establishing QueE as a moonlighting protein. We further show that QueE orthologs from enterobacteria like Salmonella typhimurium and Klebsiella pneumoniae also cause filamentation in these organisms, but the more distant counterparts from Pseudomonas aeruginosa and Bacillus subtilis lack this ability. By comparative analysis of E. coli QueE with distant orthologs, we elucidate a unique region in this protein that is responsible for QueE's secondary function as a cell division regulator. A dual-function protein like QueE is an exception to the conventional model of "one gene, one enzyme, one function", which has divergent roles across a range of fundamental cellular processes including RNA modification and translation to cell division and stress response.

Antimicrobial Peptide‐Modified Liquid Metal Nanomaterials for Enhanced Antibacterial Photothermal Therapy

The misuse of antibiotics has led to antibiotic‐resistant “superbugs,” prompting the exploration of alternative antibacterial strategies. This study focuses on the promising avenue of photothermal therapy (PTT). Despite numerous advantages, the clinical applicability of PTT as a sole sterilization strategy is hindered by the necessity for higher temperatures, potentially causing harm to healthy tissues. To overcome this challenge, this study introduces antimicrobial peptides (AMPs) to modify the surface of gallium‐based liquid metal (LM) nano‐antimicrobial agents, thereby enhancing their photothermal antibacterial effects within a lower temperature range. First, a novel LM composite nanomaterial, LM@AMP nanoparticles, is synthesized through a sonication process involving 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐N‐[carboxy(polyethylene glycol)], AMP, and LM in an aqueous solution. Herein, AMPs not only contribute to the structural stability of LM nanoparticles but also enhance their selective interaction with bacterial cell membranes. Then, a thorough characterization of LM@AMP nanoparticles is performed, encompassing analyses through electron microscopy, determination of particle size, and assessment of zeta potential. Moreover, the exceptional photothermal properties exhibited by these nanoparticles are validated. Finally, this investigation demonstrates that LM@AMP nanoparticles selectively target bacterial cell membranes, showcasing efficient bactericidal effects (near 100%) at relatively low temperatures under near‐infrared irradiation.

De Novo Antimicrobial Peptide Design with Feedback Generative Adversarial Networks

Antimicrobial peptides (AMPs) are promising candidates for new antibiotics due to their broad-spectrum activity against pathogens and reduced susceptibility to resistance development. Deep-learning techniques, such as deep generative models, offer a promising avenue to expedite the discovery and optimization of AMPs. A remarkable example is the Feedback Generative Adversarial Network (FBGAN), a deep generative model that incorporates a classifier during its training phase. Our study aims to explore the impact of enhanced classifiers on the generative capabilities of FBGAN. To this end, we introduce two alternative classifiers for the FBGAN framework, both surpassing the accuracy of the original classifier. The first classifier utilizes the k-mers technique, while the second applies transfer learning from the large protein language model Evolutionary Scale Modeling 2 (ESM2). Integrating these classifiers into FBGAN not only yields notable performance enhancements compared to the original FBGAN but also enables the proposed generative models to achieve comparable or even superior performance to established methods such as AMPGAN and HydrAMP. This achievement underscores the effectiveness of leveraging advanced classifiers within the FBGAN framework, enhancing its computational robustness for AMP de novo design and making it comparable to existing literature.

Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine

Antimicrobial peptides (AMPs), ancient scavengers of bacteria, are very poorly induced in macrophages infected by Mycobacterium tuberculosis (M. tuberculosis), but the underlying mechanism remains unknown. Here, we report that L-alanine interacts with PRSS1 and unfreezes the inhibitory effect of PRSS1 on the activation of NF-κB pathway to induce the expression of AMPs, but mycobacterial alanine dehydrogenase (Ald) Rv2780 hydrolyzes L-alanine and reduces the level of L-alanine in macrophages, thereby suppressing the expression of AMPs to facilitate survival of mycobacteria. Mechanistically, PRSS1 associates with TAK1 and disruptes the formation of TAK1/TAB1 complex to inhibit TAK1-mediated activation of NF-κB pathway, but interaction of L-alanine with PRSS1, disables PRSS1-mediated impairment on TAK1/TAB1 complex formation, thereby triggering the activation of NF-κB pathway to induce expression of AMPs. Moreover, deletion of antimicrobial peptide gene β-defensin 4 (Defb4) impairs the virulence by Rv2780 during infection in mice. Both L-alanine and the Rv2780 inhibitor, GWP-042, exhibits excellent inhibitory activity against M. tuberculosis infection in vivo. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses its own alanine dehydrogenase to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.

The role of cathelicidins in neutrophil biology.

Despite their relatively short lifespan, neutrophils are tasked with counteracting pathogens through various functions, including phagocytosis, production of reactive oxygen species (ROS), neutrophil extracellular traps (NETs), and host defence peptides. Regarding the latter, small cationic cathelicidins present a conundrum in neutrophil function. Although primarily recognized as microbicides with an ability to provoke pores in microbial cell walls, the ability of cathelicidin to modulate key neutrophil functions is also of great importance, including the release of chemo-attractants, cytokines and ROS, plus prolonging neutrophil lifespan. Cumulative evidence indicates a less recognized role of cathelicidin as an "immunomodulator;" however, this term is not always explicit and its relevance in neutrophil responses during infection and inflammation is seldom discussed. This review compiles and discusses studies of how neutrophils use cathelicidin to respond to infections, while also acknowledging immunomodulatory aspects of cathelicidin through potential crosstalk between sources of the peptide.

The Potential of QP3VH-Chitosan Peptide as Biomimetic Remineralization in Early Dental Caries Treatment: An In Vitro Study.

The development of remineralization biomimetics using organic peptide molecules is expected to resemble the hydroxyapatite (HA) mineralization process in tooth enamel. The development of an amelogenin derivative peptide combined with antimicrobial peptide was designed, resulting in QP3VH. This combination then was mixed with chitosan as a carrier. This study aimed to evaluate the biomimetic efficacy of QP3VH as a remineralizing agent combined with chitosan. Fifty deciduous mandibular incisor enamel samples were used in this study. The artificial enamel lesions were created on a buccal surface and were randomly assigned to five groups of 10 each according to the remineralizing agent used: QP3VH, NaF, QP3VH + NaF, QP3VH + CS (QP3VH + chitosan), and saline distilled water (SDW). Each group was performed pH cycling for seven days. Enamel surface morphology and evaluation of mineral content Ca/P (calcium and phosphate) using scanning electron microscopy and energy dispersive X-ray analysis. The assessment was carried out, after demineralization, and after application with remineralization agents. Data were analyzed using a one-way analysis of variance followed by least significance difference post-hoc test. The paired t-test was utilized to compare the demineralization and remineralization results. The significance level used was 95%. The remineralized group exhibited a significant increase in calcium and phosphate content on the enamel surface (p <0.05), and QP3VH + CS produced the maximum Ca/P mass percent after remineralization. Combining QP3VH with chitosan produces greatest remineralization than QP3VH, QP3VH + NaF, Naf, and SDW; therefore, QP3VH peptide has potential as a remineralizing agent, in the future.

Synthetic antimicrobial peptides: activity against vancomycin-resistant Enterococcus faecalis and modulation of chloramphenicol antibacterial activity.

Enterococcus faecalis (E. faecalis) is a leading cause of nosocomial infection and presents a wide spectrum of antibiotic resistance, being vancomycin-resistant Enterococcus (VRE) one of the most relevant. Synthetic antimicrobial peptides (SAMPs) are currently a promising option to overcome antimicrobial resistance. Thus, the purpose of this study was to assess the effect of eight SAMPs against vancomycin-resistant E. faecalis, as well as to investigate their mechanism of action and synergy with conventional antibiotics. Here, eight SAMPs, Mo-CBP3-PepI, Mo-CBP3-PepII, Mo-CBP3-PepIII, RcAlb-PepI, RcAlb-PepII, RcAlb-PepIII, PepGAT, and PepKAA, were tested for antibacterial activity in vitro against E. faecalis (ATCC® 51299) through broth microdilution. A maximum of 48% of E. faecalis growth inhibition was achieved by treatment with SAMPs alone. However, when these peptides were combined with the antibiotic chloramphenicol, assessed by checkerboard method, the inhibition increased to 55-76% of inhibition, 2-3 folds of increase if compared to the effects of the compounds alone. Microscopic analysis showed that E. faecalis cells treated with a combination of SAMPs and chloramphenicol resulted in bacterial membrane damage. The biofilm inhibition maximum was 22% for SAMPs alone, when combined with chloramphenicol the maximum increased to 33%. SAMPs and their combination with chloramphenicol demonstrate antibacterial activity against E. faecalis, possibly by inducing bacterial membrane damage.

A novel family of defensin-like peptides from Hermetia illucens with antibacterial properties.

The world faces a major infectious disease challenge. Interest in the discovery, design, or development of antimicrobial peptides (AMPs) as an alternative approach for the treatment of bacterial infections has increased. Insects are a good source of AMPs which are the main effector molecules of their innate immune system. Black Soldier Fly Larvae (BSFL) are being developed for large-scale rearing for food sustainability, waste reduction and as sustainable animal and fish feed. Bioinformatic studies have suggested that BSFL have the largest number of AMPs identified in insects. However, most AMPs identified in BSF have not yet undergone antimicrobial evaluation but are promising leads to treat critical infections. Jg7197.t1, Jg7902.t1 and Jg7904.t1 were expressed into the haemolymph of larvae following infection with Salmonella enterica serovar Typhimurium and were predicted to be AMPs using the computational tool ampir. The genes encoding these proteins were within 2 distinct clusters in chromosome 1 of the BSF genome. Following removal of signal peptides, predicted structures of the mature proteins were superimposed, highlighting a high degree of structural conservation. The 3 AMPs share primary sequences with proteins that contain a Kunitz-binding domain; characterised for inhibitory action against proteases, and antimicrobial activities. An in vitro antimicrobial screen indicated that heterologously expressed SUMO-Jg7197.t1 and SUMO-Jg7902.t1 did not show activity against 12 bacterial strains. While recombinant SUMO-Jg7904.t1 had antimicrobial activity against a range of Gram-negative and Gram-positive bacteria, including the serious pathogen Pseudomonas aeruginosa. We have cloned and purified putative AMPs from BSFL and performed initial in vitro experiments to evaluate their antimicrobial activity. In doing so, we have identified a putative novel defensin-like AMP, Jg7904.t1, encoded in a paralogous gene cluster, with antimicrobial activity against P. aeruginosa.

Upregulation of psoriasin/S100A7 correlates with clinical severity in patients with oral lichen planus

ObjectivesThe aim of this study was to: (1) investigate the expression patterns of antimicrobial peptides (AMPs), specifically psoriasin (S100A7) and calgranulin A and B (S100A8/A9), in patients with oral lichen planus (OLP) compared to healthy individuals; (2) evaluate the oral health-related quality of life (OHrQoL) in OLP patients versus healthy controls; (3) investigate the impact of clinical severity of OLP on OHrQoL; and (4) assess the influence of AMP expression on clinical severity and OHrQoL in OLP patients.Materials and methodsOral mucosal biopsies (n = 38) were collected from healthy individuals (n = 17) and patients with OLP (n = 21). Levels of AMPs (S100A7, S100A8, S100A9) and pro-inflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor alpha (TNFα) were assessed by RT-qPCR. AMP protein localization was identified by indirect immunofluorescence analysis. OHrQoL was assessed using the OHIP-G14 questionnaire, and clinical severity was evaluated with the Oral Disease Severity Score (ODSS). Correlations between OLP manifestation, OHrQoL, and AMP expression were evaluated.Results(1) S100A7 (p < 0.001), IL-8 (p < 0.001), and TNFα (p < 0.001) mRNA levels were significantly upregulated in OLP tissue compared to healthy tissue, while S100A8 (p < 0.001) and S100A9 (p < 0.001) mRNA levels were downregulated. Immunofluorescence staining revealed an enhanced expression of S100A7 and decreased protein expression of S100A9 in OLP tissue. (2) OLP patients (9.58 ± 8.32) reported significantly higher OHIP-G14 scores compared to healthy individuals (0.67 ± 0.87; p < 0.001), particularly in the categories “physical pain” (p < 0.001) and “psychological discomfort” (p = 0.025). (3,4) Clinical severity (25.21 ± 9.77) of OLP correlated positively with OHrQoL (ρ = 0.497) and psoriasin expression (ρ = 0.402).ConclusionsThis study demonstrated differential expression patterns of AMPs in OLP and highlighted the correlation between the clinical manifestation of OLP and OHrQoL. Further research approaches should address the role of psoriasin in the risk of malignant transformation of OLP.Clinical relevancePsoriasin is a putative biomarker to monitor disease severity including malignant transformation of OLP lesions. OHIP-G14 scores can be useful to monitor OHrQoL in OLP patients.

CATH-2-derived antimicrobial peptide inhibits multidrug-resistant Escherichia coli infection in chickens

Avian colibacillosis (AC), caused by infection with Escherichia coli (E. coli), is a major threat to poultry health, food safety and public health, and results in high mortality and significant economic losses. Currently, new drugs are urgently needed to replace antibiotics due to the continuous emergence and increasing resistance of multidrug-resistant (MDR) strains of E. coli caused by the irrational use of antibiotics in agriculture and animal husbandry. In recent years, antimicrobial peptides (AMPs), which uniquely evolved to protect the host, have emerged as a leading alternative to antibiotics in clinical settings. CATH-2, a member of the antimicrobial cathelicidin peptide family, has been reported to have antibacterial activity. To enhance the antimicrobial potency and reduce the adverse effects on animals, we designed five novel AMPs, named C2-1, C2-2, C2-3, C2-4 and C2-5, based on chicken CATH-2, the secondary structures of these AMPs were consistently α-helical and had an altered net charge and hydrophobicity compared to those of the CATH-2 (1-15) sequences. Subsequently, the antimicrobial activities of CATH-2 (1-15) and five designed peptides against MDR E. coli were evaluated in vitro. Specifically, C2-2 showed excellent antimicrobial activity against either the ATCC standard strain or veterinary clinical isolates of MDR E. coli, with concentrations ranging from 2-8 μg/mL. Furthermore, C2-2 maintained its strong antibacterial efficacy under high temperature and saline conditions, demonstrating significant stability. Similarly, C2-2 retained a high level of safety with no significant hemolytic activity on chicken mature red blood cells or cytotoxicity on chicken kidney cells over the concentration range of 0-64 μg/mL. Moreover, the administration of C2-2 improved the survival rate and reduced the bacterial load in the heart, liver and spleen during MDR E. coli infection in chickens. Additionally, pathological damage to the heart, liver and intestine was prevented when MDR E. coli infected chickens were treated with C2-2. Together, our study showed that C2-2 may be a promising novel therapeutic agent for the treatment of MDR E. coli infections and AC.

Eminent Antimicrobial Peptide Resistance in Zymomonas mobilis: A Novel Advantage of Intrinsically Uncoupled Energetics

Relative to several model bacteria, the ethanologenic bacterium Zymomonas mobilis is shown here to have elevated resistance to exogenous antimicrobial peptides (AMPs)—with regard to both peptide bulk concentration in the medium and the numbers of peptide molecules per cell. By monitoring the integration of AMPs in the bacterial cell membrane and observing the resulting effect on membrane energy coupling, it is concluded that the membranotropic effects of the tested AMPs in Z. mobilis and in Escherichia coli are comparable. The advantage of Z. mobilis over E. coli apparently results from its uncoupled mode of energy metabolism that, in contrast to E. coli, does not rely on oxidative phosphorylation, and hence, is less vulnerable to the disruption of its energy-coupling membrane by AMPs. It is concluded that the high resistance to antimicrobial peptides (AMPs) observed in Z. mobilis not only proves crucial for its survival in its natural environment but also offers a promising platform for AMP production and sheds light on potential strategies for novel resistance development in clinical settings.

Beyond the venom: Exploring the antimicrobial peptides from Androctonus species of scorpion.

Prevalent worldwide, the Androctonus scorpion genus contributes a vital role in scorpion envenoming. While diverse scorpionisms are observed because of several different species, their secretions to protect themselves have been identified as a potent source of antimicrobial peptide (AMP)-like compounds. Distinctly, the venom of these species contains around 24 different AMPs, with definite molecules studied for their therapeutic potential as antimicrobial, antifungal, antiproliferative and antiangiogenic agents. Our review focuses on the therapeutic potential of native and synthetic AMPs identified so far in the Androctonus scorpion genus, identifying research gaps in peptide therapeutics and guiding further investigations. Certain AMPs have demonstrated remarkable compatibility to be prescribed as anticancer drug to reduce cancer cell proliferation and serve as a potent antibiotic alternative. Besides, analyses were performed to explore the characteristics and affinities of peptides for membranes. Overall, the study of AMPs derived from the Androctonus scorpion genus provides valuable insights into their potential applications in medicine and drug development.

Exploring novel peptides in adzuki bean and mung bean hydrolysates with potent antibacterial activity

SummaryThis study delved into the antimicrobial potential of hydrolysates from adzuki bean and mung bean protein concentrates, created using Alcalase and Flavourzyme enzymes. Targeting common foodborne pathogens (Salmonella Typhimurium, Salmonella Enteritidis, Vibrio parahaemolyticus, Staphylococcus aureus, and Bacillus subtilis) and Escherichia coli, the research underscored the crucial role of peptidase in generating antibacterial peptides. Fractions F2 of Flavourzyme hydrolysed adzuki bean (ABF) and F4 of Flavourzyme hydrolysed mung bean (MBF) showed the highest antibacterial activity against S. Typhimurium and S. aureus, respectively, whereas F2 of Alcalase hydrolysed mung bean (MBA) exhibited very poor activity against S. aureus. TripleTOF LC–MS/MS analysis revealed small cationic antibacterial peptides, with lysine being prominent against S. aureus and proline–proline against S. Typhimurium. These findings highlighted the significant contribution of protease enzymes in fostering antibacterial peptide production, offering valuable insights for developing effective antimicrobial agents in the context of food safety.

A peptide-based pH-sensitive antibacterial hydrogel for healing drug-resistant biofilm-infected diabetic wounds.

Diabetic foot ulcers are a significant complication affecting roughly 15% of diabetic patients. These chronic wounds can be incredibly burdensome, leading to high treatment costs, potential amputations, and additional health complications. Microbiological studies reveal that bacterial infections are the primary culprit behind delayed wound healing. To solve the problem of infection at the wound site, the most fundamental thing is to kill the pathogenic bacteria. Herein, a neoteric strategy to construct novel antibacterial hydrogel COA-T3 that combined photosensitizers (PSs) and antimicrobial peptides (AMPs) via covalent coupling was proposed. Hydrogel COA-T3 composed of quaternized chitosan (QCS) and oxidized dextran (OD) was constructed for co-delivery of the photosensitizer TPI-PN and the antimicrobial peptide HHC10. In vitro and in vivo experiments demonstrated remarkable effectiveness of COA-T3 against drug-resistant bacteria. Furthermore, the hydrogel significantly promoted healing of diabetic infected wounds. This enhanced antibacterial activity is attributed to the pH-sensitive release of both PSs and AMPs within the hydrogel. Additionally, COA-T3 exhibits excellent biocompatibility, making it a promising candidate for wound dressing materials. These findings indicated that the COA-T3 hydrogel is a promising wound dressing material for promoting the healing of diabetic foot ulcers by providing an environment conducive to improved wound healing in diabetic patients.

The Effect of the PhoP/PhoQ System on the Regulation of Multi-Stress Adaptation Induced by Acid Stress in Salmonella Typhimurium

Acidic stress in beef cattle slaughtering abattoirs can induce the acid adaptation response of in-plant contaminated Salmonella. This may further lead to multiple resistance responses threatening public health. Therefore, the acid, heat, osmotic and antibiotic resistances of Salmonella typhimurium (ATCC14028) were evaluated after a 90 min adaption in a pH = 5.4 “mild acid” Luria–Bertani medium. Differences in such resistances were also determined between the ∆phoP mutant and wild-type Salmonella strains to confirm the contribution of the PhoP/PhoQ system. The transcriptomic differences between the acid-adapted and ∆phoP strain were compared to explore the role of the PhoP/Q two-component system in regulating multi-stress resistance. Acid adaptation was found to increase the viability of Salmonella to lethal acid, heat and hyperosmotic treatments. In particular, acid adaptation significantly increased the resistance of Salmonella typhimurium to Polymyxin B, and such resistance can last for 21 days when the adapted strain was stored in meat extract medium at 4 °C. Transcriptomics analysis revealed 178 up-regulated and 274 down-regulated genes in the ∆phoP strain. The Salmonella infection, cationic antimicrobial peptide (CAMP) resistance, quorum sensing and two-component system pathways were down-regulated, while the bacterial tricarboxylic acid cycle pathways were up-regulated. Transcriptomics and RT-qPCR analyses revealed that the deletion of the phoP gene resulted in the down-regulation of the expression of genes related to lipid A modification and efflux pumps. These changes in the gene expression result in the change in net negative charge and the mobility of the cell membrane, resulting in enhanced CAMP resistance. The confirmation of multiple stress resistance under acid adaptation and the transcriptomic study in the current study may provide valuable information for the control of multiple stress resistance and meat safety.

Metabolic pathways and antimicrobial peptide resistance in bacteria.

Antimicrobial resistance is a pressing concern that poses a significant threat to global public health, necessitating the exploration of alternative strategies to combat drug-resistant microbial infections. Recently, antimicrobial peptides (AMPs) have gained substantial attention as possible replacements for conventional antibiotics. Because of their pharmacodynamics and killing mechanisms, AMPs display a lower risk of bacterial resistance evolution compared with most conventional antibiotics. However, bacteria display different mechanisms to resist AMPs, and the role of metabolic pathways in the resistance mechanism is not fully understood. This review examines the intricate relationship between metabolic genes and AMP resistance, focusing on the impact of metabolic pathways on various aspects of resistance. Metabolic pathways related to guanosine pentaphosphate (pppGpp) and guanosine tetraphosphate (ppGpp) [collectively (p)ppGpp], the tricarboxylic acid (TCA) cycle, haem biosynthesis, purine and pyrimidine biosynthesis, and amino acid and lipid metabolism influence in different ways metabolic adjustments, biofilm formation and energy production that could be involved in AMP resistance. By targeting metabolic pathways and their associated genes, it could be possible to enhance the efficacy of existing antimicrobial therapies and overcome the challenges exhibited by phenotypic (recalcitrance) and genetic resistance toward AMPs. Further research in this area is needed to provide valuable insights into specific mechanisms, uncover novel therapeutic targets, and aid in the fight against antimicrobial resistance.

Evidence that Alzheimer's Disease Is a Disease of Competitive Synaptic Plasticity Gone Awry.

Mounting evidence indicates that a physiological function of amyloid-β (Aβ) is to mediate neural activity-dependent homeostatic and competitive synaptic plasticity in the brain. I have previously summarized the lines of evidence supporting this hypothesis and highlighted the similarities between Aβ and anti-microbial peptides in mediating cell/synapse competition. In cell competition, anti-microbial peptides deploy a multitude of mechanisms to ensure both self-protection and competitor elimination. Here I review recent studies showing that similar mechanisms are at play in Aβ-mediated synapse competition and perturbations in these mechanisms underpin Alzheimer's disease (AD). Specifically, I discuss evidence that Aβ and ApoE, two crucial players in AD, co-operate in the regulation of synapse competition. Glial ApoE promotes self-protection by increasing the production of trophic monomeric Aβ and inhibiting its assembly into toxic oligomers. Conversely, Aβ oligomers, once assembled, promote the elimination of competitor synapses via direct toxic activity and amplification of "eat-me" signals promoting the elimination of weak synapses. I further summarize evidence that neuronal ApoE may be part of a gene regulatory network that normally promotes competitive plasticity, explaining the selective vulnerability of ApoE expressing neurons in AD brains. Lastly, I discuss evidence that sleep may be key to Aβ-orchestrated plasticity, in which sleep is not only induced by Aβ but is also required for Aβ-mediated plasticity, underlining the link between sleep and AD. Together, these results strongly argue that AD is a disease of competitive synaptic plasticity gone awry, a novel perspective that may promote AD research.