Altered Membrane Permeability Research Articles

Combating Antibiotic Resistance: Mechanisms, Multidrug-Resistant Pathogens, and Novel Therapeutic Approaches: An Updated Review

The escalating global health crisis of antibiotic resistance, driven by the rapid emergence of multidrug-resistant (MDR) bacterial pathogens, necessitates urgent and innovative countermeasures. This review comprehensively examines the diverse mechanisms employed by bacteria to evade antibiotic action, including alterations in cell membrane permeability, efflux pump overexpression, biofilm formation, target site modifications, and the enzymatic degradation of antibiotics. Specific focus is given to membrane transport systems such as ATP-binding cassette (ABC) transporters, resistance–nodulation–division (RND) efflux pumps, major facilitator superfamily (MFS) transporters, multidrug and toxic compound extrusion (MATE) systems, small multidrug resistance (SMR) families, and proteobacterial antimicrobial compound efflux (PACE) families. Additionally, the review explores the global burden of MDR pathogens and evaluates emerging therapeutic strategies, including quorum quenching (QQ), probiotics, postbiotics, synbiotics, antimicrobial peptides (AMPs), stem cell applications, immunotherapy, antibacterial photodynamic therapy (aPDT), and bacteriophage. Furthermore, this review discusses novel antimicrobial agents, such as animal-venom-derived compounds and nanobiotics, as promising alternatives to conventional antibiotics. The interplay between clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) in bacterial adaptive immunity is analyzed, revealing opportunities for targeted genetic interventions. By synthesizing current advancements and emerging strategies, this review underscores the necessity of interdisciplinary collaboration among biomedical scientists, researchers, and the pharmaceutical industry to drive the development of novel antibacterial agents. Ultimately, this comprehensive analysis provides a roadmap for future research, emphasizing the urgent need for sustainable and cooperative approaches to combat antibiotic resistance and safeguard global health.

Insights into the mobility and bacterial hosts of antibiotic resistance genes under dinotefuran selection pressure in aerobic granular sludge based on metagenomic binning and functional modules.

Insights into the mobility and bacterial hosts of antibiotic resistance genes under dinotefuran selection pressure in aerobic granular sludge based on metagenomic binning and functional modules.

Peroxidase-like copper-doped carbon-dots embedded in hydrogels for stimuli-responsive bacterial biofilm elimination and wound healing.

Peroxidase-like copper-doped carbon-dots embedded in hydrogels for stimuli-responsive bacterial biofilm elimination and wound healing.

The Evolution of Antimicrobial Resistance in Acinetobacter baumannii and New Strategies to Fight It.

Acinetobacter baumannii is considered one of the prioritized ESKAPE microorganisms for the research and development of novel treatments by the World Health Organization, especially because of its remarkable persistence and drug resistance. In this review, we describe how this can be acquired by the enzymatic degradation of antibiotics, target site modification, altered membrane permeability, multidrug efflux pumps, and their ability to form biofilms. Also, the evolution of drug resistance in A. baumannii, which is mainly driven by mobile genetic elements, is reported, with particular reference to plasmid-associated resistance, resistance islands, and insertion sequences. Finally, an overview of existing, new, and alternative therapies is provided.

Bacteriophage Treatment Induces Phenotype Switching and Alters Antibiotic Resistance of ESBL Escherichia coli.

Background/Objectives: Bacteriophage therapy represents a promising strategy to combat multidrug-resistant pathogens, such as Escherichia coli. In this study, we explored the effects of a bacteriophage infection on an Extended Spectrum Beta-Lactamase (ESBL) positive E. coli isolate. Methods: We used next generation sequencing, proteomics and phenotypic screens to investigate the effect of bacteriophage infections on E. coli metabolism and resistance phenotypes. Results: The bacteriophage infection led to notable alterations in colony morphology, indicating profound changes in bacterial metabolism. Proteomic analysis revealed significant shifts in protein expression, with 65 proteins upregulated and 246 downregulated post-infection. The downregulated proteins were involved in various metabolic pathways, including nucleic acid, protein and lipid metabolism, and iron acquisition. Bacteriophage treatment also led to increased bacterial membrane permeability. Altogether, these alterations in bacterial metabolism and membrane permeability may lead to a general reduction in antibiotic resistance. Indeed, the bacteriophage-infected E. coli exhibited increased sensitivity to various classes of antibiotics, including beta-lactams, fluoroquinolones, trimethoprim-sulfamethoxazole, and aminoglycosides. Conclusions: Our findings highlight the potential of bacteriophage therapy as an adjunct to existing antibiotics, enhancing their efficacy against resistant strains.

Improved mechanism of the bioactive compounds isolated from Lactobacillus plantarum TWK10-fermented soymilk in periodontal disease.

Lactic acid bacteria (LAB) possess immunomodulatory, antioxidant, and antimicrobial properties, making them promising for oral health applications. This study investigated the antibacterial and anti-biofilm activities of TWK10-fermented soymilk extract (TWK10FSEE) against Porphyromonas gingivalis (Pg) and Aggregatibacter actinomycetemcomitans (Aa). TWK10FSEE disrupted the cell membrane integrity, altered membrane permeability, and inhibited the growth of these periodontal pathogens. In a drip-flow biofilm reactor simulating the oral environment, TWK10FSEE regulated biofilm-related gene expression, reduced fimbriae and extracellular polysaccharide production, and retarded biofilm formation. Structural identification revealed succinic acid (SA) and a mixture of daidzein and genistein (MDG) as the primary antimicrobial components. Both SA and MDG effectively inhibited Pg and Aa growth and biofilm formation. TWK10FSEE shows potential as a functional ingredient for periodontal health.

Mitochondrial dysfunction in pancreatic acinar cells: mechanisms and therapeutic strategies in acute pancreatitis.

Acute pancreatitis (AP) is an inflammatory disease of the pancreas and a complex process involving multiple factors, with mitochondrial damage playing a crucial role. Mitochondrial dysfunction is now considered a key driver in the development of AP. This dysfunction often presents as increased oxidative stress, altered membrane potential and permeability, and mitochondrial DNA damage and mutations. Under stress conditions, mitochondrial dynamics and mitochondrial ROS production increase, leading to decreased mitochondrial membrane potential, imbalanced calcium homeostasis, and activation of the mitochondrial permeability transition pore. The release of mitochondrial DNA (mtDNA), recognized as damage-associated molecular patterns, can activate the cGAS-STING1 and NF-κB pathway and induce pro-inflammatory factor expression. Additionally, mtDNA can activate inflammasomes, leading to interleukin release and subsequent tissue damage and inflammation. This review summarizes the relationship between mitochondria and AP and explores mitochondrial protective strategies in the diagnosis and treatment of this disease. Future research on the treatment of acute pancreatitis can benefit from exploring promising avenues such as antioxidants, mitochondrial inhibitors, and new therapies that target mitochondrial dysfunction.

Metagenomic Analysis Reveals the Effects of Microplastics on Antibiotic Resistance Genes in Sludge Anaerobic Digestion.

Sewage sludge is recognized as both a source and a reservoir for antibiotic resistance genes (ARGs). Within an anaerobic digestion (AD) system, the presence of microplastics (MPs) has been observed to potentially facilitate the proliferation of these ARGs. Understanding the influence of MPs on microbial behavior and horizontal gene transfer (HGT) within the AD system is crucial for effectively managing the dissemination of ARGs in the environment. This study utilized metagenomic approaches to analyze the dynamics of various types of ARGs and potential microbial mechanisms under exposure to MPs during the AD process. The findings indicated that MPs in the AD process can enhance the proliferation of ARGs, with the extent of this enhancement increasing with the dosage of MPs: polyethylene (PE), polyethylene terephthalate (PET), and polylactic acid (PLA) MPs increased the abundance of ARGs in the anaerobic digestion system by up to 29.90%, 18.64%, and 14.15%, respectively. Additionally, the presence of MPs increased the relative abundance of mobile genetic elements (MGEs) during the AD process. Network correlation analysis further revealed that plasmids represent the predominant category of MGEs involved in the HGT of ARGs. Propionibacterium and Alicycliphilus were identified as the primary potential hosts for these ARGs. The results of gene function annotation indicated that exposure to MPs led to an increased the relative abundance of genes related to the production of reactive oxygen species (ROS), alterations in membrane permeability, ATP synthesis, and the secretion of extracellular polymeric substances (EPS). These genes play crucial roles in influencing the HGT of ARGs.

Targeting cholangiocarcinoma cells by cold piezoelectric plasmas: in vitro efficacy and cellular mechanisms

Cold piezoelectric plasma (CPP) is a novel approach in cancer therapy, enabling the development of portable treatment devices capable of triggering cancer cell death. While its effectiveness remains underexplored, this research focuses on its application against cholangiocarcinoma (CCA), an aggressive cancer of the biliary tract. A CPP device is utilized to generate either a corona discharge (Pz-CD) or a dielectric barrier discharge (Pz-DBD) for in vitro experiments. Notably, Pz-CD can deliver more power than Pz-DBD, although both sources produce significant levels of reactive species in plasma and liquid phases. This work shows that CPP causes a gradient increase in medium temperature from the center towards the edges of the culture well, especially for longer treatment times. Although Pz-CD heats more significantly, it cools quickly after plasma extinction. When applied to human CCA cells, CPP shows immediate and long-term effects, more localized for Pz-CD, while more uniform for Pz-DBD. Immediate effects result also in actin cytoskeleton remodeling without alteration of the cell membrane permeability. Long-term effects of CPP, although the antioxidant system is engaged, include activation of the DNA damage response pathway leading to cell death. In conclusion, CPP should be recognized as a promising antitumor therapy.

Assessment of molecular modulation by multifrequency electromagnetic pulses to preferably eradicate tumorigenic cells

Physics methods of cancer therapy are extensively used in clinical practice, but they are invasive and often confront undesired side effects. A fully new equipment that allows sustained emission of intense and time-controlled non-ionizing multifrequency electromagnetic pulse (MEMP), has been applied to eukaryotic cells in culture. The equipment discriminates the overall electronegative charge of the cell cultures, and its subsequent proportional emission may thereby become higher and lethal to cancer cells of generally high metabolic activity. In contrast, low tumorigenic cells would be much less affected. We tested the specificity and efficacy of the equipment against a collection of (i) highly tumorigenic cells of human (glioblastoma, cervical carcinoma, and skin) and mouse (colon adenocarcinoma) origin; (ii) cell lines of much lower tumorigenicity (non-human primate kidney and mouse fibroblasts), and (iii) primary porcine macrophages lacking tumorigenicity. Time and intensity control of the MEMP allowed progressive decay of viability fairly correlating to cell tumorigenicity, which was provoked by a proportional alteration of the cytoplasmic membrane permeability, cell cycle arrest at G2, and general collapse of the actin cytoskeleton to the perinuclear region. Correspondingly, these effects drastically inhibited the proliferative capacity of the most tumorigenic cells in clonogenic assays. Moreover, MEMP suppressed in a dose-dependent manner the tumorigenicity of retrovirally transduced luciferase expressing colon adenocarcinoma cells in xenografted immune-competent mice, as determined by tumor growth in a bioluminescence imaging system. Our results support MEMP as an anti-cancer non-invasive physical treatment of substantial specificity for tumorigenic cells with promising therapeutic potential in oncology.

Colistin Resistance Mechanism and Management Strategies of Colistin-Resistant Acinetobacter baumannii Infections.

The emergence of antibiotic-resistant Acinetobacter baumannii (A. baumannii) is a pressing threat in clinical settings. Colistin is currently a widely used treatment for multidrug-resistant A. baumannii, serving as the last line of defense. However, reports of colistin-resistant strains of A. baumannii have emerged, underscoring the urgent need to develop alternative medications to combat these serious pathogens. To resist colistin, A. baumannii has developed several mechanisms. These include the loss of outer membrane lipopolysaccharides (LPSs) due to mutation of LPS biosynthetic genes, modification of lipid A (a constituent of LPSs) structure through the addition of phosphoethanolamine (PEtN) moieties to the lipid A component by overexpression of chromosomal pmrCAB operon genes and eptA gene, or acquisition of plasmid-encoded mcr genes through horizontal gene transfer. Other resistance mechanisms involve alterations of outer membrane permeability through porins, the expulsion of colistin by efflux pumps, and heteroresistance. In response to the rising threat of colistin-resistant A. baumannii, researchers have developed various treatment strategies, including antibiotic combination therapy, adjuvants to potentiate antibiotic activity, repurposing existing drugs, antimicrobial peptides, nanotechnology, photodynamic therapy, CRISPR/Cas, and phage therapy. While many of these strategies have shown promise in vitro and in vivo, further clinical trials are necessary to ensure their efficacy and widen their clinical applications. Ongoing research is essential for identifying the most effective therapeutic strategies to manage colistin-resistant A. baumannii. This review explores the genetic mechanisms underlying colistin resistance and assesses potential treatment options for this challenging pathogen.

Targeting Lipid Metabolism in Cancer Stem Cells for Anticancer Treatment.

Cancer stem cells (CSCs), or tumor-initiating cells (TICs), are small subpopulations (0.0001-0.1%) of cancer cells that are crucial for cancer relapse and therapy resistance. The elimination of each CSC is essential for achieving long-term remission. Metabolic reprogramming, particularly lipids, has a significant impact on drug efficacy by influencing drug diffusion, altering membrane permeability, modifying mitochondrial function, and adjusting the lipid composition within CSCs. These changes contribute to the development of chemoresistance in various cancers. The intricate relationship between lipid metabolism and drug resistance in CSCs is an emerging area of research, as different lipid species play essential roles in multiple stages of autophagy. However, the link between autophagy and lipid metabolism in the context of CSC regulation remains unclear. Understanding the interplay between autophagy and lipid reprogramming in CSCs could lead to the development of new approaches for enhancing therapies and reducing tumorigenicity in these cells. In this review, we explore the latest findings on lipid metabolism in CSCs, including the role of key regulatory enzymes, inhibitors, and the contribution of autophagy in maintaining lipid homeostasis. These recent findings may provide critical insights for identifying novel pharmacological targets for effective anticancer treatment.

Lysosomal disruption, mitochondrial impairment, histopathological and oxidative stress in rat's nervous system after exposure to a neonicotinoid (imidacloprid).

Imidacloprid (IMI), a neonicotinoid pesticide, has been widely used due to its high efficiency against insect pests. However, its prolonged exposure may pose significant risks to non-target organisms, including mammals. Recent studies have raised concerns about its potential neurotoxicity, yet the underlying mechanisms remain poorly understood. This study aimed to assess the neurotoxic effects of chronic Imidacloprid exposure in Wistar rats, focusing on oxidative stress, mitochondrial dysfunction, and lysosomal disruption. Wistar rats were orally administered two doses of Imidacloprid (5mg/kg and 50mg/kg body weight) for three months. Neurotoxic effects were assessed by measuring key biochemical markers such as the enzymatic activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and glutathione S-transferase (GST). Non-enzymatic markers, including glutathione (GSH) levels and malondialdehyde (MDA) index, were also evaluated. Mitochondrial function was assessed by analyzing oxygen consumption, swelling, and membrane permeability and histopathological changes. Lysosomal stability was examined using the Neutral Red Retention Time (NRRT) assay. Neutral red is a dye that accumulates in the acidic environment of lysosomes. Healthy lysosomes retain the dye, while compromised lysosomes lose it, indicating destabilization. By measuring the amount of neutral red retained in lysosomes, the NRRT assay assesses lysosomal integrity. Lysosomal pH variations were also monitored to evaluate functional changes. Microscopic analysis provided insight into structural changes in lysosomes and other cell components. Lysosomal destabilization was further confirmed by morphological alterations observed through light microscopy, revealing a progressive, time-dependent degeneration of lysosomal structures, including lysosomal expansion, neutral red dye leakage, and cell rounding. These changes reflected a temporal evolution of lysosomal damage, progressing from minor structural disruptions to more severe alterations as exposure continued, observable at the microscopic level. During the study, clinical observations of intoxicated rats included symptoms such as lethargy, reduced activity levels, and impaired motor coordination. High-dose Imidacloprid exposure led to noticeable behavioral changes, including decreased exploratory behavior and altered grooming patterns. Additionally, signs of neurotoxic effects, such as tremors or ataxia, were observed in the rats exposed to the higher dose, reflecting the systemic impact of chronic pesticide exposure. The results revealed a significant decrease in the enzymatic activities of CAT, GPx, and SOD, accompanied by an increase in GST activity. A notable reduction in glutathione levels and a rise in MDA index were observed, indicating enhanced oxidative stress in the brain. Mitochondrial impairment was evidenced by disturbances in oxygen consumption, increased swelling, and altered membrane permeability. Lysosomal destabilization was confirmed by reduced retention of neutral red dye, structural changes in lysosomes, and a significant rise in lysosomal pH in the IMI-exposed groups. In addition, the histopathological features indicate that imidacloprid at the given dose and exposure duration may have caused notable neurotoxic effects in Wistar rat brain tissue. Chronic exposure to Imidacloprid induces oxidative stress, mitochondrial dysfunction, lysosomal disruption and histopathological alterations in the central nervous system of Wistar rats. These findings provide valuable insights into the neurotoxic mechanisms of neonicotinoid pesticides, highlighting the need for further research to understand the long-term effects of Imidacloprid exposure on mammalian health.

648P MRI demonstrates altered skeletal muscle membrane permeability in Becker muscular dystrophy, representing a potential biomarker for disease activity

648P MRI demonstrates altered skeletal muscle membrane permeability in Becker muscular dystrophy, representing a potential biomarker for disease activity

Combinatorial Effects of Ursodeoxycholic Acid and Antibiotic in Combating Staphylococcus aureus Biofilm: The Roles of ROS and Virulence Factors.

Staphylococcus aureus is a biofilm-forming bacterium responsible for various human infections, one particularly challenging to treat due to its antibiotic resistance. Biofilms can form on both soft tissues and medical devices, leading to persistent and hard-to-treat infections. Combining multiple antimicrobials is a potential approach to overcoming this resistance. This study explored the effects of ursodeoxycholic acid (UDCA) combined with the antibiotic ciprofloxacin against S. aureus biofilms, aiming to evaluate any synergistic effects. Results showed that UDCA and ciprofloxacin co-treatment significantly reduced biofilm formation and disrupted pre-formed biofilms more effectively than either agent alone (p < 0.01). The combination also displayed a slight synergistic effect, with a fractional inhibitory concentration of 0.65. Additionally, the treatment reduced the production of extracellular polymeric substances, increased reactive oxygen species production, decreased metabolic activity, altered cell membrane permeability, and lowered cell surface hydrophobicity in S. aureus. Furthermore, it diminished biofilm-associated pathogenic factors, including proteolytic activity and staphyloxanthin production. Overall, the UDCA-ciprofloxacin combination shows considerable promise as a strategy to combat infections related to staphylococcal biofilms, offering a potential solution to the healthcare challenges posed by antibiotic-resistant S. aureus.

Thiazine-derived compounds in inhibiting efflux pump in Staphylococcus aureus K2068, mepA gene expression, and membrane permeability alteration

Thiazine-derived compounds in inhibiting efflux pump in Staphylococcus aureus K2068, mepA gene expression, and membrane permeability alteration

Recent Advances in Marine-Derived Compounds as Potent Antibacterial and Antifungal Agents: A Comprehensive Review.

The increase in antimicrobial resistance (AMR) in microorganisms is a significant global health concern. Various factors contribute to AMR, including alterations in cell membrane permeability, increased efflux pump activity, enzymatic modification or inactivation of antibiotics, target site changes, alternative metabolic pathways, and biofilm formation. Marine environments, with their extensive biodiversity, provide a valuable source of natural products with a wide range of biological activities. Marine-derived antimicrobial compounds show significant potential against drug-resistant bacteria and fungi. This review discusses the current knowledge on marine natural products such as microorganisms, sponges, tunicates and mollusks with antibacterial and antifungal properties effective against drug-resistant microorganisms and their ecological roles. These natural products are classified based on their chemical structures, such as alkaloids, amino acids, peptides, polyketides, naphthoquinones, terpenoids, and polysaccharides. Although still in preclinical studies, these agents demonstrate promising in vivo efficacy, suggesting that marine sources could be pivotal in developing new drugs to combat AMR, thereby fulfilling an essential medical need. This review highlights the ongoing importance of marine biodiversity exploration for discovering potential antimicrobial agents.

Antimicrobial activity and mechanisms of carbon quantum dot decorated modified zinc oxide nanoparticles against oral pathogenic bacteria

Antimicrobial activity and mechanisms of carbon quantum dot decorated modified zinc oxide nanoparticles against oral pathogenic bacteria

The potential of antifungal peptides derived from Lactiplantibacillus plantarum WYH for biocontrol of Aspergillus flavus contamination

The potential of antifungal peptides derived from Lactiplantibacillus plantarum WYH for biocontrol of Aspergillus flavus contamination

Exploring therapeutic approaches against Naegleria fowleri infections through the COVID box

Exploring therapeutic approaches against Naegleria fowleri infections through the COVID box