Drug-resistant Infections Research Articles

Antimicrobial Potentials of Haliclona fibulata Derived Compounds for Combatting Drug-Resistant Bacterial Infections in Zebrafish Model.

The rising threat of antimicrobial resistance among pathogens highlights the critical need for novel antimicrobial agents. This study explores the potential of natural products by investigating hexane extracts from the marine sponge Haliclona fibulata (HF) for their antibacterial efficacy. The well diffusion method of HF extract showed significant antibacterial activity against P. aeruginosa, E. coli and S. aureus with inhibition zones of 20 ± 0.66 mm, 27 ± 0.58 mm, and 22 ± 0.33 mm, respectively. Scanning electron microscopy investigations confirmed the disruptive impact of the extracts on bacterial cell morphology. Further investigations using P. aeruginosa-infected zebrafish model revealed that HF treatment improved survival rates in a dose-dependent manner. Additionally, oxidative stress and apoptosis were significantly reduced in the 100 μg/mL (HF100) treatment group, alongside down-regulation of inflammatory markers such as il-1β, nf-kβ, tnf-α, and inos. Histological assessments showed reduced intestinal damage and fewer circulating macrophages in HF100-treated zebrafish larvae. Identifying potent bioactive compounds within the extracts suggests that HFcould be a valuable source of natural antimicrobials, warranting further exploration for developing treatments against pathogenic infections.

Deep Red-Light-Mediated Nitric Oxide and Photodynamic Synergistic Antibacterial Therapy for the Treatment of Drug-Resistant Bacterial Infections.

Infections caused by persistent, drug-resistant bacteria pose significant challenges in inflammation treatment, often leading to severe morbidity and mortality. Herein, the photosensitizer rhodamine derivatives are selected as the light-trapping dye and the electron-rich substituent N-nitrosoaminophen as the nitric oxide (NO)-releasing component to develop a multifunctional (deep) red-light activatable NO photocage/photodynamic prodrug for efficient treatment of wounds and diabetic foot infections. The prodrug, RhB-NO-2 integrates antimicrobial photodynamic therapy (aPDT), NO sterilization, and NO-mediated anti-inflammatory properties within a small organic molecule and is capable of releasing NO and generating Reactive oxygen species (ROS) when exposed to (deep) red laser (660nm). This strategy overcomes the limitation of using a single photosensitizer, which is often inadequate for eliminating drug-resistant bacteria. Additionally, it demonstrates that NO released from the prodrug can interact with superoxide anions (O2 •-) generated by PDT to form a more reactive and oxidative agent, peroxynitrite (ONOO-). These three components act synergistically to enhance the antimicrobial effects. Furthermore, the released NO can inhibit the NF-κB pathway by regulating the expression of toll-like receptor 2 (TRL2) and tumor necrosis factor-α (TNF-α), thereby alleviating tissue inflammation. The developed prodrug ， RhB-NO-2 has the potential to expedite the healing of superficial infected wounds and offer a promising approach for treating diabetic foot ulcers (DFUs).

CMCS-PVA@CA hydrogel dressing: A promoter of wound healing with MRSA virulence attenuation function.

Traditional wound dressings, primarily centered on antimicrobial or bactericidal strategies, have inadvertently contributed to the rise of drug-resistant bacterial colonies at wound sites, thus prolonging the healing process. In this study, we developed an innovative hydrogel dressing, CMCS-PVA@CA, incorporating carboxymethyl chitosan (CMCS), polyvinyl alcohol (PVA), and cichoric acid (CA), specifically designed to treat skin wounds infected with methicillin-resistant Staphylococcus aureus (MRSA). Computational biology analyses reveal that CA exerts substantial anti-virulence activity by targeting serine/threonine phosphatase (Stp1), achieving an IC50 of 3.912μM, thereby mitigating MRSA pathogenicity. Notably, CA lacks intrinsic antibacterial properties, minimizing the risk of fostering drug resistance. Furthermore, CMCS-PVA@CA demonstrates effective wound healing acceleration and meets clinical application standards, with its robust mechanical properties enhancing patient comfort. In essence, this study presents CMCS-PVA@CA as a promising hydrogel dressing offering a viable solution for treating drug-resistant bacterial infections in skin wounds.

Ventilator-Associated Pneumonia After Cardiac Arrest and Prevention Strategies: A Narrative Review.

Background and Objectives: Ventilator-associated pneumonia (VAP) poses a significant threat to the clinical outcomes and hospital stays of mechanically ventilated patients, particularly those recovering from cardiac arrest. Given the already elevated mortality rates in cardiac arrest cases, the addition of VAP further diminishes the chances of survival. Consequently, a paramount focus on VAP prevention becomes imperative. This review endeavors to comprehensively delve into the nuances of VAP, specifically in patients requiring mechanical ventilation in post-cardiac arrest care. The overarching objectives encompass (I) exploring the etiology, risk factors, and pathophysiology of VAP, (II) delving into available diagnostic modalities, and (III) providing insights into the management options and recent treatment guidelines. Methods: A literature search was conducted using PubMed, MEDLINE, and Google Scholar databases for articles about VAP and Cardiac arrest. We used the MeSH terms "VAP", "Cardiac arrest", "postcardiac arrest syndrome", and "postcardiac arrest syndrome". The clinical presentation, diagnostic, and management strategies of VAP were summarized, and all authors reviewed the selection and decided which studies to include. Key Content and Findings: The incidence and mortality rates of VAP exhibit significant variability, yet a recurring pattern emerges, marked by prolonged hospitalization and exacerbated clinical outcomes. This pattern is attributed to the elevated incidence of drug-resistant infections and the delayed initiation of antimicrobial treatment. This review focuses on VAP, aiming to offer valuable insights into the efficient identification and management of this fatal complication in post-cardiac arrest patients. Conclusion: The prognosis for survival after cardiac arrest is already challenging, and the outlook becomes even more daunting when complicated by VAP. The timely diagnosis of VAP and initiation of antibiotics pose considerable challenges, primarily due to the invasive nature of obtaining high-quality samples and the time required for speciation and identification of antimicrobial sensitivity. The controversy surrounding prophylactic antibiotics persists, but promising new strategies have been proposed; however, they are still awaiting well-designed clinical trials.

Metabolic response to burn injury: a comprehensive bibliometric study.

Burns lead to systemic changes manifested by systemic disturbances in water-electrolyte balance and systemic metabolic and inflammatory responses. The hypermetabolic response after a burn injury relies on metabolic, hormonal, and inflammatory dysregulation mechanisms. This study aimed to provide a comprehensive bibliometric analysis of the burn metabolism research field, identifying key trends, influential contributors, and emerging research hotspots to inform future investigative efforts. Ultimately, we conducted an extensive review of the literature, synthesizing the findings to clarify the present understanding within our field of study. We obtained 8,823 scientific publications on burn injury and metabolism from the core Web of Science (WOS) database collection. In this work, biblioshiny was used to visualize and analyze the data, and VOSviewer was used to verify the results. From a total of 8,823 publications, we found a general upward trend in annual publications and citation frequency. According to Bradford's Law, 21 high-production journals were classified as core sources based on the number of publications, and the most productive journal was Burns. The most published countries and authors in this field were the United States and Herndon DN. The most local cited document in this field was the article titled "Catecholamines: Mediator of the Hypermetabolic Response to Thermal Injury" authored by Wilmore DW. The thematic map showed that studies on injury, thermal injury, and sepsis were relatively mature. In contrast, research on metabolism, stress, and responses, and research on mortality, resistance, and management were less well-developed but were essential for the field. Research on burns and metabolism is increasing. Based on the bibliometric analysis, our study summarized the complex interplay between burn-induced systemic metabolic alterations and inflammatory responses, emphasizing the significance of hypermetabolism and its management. The role of propranolol, insulin, oxandrolone, and nutritional interventions in modulating the hypermetabolic state was discussed. Additionally, our study underscored the challenges of managing sepsis and drug-resistant infections in burn patients as an important future area of research.

Aprepitant ameliorates vancomycin-induced kidney injury: Role of GPX4/system Xc- and oxidative damage.

Vancomycin, a glycopeptide antibiotic, is used in cases of drug-resistant bacterial infections, but unfortunately is associated with acute kidney injury (AKI). We here explore the protective potential of aprepitant against vancomycin-induced AKI. Vancomycin (500mg/kg/i.p) was given to rats for seven days and aprepitant (20mg/kg/p.o) was administered one day before and for seven days concomitant with vancomycin. At the end of the experiment, kidney function, oxidative stress, autophagy and ferroptosis markers were assessed. We show that aprepitant reduced kidney/body weight ratio, serum creatinine and blood urea nitrogen levels. It improved renal structure and enhanced the antioxidant machinery as indicated by elevated catalase activity and GSH levels and reduced renal MDA. Aprepitant managed to inhibit ferroptosis by decreasing system Xc- and GPX4 renal levels. As a result, levels of autophagic markers ATG3, LC3A and LC3B were attenuated. These results were confirmed by electron microscopy examination of cellular structures. In addition, aprepitant increased p62 protein expression. Moreover, aprepitant decreased the apoptotic marker cleaved caspase-3 levels. Our results suggest a new repurposed role for aprepitant in protecting against AKI. This protective effect relies on its antioxidant effect and the influence of inhibiting ferroptosis which resulted in downregulation of autophagy and apoptosis.

Microwave-Assisted Synthesized ZnO@APTES Quantum Dots Exhibits Potent Antibacterial Efficacy Against Methicillin-Resistant Staphylococcus aureus Without Inducing Resistance.

Antibiotic resistance of many bacteria, including Methicillin-resistant Staphylococcus aureus (MRSA), has become a major threat to global health. Zinc Oxide Quantum dots (ZnO-QDs) show good antibacterial activity, but most of them are insoluble in water, limiting their application range, and there is a lack of research on drug resistance inducement. The water-soluble zinc oxide quantum dots modified by APTES (ZnO@APTES QDs) were prepared by a microwave assisted synthesis. Then ZnO@APTES QDs were characterized through various methods. After confirmation of synthesized ZnO@APTES QDs, its bactericidal effect on MRSA was detected through in vitro and in vivo experiments, and its mechanism of action was analyzed. Characterization analysis revealed that the ZnO@APTES QDs have a particle size of 5 nm. The minimum inhibitory concentrations (MIC) were determined to be 64 µg mL-1 for Escherichia coli (E. coli) and 32 µg mL-1 for MRSA. The ZnO@APTES QDs showed significant inhibition of MRSA biofilm formation and effectively disrupted mature biofilms. Notably, the ZnO@APTES QDs did not induce tolerance or resistance even after 30 days of repeated exposure, whereas antibiotics led to a rise in bacterial MIC within 3 days and a 60-fold increase after 30 days. Mechanistic analysis indicated that the positively charged quantum dots interact with bacterial surfaces, altering membrane fluidity. Once inside the bacteria, the ZnO@APTES QDs generate reactive oxygen species (ROS), causing DNA damage and bacterial cell death. Moreover, the ZnO@APTES QDs possessed good biocompatibility and demonstrated significant therapeutic efficacy against drug-resistant bacterial infections in both macrophage and mouse wound infection models. In summary, we have synthesized a highly effective water-soluble ZnO@APTES QDs that shows strong antibacterial and therapeutic efficacy against MRSA and other bacteria. The ZnO@APTES QDs holds significant potential for development as a new treatment agent for combating antibiotic-resistant infections.

Synthesis, biological evaluation and validation of IMB-881 derivatives as anti-Gram-negative bacterial agents.

Infectious diseases caused by drug-resistant bacteria represent one of the most significant global public challenges of this century. There is an urgent need for the treatment of drug-resistant Gram-negative bacterial infections. A series of 3,4-dihydro-2H-[1,3]oxazino[5,6-h]quinoline derivatives were synthesized and evaluated for their antibacterial activity against Gram-negative bacteria including strains from ATCC and clinical isolates, initially revealing the structure-activity relationship. Among them, 22 compounds demonstrated inhibitory activity (MICs: 3.125-12.5μg/mL) against Escherichia coli (E. coli) ATCC 25922 and Acinetobacter baumannii (A. baumannii) ATCC 19606. Among these, 7 compounds exhibited good inhibitory activity against MDR A. baumannii clinical isolates, with MICs ranging from 3.125 to 12.5μg/mL. Most of these compounds also showed lower cytotoxicity than IMB-881. Notably, 2 compounds, 4n1 and 4b3, significantly extended the survival of Galleria mellonella larvae infected with E. coli. Mechanism studies have revealed that compounds 4n1 and 4b3 might disrupt the interaction between LptA and LptC, showing moderate affinity for LptA protein. These compounds also induce abnormal bacterial morphology and cause outer membrane damage. This finding provides a novel class of antibiotic sensitizers with the potential to effectively fight against E. coli and A. baumannii.

Nitrofurantoin Drug Resistance Among Gram-Negative Bacteria Isolated from Urinary Tract Infections

Background Nitrofurantoin is a preferred choice of antibiotic for treating urinary tract infections UTIs caused by vancomycin-sensitive and vancomycin-resistant strains including cases associated with catheter use. Recently there has been an emergence of resistance among Enterobacteriaceae Gram negative bacteria and this indicates extensively drug resistant XDR phenotype that makes the treatment of uncomplicated UTI difficult.Methods Clean catch midstream urine sample was collected from adults after providing instructions about the method of sample collection. Catheter specimen was collected in non-ambulatory patients. Collection of sample from urine bag was strictly avoided. The samples were transported at the earliest to the laboratory and subjected to processing as per the standard operative procedure for processing urine specimen. Microscopy semi-quantitative culture of the colonies species identification and antibiotic susceptibility tests of the organisms isolated were performed. Special reference to nitrofurantoin susceptibility was noted.Results Out of the 50 samples collected from patients who reported with the symptoms of UTI 78 exhibited growth while 22 showed no growth. Escherichia coli was the most frequently isolated organism followed by Klebsiella pneumoniae Pseudomonas species. Nitrofurantoin resistance was the highest in Acinetobacter sp.Conclusion Nitrofurantoin drug is commonly prescribed in uncomplicated UTIs and is frequently used in the treatment of multi drug resistant infections. It is very important to identify urinary tract pathogens up to species level. This avoids prescription of Nitrofurantoin in cases where organisms with increasing resistance have been identified.

Efficacy of lipid nanoparticles-based vaccine to protect against vulvovaginal candidiasis (VVC): Implications for women's reproductive health.

Vulvovaginal candidiasis (VVC) is a common women's health issue, with rising antifungal resistance. This study was aimed to prepare and evaluate the efficacy of a lipid nanoparticle-based vaccine in a murine model of VVC. Dried and reconstituted vesicles containing C. albicans antigens (DRNPs-Ca-Ags) vaccine, formulated with phosphatidylcholine and cholesterol-based lipid nanoparticles via film hydration and freeze-drying. The safety evaluation of DRNPs-CaAgs was conducted by determining hepatic (AST, ALT) or renal (BUN, creatinine) biomarkers. Female mice were immunized with DRNPs-CaAgs or Alum-CaAgs, and immune responses were evaluated via antibody titers, IgG isotypes, and splenocyte proliferation. Protective efficacy of vaccine formulations was assessed through fungal burden, biofilm formation, cytokine levels, and histopathological analysis of vaginal tissues. Mice vaccinated with DRNPs-CaAgs showed significantly enhanced immune responses, with higher antibody titers and IgG2a levels as compared to the Alum-CaAgs group. Vaginal fungal burden was dramatically reduced (665±78 CFUs in DRNPs-CaAgs immunized group vs. 12,944±3540 CFUs in Alum-CaAgs group, p<0.01). Biofilm formation decreased by 45% (p<0.05), and inflammatory cytokines were significantly lowered. Histopathological analysis revealed minimal tissue damage in DRNPs-CaAgs vaccinated mice. The findings suggest DRNPs-CaAgs as a promising vaccine for VVC, eliciting strong immunity, reducing fungal load, and minimizing inflammation. While the reliance on a murine model is a limitation, future clinical trials are essential to evaluate its efficacy and safety in humans, offering a potential strategy to combat drug-resistant infections and improve women's reproductive health.

Tuberculosis Preventive Treatment in High TB-Burden Settings: A State-of-the-Art Review.

Tuberculosis (TB) is the leading cause of death from a single infectious agent. The burden is highest in some low- and middle-income countries. One-quarter of the world's population is estimated to have been infected with TB, which is the seedbed for progressing from TB infection to the deadly and contagious disease itself. Although some individuals may clear their infections through innate and acquired immunity, many do not. People living with HIV, TB-exposed household contacts, other individuals recently infected, and immunosuppressed individuals are at especially high risk of progressing to TB disease. There have been major advances in recent years to support the programmatic management of TB infection. New tests of infection, including those that predict progression to TB disease, have become available. Numerous World Health Organization-recommended TB preventive treatment (TPT) regimens are available for all ages and for both drug-susceptible and drug-resistant TB infection. All regimens are generally safe, efficacious, and cost effective and have a low risk of generating resistance. TPT is recommended for pregnant women who are at risk for developing TB, but some regimens are associated with an increased likelihood of poor obstetric and fetal outcomes, and newer regimens have not yet been tested in pregnancy. New formulations of rifapentine-based TPT have been developed, and the cost has been radically reduced. Innovative models of delivery to support the scale up of TPT have been developed. Modeling suggests that scaling up TPT, especially regimens with optimal target product profile characteristics, can contribute substantially to ending the TB epidemic. The global uptake of TPT has increased substantially, especially for people living with HIV. Implementation gaps remain, particularly for children, pregnant women, and other household contacts. Further innovation is required to support the continued scale up of TPT and to contribute to ending the TB epidemic.

Escherichia coli phage ΦPNJ-9 adheres to mucus via a variant Hoc protein.

Phages, as antagonists of bacteria, hold significant promise for combating drug-resistant bacterial infections. Their host specificity allows phages to target pathogenic bacteria without disrupting the gut microbiota, offering distinct advantages in the prevention and control of intestinal pathogens. The interaction between the phage and the gut plays a crucial role in the efficacy of phage-mediated bacterial killing. However, the mechanisms underlying these interactions remain poorly understood. In this study, we demonstrate that the clinically isolated T4-like phage, ΦPNJ-9, effectively adheres to the intestinal mucosa in vivo. This adhesion is mediated by the phage's Hoc protein, which interacts with MUC2 in the mucus. The Hoc protein of ΦPNJ-9 represents a variant, consisting of only three domains and lacking Domain 3, in contrast to phage T4. The key interacting sites on ΦPNJ-9 Hoc are amino acids S183, L184, and T185 within Domain 2. Displaying Domain 2 of ΦPNJ-9 Hoc on the surface of M13 phage significantly enhances its adhesion to the intestinal mucosa. Additionally, we identify fucose residues in MUC2 as the critical binding sites for the phage. Through this adhesion, the phage occupies the intestinal niche, thereby protecting the mucosal layer from pathogenic Escherichia coli infections. Our findings highlight the role of Hoc proteins in phage adhesion to intestinal mucus and the variation in binding sites, providing key insights for phage-based strategies aimed at preventing and controlling intestinal pathogens.IMPORTANCEThe rise in antibiotic-resistant pathogenic bacteria has sparked renewed interest in phage therapy as a promising alternative, particularly for targeting intestinal pathogens due to phage's host specificity. However, clinical applications have revealed that many phages are ineffective in eliminating bacteria within the gut, primarily due to the complex interactions between the phage and the gut environment. However, the mechanisms underlying these interactions remain poorly understood. Our previous study demonstrated that a T4-like phage adheres to the intestinal mucosa through the interaction between its Hoc protein and MUC2 in the mucus. Whether this model is widespread among T4-like phages remains unknown. Here, we characterize a variant Hoc protein from a T4-like phage, and identify new binding sites within this protein. Our findings suggest that the interaction between Hoc and MUC2 is likely common, but the critical binding sites vary depending on the specific phage.

Identifying potential predictive indicators for reimplantation timing in two-stage revision: a meta-analysis and system review.

The two-stage exchange revision represents a pivotal strategy in the management of prosthetic joint infections, wherein the judicious timing of reimplantation serves as a crucial determinant for therapeutic success. At present, attempts have been made to utilize predictive models to establish the optimal timing for reimplantation; however, their predictive accuracy remains unsatisfactory. This inadequacy primarily arises from the lack of dependable predictive indicators, which demonstrate inconsistent effectiveness across various studies and occasionally yield contradictory outcomes. Therefore, identifying solid predictive indicators is in desperate need. Studies reporting outcomes of the two-stage exchange revision till June, 2023 were systematically retrieved, screened and subject to quality analysis. Basic characteristics of these studies were firstly summarized. Subsequently, factors of interest regarding clinical information, blood and body fluid test results, pathogen test results of the recurrent and recurrent-free cohorts were extracted and submitted to a fixed or random effects model. Meanwhile, evaluation of publication bias and sensitivity was performed. After filtering, a total of 45 studies were finally involved. Pooled analysis suggested that the recurrent cohort exhibited elevated incidences of body mass index (BMI) > 30, smoking and alcohol habits, diabetes, sinus tract, positive culture, and G-, polymicrobial and drug-resistant infections. Additionally, higher levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), synovial white blood cell (WBC) count, and polymorphonuclear percentage (PMN%) were observed in the recurrent cohort. On the other hand, the results of D-dimer and fibrinogen were ambiguous, and no difference regarding peripheral WBC count was observed. Forest plots suggested a low risk of publication bias. Besides, sensitivity analysis indicated good stability of the aforementioned indicators, except D-dimer and fibrinogen. To sum up, BMI > 30, smoking and alcohol habits, diabetes, sinus tract, positive culture, and G-, polymicrobial and drug-resistant infections, CRP, ESR, synovial WBC and PMN% exhibited significant differences between recurrent and recurrent-free cohorts. Therefore, these indicators may be considered as potential predictive factors for the further development of a prognostic model that aids the determination of reimplantation timing. Nevertheless, the efficacy of these indicators remains to be further confirmed. Prospero ID: CRD42022296568.

Gene editing tool-loaded biomimetic cationic vesicles with highly efficient bacterial internalization for in vivo eradication of pathogens

In the post-COVID-19 era, drug-resistant bacterial infections emerge as one of major death causes, where multidrug-resistant Acinetobacter baumannii (MRAB) and drug-resistant Pseudomonas aeruginosa (DRPA) represent primary pathogens. However, the classical antibiotic strategy currently faces the bottleneck of drug resistance. We develop an antimicrobial strategy that applies the selective delivery of CRISPR/Cas9 plasmids to pathogens with biomimetic cationic hybrid vesicles (BCVs), irrelevant to bacterial drug resistance. CRISPR/Cas9 plasmids were constructed, replicating in MRAB or DRPA and expressing ribonucleic proteins, leading to irreparable chromosomal lesions; however, delivering the negatively charged plasmids with extremely large molecular weight to the pathogens at the infection site became a huge challenge. We found that the BCVs integrating the bacterial out membrane vesicles and cationic lipids efficiently delivered the plasmids in vitro/in vivo to the pathogens followed by effective internalization. The BCVs were used by intratracheal or topical hydrogel application against MRAB pulmonary infection or DRPA wound infection, and both of the two pathogens were eradicated from the lung or the wound. CRISPR/Cas9 plasmid-loaded BCVs become a promising medication for drug-resistant bacteria infections.

Venomics AI: a computational exploration of global venoms for antibiotic discovery.

The relentless emergence of antibiotic-resistant pathogens, particularly Gram-negative bacteria, highlights the urgent need for novel therapeutic interventions. Drug-resistant infections account for approximately 5 million deaths annually, yet the antibiotic development pipeline has largely stagnated. Venoms, representing a remarkably diverse reservoir of bioactive molecules, remain an underexploited source of potential antimicrobials. Venom-derived peptides, in particular, hold promise for antibiotic discovery due to their evolutionary diversity and unique pharmacological profiles. In this study, we mined comprehensive global venomics datasets to identify new antimicrobial candidates. Using machine learning, we explored 16,123 venom proteins, generating 40,626,260 venom-encrypted peptides (VEPs). Using APEX, a deep learning model combining a peptide-sequence encoder with neural networks for antimicrobial activity prediction, we identified 386 VEPs structurally and functionally distinct from known antimicrobial peptides. Our analyses showed that these VEPs possess high net charge and elevated hydrophobicity, characteristics conducive to bacterial membrane disruption. Structural studies revealed considerable conformational flexibility, with many VEPs transitioning to α-helical conformations in membrane-mimicking environments, indicative of their antimicrobial potential. Of the 58 VEPs selected for experimental validation, 53 displayed potent antimicrobial activity. Mechanistic assays indicated that VEPs primarily exert their effects through bacterial membrane depolarization, mirroring AMP-like mechanisms. In vivo studies using a mouse model of Acinetobacter baumannii infection demonstrated that lead VEPs significantly reduced bacterial burdens without notable toxicity. This study highlights the value of venoms as a resource for new antibiotics. By integrating computational approaches and experimental validation, venom-derived peptides emerge as promising candidates to combat the global challenge of antibiotic resistance.

Inhibitory effects of berberine on fungal growth, biofilm formation, virulence, and drug resistance as an antifungal drug and adjuvant with prospects for future applications.

Berberine (BBR), an isoquinoline alkaloid found in medicinal plants such as Coptidis rhizoma, Berberis sp., and Hydrastis canadensis, is a distinctive compound known for its dual ability to exhibit broad-spectrum antifungal activity while offering beneficial effects to the host. These attributes make it a highly valuable candidate for antifungal therapy and as an antibiotic adjuvant. This review provides a comprehensive evaluation of BBR's antifungal properties, focusing on its in vitro and in vivo activity, underlying mechanisms, and its influence on fungal pathogenicity, including virulence, biofilm formation, and resistance. Additionally, the antifungal potential of BBR extracts, derivatives, and nanoformulations is examined in detail. BBR demonstrates fungicidal effects through multiple mechanisms. It targets critical fungal components such as mitochondria, cell membranes, and cell walls, while also inhibiting enzymatic activity and transcription processes. Furthermore, it suppresses the expression of virulence factors, effectively diminishing fungal pathogenicity. Beyond its direct antifungal activity, BBR exerts beneficial effects on the host by modulating gut microbiota, thereby bolstering host defenses against fungal infections and reducing potential adverse effects. BBR's interaction with conventional antifungal drugs presents a unique complexity, particularly in the context of resistance mechanisms. When used in combination therapies, conventional antifungal drugs enhance the intracellular accumulation of BBR, thereby amplifying its antifungal potency as the primary active agent. These synergistic effects position BBR as a promising candidate for combination strategies, especially in addressing drug-resistant fungal infections and persistent biofilms. As antifungal resistance and biofilm-associated infections continue to rise, the multifaceted properties of BBR and its advanced formulations highlight their significant therapeutic potential. However, the scarcity of robust in vivo and clinical studies limits a full understanding of its efficacy and safety profile. To bridge this gap, future investigations should prioritize well-designed in vivo and clinical trials to thoroughly evaluate the therapeutic effectiveness and safety of BBR in diverse clinical settings. This approach could pave the way for its broader application in combating fungal infections.

Effect of Mn(II) and Co(II) on Anti-Candida Metabolite Production by Aspergillus sp. an Endophyte Isolated from Dizygostemon riparius (Plantaginaceae).

Background/Objectives: This study evaluates the effect of Mn(II) and Co(II) ions on the production of anti-Candida metabolites by the endophytic fungus Aspergillus sp., isolated from Dizygostemon riparius. The objective was to identify metal-induced secondary metabolites with antifungal potential against drug-resistant Candida species. Methods: Aspergillus sp. was cultivated in Czapek agar supplemented with MnCl₂ (400 µM) or CoCl₂ (200 µM). Metabolite profiles were analyzed using UHPLC-DAD and LC-ESI-HRMS, followed by structural elucidation via NMR. Antifungal and biofilm inhibition activities were tested against Candida albicans and Candida parapsilosis. Toxicity was assessed using Tenebrio molitor larvae. Results: Key metabolites, including pyrophen, penicillquei B, and fonsecinone B, demonstrated antifungal activity with MIC values of 4.37-280.61 µg/mL. Fonsecinone B exhibited superior biofilm inhibition, surpassing fluconazole in reducing biofilm biomass and viability. In vivo assays showed low toxicity, with survival rates above 80% at 2× MIC/kg. Conclusions: Mn(II) and Co(II) significantly modulated the production of antifungal metabolites in Aspergillus sp. Fonsecinone B emerged as a promising candidate for antifungal therapy due to its potent activity and low toxicity. These findings support further investigation into the therapeutic potential of metal-induced fungal metabolites for combating drug-resistant Candida infections.

Oligostyrylbenzene Derivatives with Antiparasitic and Antibacterial Activity as Potent G-Quadruplex Ligands.

G-quadruplexes (G4s) are non-canonical secondary structures that play a crucial role in the regulation of genetic expression. This study explores the interaction between G4s and a small family of oligostyrylbenzene (OSB) derivatives, characterized by tris(styryl)benzene and tetrastyrylbenzene backbones, functionalized with either trimethylammonium or 1-methylpyridinium groups. Initially identified as DNA ligands, these OSB derivatives have now been recognized as potent G4 binders, surpassing in binding affinity commercially available ligands such as pyridostatin and displaying good selectivity for G4s over duplex DNA. Furthermore, OSB derivatives 1 and 2 demonstrated significant antiparasitic activity against bloodstream forms of T. brucei and extracellular L. major, with high selectivity indices when compared to MRC-5 healthy control cells. Derivatives 1 and 2 exhibited moderate biocidal effects against a range of Gram-positive and Gram-negative bacterial strains. Notably, a synergistic antibacterial effect was observed when these compounds were combined with traditional antibiotics, particularly against Acinetobacter baumannii, highlighting their potential utility in addressing drug-resistant bacterial infections. The differences in bioactivity among the OSB derivatives can be attributed to variations in cellular uptake, as proved by flow cytometry analysis. This suggests that the degree of cellular internalization plays a pivotal role in the observed antiparasitic and antibacterial efficacy.

Biomaterials-based phototherapy for bacterial infections.

Bacterial infections and antibiotic resistance are global health problems, and current treatments for bacterial infections still rely on the use of antibiotics. Phototherapy based on the use of a photosensitizer has high efficiency, a broad spectrum, strong selectivity, does not easily induce drug resistance, and is expected to become an effective strategy for the treatment of bacterial infections, particularly drug-resistant infections. This article reviews antimicrobial strategies of phototherapy based on photosensitizers, including photodynamic therapy (PDT), photothermal therapy (PTT), and their combination. These methods have significant application potential in combating multi-drug-resistant bacterial and biofilm infections, providing an alternative to traditional antibiotics and chemical antibacterial agents.

ClpS Directs Degradation of N-Degron Substrates With Primary Destabilizing Residues in Mycolicibacterium smegmatis.

Drug-resistant tuberculosis infections are a major threat to global public health. The essential mycobacterial ClpC1P1P2 protease has received attention as a prospective target for novel antibacterial therapeutics. However, efforts to probe its function in cells are constrained by our limited knowledge of its physiological proteolytic repertoire. Here, we interrogate the role of mycobacterial ClpS in directing N-degron pathway proteolysis by ClpC1P1P2 in Mycolicibacterium smegmatis. Binding assays demonstrate that mycobacterial ClpS binds canonical primary destabilizing residues (Leu, Phe, Tyr, Trp) with moderate affinity. N-degron binding restricts the conformational flexibility of a loop adjacent to the ClpS N-degron binding pocket and strengthens ClpS•ClpC1 binding affinity ~30-fold, providing a mechanism for cells to prioritize N-degron proteolysis when substrates are abundant. Proteolytic reporter assays in M. smegmatis confirm degradation of substrates bearing primary N-degrons, but suggest that secondary N-degrons are absent in mycobacteria. This work expands our understanding of the mycobacterial N-degron pathway and identifies ClpS as a critical component for substrate specificity, providing insights that may support the development of improved Clp protease inhibitors.