Search Results (1,694)

Background: Streptococcus suis serotype 2 is a major zoonotic pathogen responsible for severe systemic infections in pigs and humans, including septicemia, meningitis, and high mortality outcomes. Cefquinome, a fourth-generation β-lactam antibiotic widely used in veterinary medicine, is commonly applied for the treatment of S. suis infections. However, optimized dosing strategies remain insufficiently defined, particularly under conditions of varying bacterial burden, inoculum size, and reduced susceptibility or resistance phenotypes. These factors may significantly alter pharmacodynamic responses and compromise the predictive value of conventional MIC-based approaches. Objectives: This study aimed to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of cefquinome against S. suis serotype 2 using an integrated ex vivo serum time-kill experiments and semi-mechanistic PK/PD modeling. A secondary objective was to evaluate optimized dosing regimens across different inoculum levels and susceptibility phenotypes, including a cefquinome-resistant mutant. Methods: Cefquinome pharmacokinetics following intramuscular administration at 2 and 4 mg/kg in piglets were described using a two-compartment model. Dose proportionality, exposure linearity, and clearance parameters were assessed. Ex vivo serum time-kill experiments were conducted using a parental strain and a cefquinome-resistant mutant (M1) under normal-inoculum (NI), high-inoculum (HI), and mutant/resistant (MS) conditions. A semi-mechanistic PK/PD model incorporating logistic bacterial growth, sigmoidal Emax killing, nutrient limitation, and a time-delay function was developed to describe dynamic bacterial responses. Model parameters (k₀, k_max, EC₅₀) were estimated using nonlinear least-squares regression (Scientist v2.0), and simulations were performed by integrating time-varying PK input functions. Results: Cefquinome demonstrated linear pharmacokinetics with dose-proportional increases in Cmax and AUC between 2 and 4 mg/kg, with comparable clearance across doses. Ex vivo studies revealed time-dependent antibacterial activity with a pronounced inoculum effect. Higher bacterial burdens significantly reduced bactericidal efficiency and promoted regrowth during declining drug exposure. No tested concentrations achieved ≥3-log₁₀ killing in HI or MS conditions, whereas the NI group achieved a maximal reduction of 3.5-log₁₀ CFU/mL. MIC values in serum and medium were consistent (0.03, 0.06, and 0.24 µg/mL for NI, HI, and MS, respectively), indicating minimal protein binding influence. The semi-mechanistic model accurately described observed bacterial dynamics (R² > 0.99; MSC > 1.5), capturing delayed drug effects, inoculum-dependent growth suppression, and regrowth phenomena. Growth rates were reduced under serum conditions, reflecting nutrient limitation. Importantly, inoculum size exerted a stronger impact on pharmacodynamic outcomes than resistance phenotype, as reflected by reductions in kmax and increases in EC₅₀ under HI conditions. Although %T>MIC exceeded conventional β-lactam targets (>40%) in most regimens, MIC-based indices poorly correlated with observed dynamic killing responses. Conclusions: Cefquinome exhibited time-dependent antibacterial activity against S. suis serotype 2, strongly modulated by inoculum size and reduced susceptibility. The developed semi-mechanistic PK/PD model provided robust prediction of bacterial time-kill behavior and outperformed MIC-based metrics in guiding dose optimization. Simulation results support 2 mg/kg every 24 h for normal infections and 2 mg/kg every 12 h for high-inoculum or less susceptible infections, emphasizing the value of model-informed dosing strategies for optimizing β-lactam therapy. Full article

Among the many concerns surrounding global health, antimicrobial resistance (AMR) is widely recognized as a major threat, especially critical within livestock production, where restrictions on antibiotic use demand effective preventive alternatives. The documented health benefits and structural stability have positioned yeast-derived postbiotics as an attractive alternative, but research has largely focused on Saccharomyces cerevisiae, leaving non-Saccharomyces yeast species underexplored. To this end, in this study nine non-conventional yeast strains were selected and subjected to different thermal and chemical inactivation methods to determine the most suitable conditions for postbiotic obtention. Based on their physicochemical characterization and scalability potential, heat-treated postbiotics were selected for subsequent in vitro evaluation. Immunomodulatory assays demonstrated that heat-inactivated postbiotics from the different yeast strains were internalized by macrophages and induced dose-and-species-dependent expression of maturation markers CD40 and CD86, as well as TNF-α production, eliciting a proinflammatory response in vitro. Moreover, among all the species evaluated in this work, Rhodotorula mucilaginosa and Wickerhamomyces anomalus stood out for their ability to significantly reduce the adhesion of the enteropathogen enterotoxigenic Escherichia coli (ETEC) to intestinal cells in vitro. These results highlight the species-dependent immunomodulatory and anti-infective properties of selected yeast-derived postbiotics. Full article

Stenotrophomonas maltophilia is increasingly recognized as a difficult-to-treat healthcare-associated opportunistic pathogen, particularly in critically ill and immunocompromised patients, in whom it causes severe respiratory, bloodstream, and device-associated infections. Its intrinsic resistance to multiple antimicrobial classes, capacity to acquire additional resistance determinants, and ability to establish persistent biofilms substantially limit therapeutic options. This review integrates current knowledge of the structural basis, regulatory circuitry, and ecological interactions governing S. maltophilia biofilm development and examines how these processes converge with antimicrobial resistance. Biofilm formation is driven by coordinated adhesion and motility, extracellular matrix production, quorum sensing, cyclic di-GMP signaling, two-component regulatory systems, and adaptive responses to iron limitation and oxidative stress. Multidrug efflux systems contribute not only to antibiotic extrusion but also to membrane homeostasis, motility, stress adaptation, and biofilm-associated phenotypes, thereby providing a functional link between antimicrobial resistance and bacterial persistence. In polymicrobial communities, interspecies signaling and competitive or cooperative interactions further reshape biofilm architecture and antimicrobial tolerance. Collectively, current evidence indicates that S. maltophilia biofilm formation arises from interconnected regulatory networks rather than isolated molecular determinants. Targeting matrix assembly, signaling pathways, stress adaptation, or resistance-associated physiology may therefore complement conventional antimicrobial therapy. Future studies should prioritize clinically representative isolates, physiologically relevant multispecies models, and in vivo validation to translate mechanistic insights into effective anti-biofilm interventions. Full article

Chronic wounds are complex environments marked by persistent inflammation, oxidative stress, hypoxia, and conditions that favor antimicrobial resistance (AMR). Conventional antibiotics often fail due to bacterial persistence and the physicochemical barriers of the wound milieu. Biofilm-associated extracellular polymeric substances (EPS), efflux pump activity, quorum sensing (QS), and horizontal gene transfer (HGT) collectively drive antimicrobial tolerance and resistance dissemination, turning chronic wounds into reservoirs of multidrug-resistant pathogens. Consequently, emerging wound therapies demand multifunctional strategies that modulate the wound microenvironment while interfering with resistance-associated phenotypes. Hydrogel–metal–organic framework (MOF) composites have been explored as multifunctional interfaces that combine extracellular matrix-mimetic properties, tunable porosity, stimuli-responsiveness, and controlled therapeutic delivery with the bioactive functions of MOFs. Depending on their composition and architecture, these systems may exert antimicrobial and antibiofilm effects through ionic, electrostatic, osmotic, catalytic, and oxidative mechanisms, while also influencing ROS levels, inflammation, angiogenesis, and local drug transport. However, antimicrobial activity alone does not equate to resistance modulation. Evidence for direct effects on efflux systems, resistance phenotypes, or HGT remains inconsistent across reported platforms. This review critically examines representative hydrogel–MOF systems for chronic wound applications, comparing their composition, physicochemical properties, biological functions, proposed resistance-related mechanisms, advantages, limitations, and current level of evidence. We emphasize distinguishing experimentally demonstrated resistance-modulating effects from mechanistically proposed functions, and identifying design trade-offs and evidence gaps that must be addressed to develop wound interfaces capable of both supporting tissue regeneration and improving infection control. Full article

Oily wastewater commonly contains dissolved organic contaminants such as dyes, antibiotics, and phenolic compounds. Conventional stepwise treatment processes involve complex operation, high energy consumption, and severe membrane fouling. Multifunctional membranes integrating oil/water separation, pollutant adsorption or catalytic degradation, and membrane self-cleaning provide a promising solution for treating complex oily wastewater. This review summarizes recent advances in multifunctional membranes based on metal oxides, two-dimensional (2D) materials, three-dimensional (3D) porous structures, and biomass-derived materials. Key strategies, including micro and nanoscale structure regulation, wettability control, interlayer channel optimization, heterojunction construction, and active site engineering, are discussed together with the synergistic mechanisms involving oil/water separation, adsorption enrichment, photocatalysis, and Fenton reactions. Approaches for improving membrane flux, separation efficiency, degradation activity, antifouling performance, and cycling stability are also reviewed. Finally, challenges related to scalable fabrication, adaptability to real wastewater, long-term stability, and standardized evaluation are outlined, providing guidance for the design and practical application of multifunctional membranes. Full article

Punica granatum L. (pomegranate) is one of the oldest medicinal plants known to humankind, valued across ancient civilisations for treating parasitic, microbial, and metabolic diseases. Its exceptionally rich phytochemical composition, dominated by punicalagins, ellagic acid, anthocyanins, flavonoids, piperidine alkaloids, and the unique conjugated fatty acid punicic acid, confers a remarkably broad spectrum of biological activities of direct relevance to contemporary veterinary medicine. While human-health applications have been extensively reviewed, a comprehensive synthesis of veterinary evidence across multiple species remains lacking. This review consolidates current preclinical and field knowledge on the pharmacological effects of pomegranate preparations in poultry, ruminants, swine, fish, companion animals, and laboratory models. In poultry—the most extensively studied taxon—dietary inclusion of pomegranate peel powder or extract consistently enhances growth performance, antioxidant status, and humoral immunity while exerting meaningful anticoccidial activity. The antiparasitic properties are compellingly supported by evidence against gastrointestinal nematodes of ruminants, tapeworms, schistosomes, and protozoa including Giardia, Cryptosporidium, and Leishmania spp., as well as monogenean fish parasites. Broad-spectrum antimicrobial activity extends to major veterinary pathogens such as Salmonella, Escherichia coli, Staphylococcus aureus (including MRSA), and Clostridium perfringens. Rodent models have validated antidiabetic, hepatoprotective, nephroprotective, and reproductive benefits, including improved post-thaw sperm quality and enhanced litter size. The safety profile is generally favourable at conventional doses, although high dietary inclusion elicits anti-nutritional effects from condensed tannins, and potential drug interactions via cytochrome P450 inhibition warrant clinical caution. Despite this substantial evidence, significant translational barriers persist, including extract heterogeneity, absence of pharmacokinetic data in target species, and scarcity of controlled clinical trials. By providing a species- and pathology-driven synthesis, this review identifies critical research priorities and highlights the immense potential of this ancient, accessible, and economically viable phytobiotic as a natural alternative to antibiotic growth promoters and synthetic antiparasitics in veterinary practice. Full article

Implant-associated infections (IAIs) persist as a critical complication in biomaterial transplantation, driven by rapid microbial colonization, biofilm encapsulation, and escalating antibiotic resistance. Conventional antibiotic-based treatments and passive antimicrobial coatings often fail to achieve long-term infection control due to limited biofilm penetration, localized cytotoxicity, and active agent depletion. To overcome these limitations, piezoelectric nanocomposite coatings utilize a dynamic, stimulus-responsive framework that converts physiological mechanical forces or external ultrasound into localized electrical signals. These surface-bound electric fields systematically mitigate bacterial adhesion, eradicate mature biofilms via targeted reactive oxygen species (ROS) generation, disrupt microbial metabolic pathways, and favorably modulate the peri-implant immune microenvironment while supporting host tissue repair. This review evaluates the material design principles and classifications of inorganic, organic, and hybrid piezoelectric nanocoatings. We detail their multifaceted antibacterial mechanisms and trace their therapeutic potential in orthopedic and dental implants, as well as wound management. Lastly, we analyze current engineering bottlenecks to chart a clear trajectory for their clinical translation. Full article

Background: This study evaluated the antibacterial, antibiofilm, and biofilm eradication activities of biogenically synthesized silver nanoparticles (AgNPs-L, AgNPs-R) mediated by extracts of Lavandula angustifolia and Salvia rosmarinus, individually and in combination with their respective essential oils (EOs) and ampicillin (AMP), against a multidrug-resistant biofilm-forming Staphylococcus equorum strain. Physicochemical characterization confirmed the successful biosynthesis of spherical AgNPs-L (10–25 nm) and AgNPs-R (5–15 nm). Individual treatments exhibited distinct antibacterial activity, with MIC values of 25 µg/mL for AgNPs-L, 12.5 µg/mL for AgNPs-R, and 0.1% (v/v) for both EOs; however, they showed no ability to eradicate preformed biofilms. Dual AgNPs/EO combinations at subinhibitory concentrations demonstrated borderline additive effects (FICI = 0.501) and significantly potentiated antibacterial and antibiofilm activity compared with individual treatments. Triple AgNPs/EO/AMP combinations exhibited the most pronounced biological effects, with predominantly additive interactions depending on AMP concentration. Lavender-based triple combinations achieved up to 63.9% inhibition of planktonic growth, 78.1% prevention of biofilm formation, and 37.3% eradication of mature biofilms, whereas rosemary-based combinations resulted in 57.1%, 69.4%, and 42.7% inhibition, respectively. These findings highlight the potential of multi-component systems integrating biogenic nanomaterials, phytochemicals, and conventional antibiotics as a promising strategy to enhance antimicrobial efficacy against persistent biofilm-forming non-aureus staphylococci. Full article

Background/Objectives: Synthetic compounds, particularly thiadiazine derivatives with antibacterial properties, have emerged as promising candidates in addressing the growing challenge of bacterial multidrug resistance. Thiadiazine derivatives are six-membered heterocyclic compounds containing two nitrogen atoms and one sulfur atom, exhibiting diverse medical and pharmacological activities. This study aimed to evaluate the potentiating activity of thiadiazine derivatives against multidrug-resistant bacteria. Methods: ADMET (absorption, distribution, metabolism, excretion, and toxicity) assays were performed to assess similarity with more than 370,000 three-dimensional structures of bioactive compounds. The multidrug-resistant bacterial strains Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to investigate both the direct antibacterial activity and the antibiotic-modifying activity of thiadiazine derivatives. Results: The thiadiazine analogs did not exhibit direct antibacterial activity, presenting a minimum inhibitory concentration of 1024 μg/mL. However, they demonstrated a significant antibiotic-modifying effect, potentiating the activity of conventional antibiotics, particularly norfloxacin, against the tested strains. In silico analyses indicated that the analogs predominantly exhibited affinity for G protein-coupled receptors and possessed physicochemical characteristics compatible with potential drug candidates. Conclusions: Although the evaluated thiadiazine derivatives lacked direct antibacterial activity, they significantly enhanced the efficacy of antibiotics against multidrug-resistant bacteria. Combined with their favourable in silico pharmacokinetic and physicochemical profiles, these findings suggest that thiadiazine derivatives may represent promising antibiotic adjuvants for combating multidrug-resistant bacterial infections. Full article

Background/objectives: Multidrug-resistant and extensively drug-resistant Gram-negative pathogens are a major cause of severe ocular infections, yet treatment options are increasingly compromised by escalating antibiotic resistance. Membrane-active peptides (colistin and Mel4) offer the potential to restore antibiotic susceptibility. This study investigated the efficacy of peptide- and colistin-based adjuvant strategies in enhancing the activity of conventional antibiotics. Methods: Antibacterial activity was assessed using MIC/MBC testing, checkerboard assays, time–kill kinetics, and biofilm disruption studies, supported by confocal microscopy. Toxicity was assessed using L929 fibroblasts and red blood cells. A mechanistic study was performed with a membrane permeability assay. Results: Clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae showed high resistance to six antibiotic classes (up to MICs > 2048 mg/L), while polymyxin B and colistin remained active (MIC ≤ 2 mg/L). Mel4 displayed variable activity (MIC 7.8–500 mg/L). A total of 102 antibiotic–antibiotic, antibiotic–Mel4, and antibiotic–colistin combination tests were performed, of which 45 showed synergistic interactions. Combining traditional antimicrobials with either colistin or Mel4 restored antibiotic susceptibility, reducing MICs up to 2048-fold. Aminoglycoside–colistin combinations significantly lowered MICs, especially against K. pneumoniae. Time–kill assays confirmed rapid bactericidal effects (>3 log10 reduction in 3 h). The ciprofloxacin–Mel4 combination effectively disrupted biofilms (62–92%) with low toxicity and high cell viability. Membrane permeability assays showed that ciprofloxacin has limited activity, whereas both Mel4 and the ciprofloxacin–Mel4 combination showed enhanced activity across concentration gradients and over time. Conclusions: Membrane-active antimicrobials, colistin and Mel4, enhance conventional antibiotics against multidrug- and extensively drug-resistant ocular Gram-negative pathogens by restoring susceptibility, accelerating bactericidal effects, and disrupting biofilms. With low toxicity, these combinations represent promising therapeutic strategies for severe multidrug-resistant ocular infections. Full article

Background: Episiotomy remains one of the most common obstetric procedures worldwide, and suboptimal healing of the perineal wound continues to cause pain, dehiscence, and long-term impairment of postpartum quality of life. Obstetric anal sphincter injury (OASI) carries the greatest risk of severe wound morbidity among perineal trauma types and is managed with prophylactic antibiotics and adjunctive measures; episiotomy, by contrast, is repaired without a comparable prophylactic package and is far more frequent, so that even a modest per-case complication rate carries a substantial absolute burden. Platelet-rich plasma (PRP), an autologous concentrate rich in growth factors, has demonstrated favourable effects on wound healing and scar quality across several surgical contexts, including caesarean section, raising the question of whether it could similarly benefit episiotomy repair. Methods: We conducted a structured, date-stamped search of PubMed, Scopus and Google Scholar, together with two trial registries (ClinicalTrials.gov, WHO ICTRP), forward and backward citation tracking, and reference-list screening of relevant reviews (final search 24 July 2026), to identify clinical studies of PRP for obstetric episiotomy or intrapartum perineal wound healing. Results: Five primary clinical studies and one systematic review were identified. One single-centre randomized controlled trial of 200 primiparous women, published in a regionally indexed journal covered by neither PubMed nor Scopus, evaluated PRP specifically for episiotomy wound healing and reported significantly lower REEDA, Vancouver and pain scores in the PRP arm; it was not prospectively registered, reported neither a sample-size calculation nor blinded outcome assessment, lost 12% of participants to follow-up, and contains internal inconsistencies in the reported data. The remaining evidence comprises one randomized trial of PRP for postpartum levator ani muscle recovery (a distinct target, with a null result), one non-randomized comparative study in grade III–IV intrapartum perineal laceration repair, two case reports, and one broad systematic review of PRP in pelvic floor disorders in which episiotomy was not analyzed as a distinct entity. Conclusions: PRP for episiotomy healing is therefore not wholly untested, but the single existing randomized trial is small, methodologically limited, not independently replicated, and effectively invisible to conventional database searching. We describe this evidence base and introduce PRP-EpiHeal (ClinicalTrials.gov ID: NCT07669285), designed to provide the first prospectively registered, adequately powered and assessor-blinded randomized evidence on this question, with REEDA scale assessment at six weeks postpartum as the primary outcome. Full article

Background/Objectives: This study aims to assess changes in seminal parameters and sperm DNA fragmentation (SDF) index after empirical oral antibiotic therapy in infertile men with baseline SDF index > 15%. Methods: This retrospective, paired, uncontrolled pre- and post-intervention study included 98 infertile men with elevated baseline SDF index. Semen samples were obtained before treatment and at least two months after simultaneous oral treatment with ciprofloxacin 1000 mg/day for 21 days and doxycycline 100 mg/day for 10 days. Semen volume, sperm concentration, total sperm count, progressive motility, sperm morphology, round cell concentration, and SDF index were assessed before and after treatment. Results: After treatment, conventional semen parameters did not change significantly. Round cell concentration decreased from 0.3 to 0.2 × 10⁶/mL (p = 0.003), and median SDF index decreased from 30% to 20% (p < 0.0001). Conclusions: Empirical oral antibiotic therapy was associated with reductions in the SDF index and round cell concentration in this cohort. Because microbiological confirmation and an untreated control group were lacking, causality cannot be established, and controlled studies are required before routine clinical adoption. Full article

Bacterial colonization and biofilm formation on orthopedic and dental implants remain major clinical complications, while conventional systemic antibiotics are often limited by poor penetration into biofilms and infected bone. These limitations have motivated the development of biomaterials with intrinsic antibacterial activity. Hydroxyapatite (HA), a major inorganic component of bone and teeth, possesses excellent biocompatibility, osteoconductivity, and bone-bonding ability but exhibits limited inherent antibacterial activity. Incorporation of therapeutic metal ions, including Ag⁺, Cu²⁺, Zn²⁺, Ti⁴⁺, Co²⁺, Ga³⁺, Sr²⁺, and Ce³⁺, has therefore emerged as a promising strategy for developing multifunctional HA-based biomaterials. This review critically examines the crystal-chemical basis of metal-ion incorporation into HA and discusses how ionic radius, oxidation state, charge-compensation mechanisms, dopant concentration, and synthesis conditions influence lattice occupancy, physicochemical properties, and biological performance. The antibacterial activity of metal-substituted and metal-modified HA systems generally involves interconnected mechanisms, including bacterial membrane damage, intracellular metabolic disruption, interference with enzymes and nucleic acids, reactive oxygen species (ROS)-mediated oxidative stress, and inhibition of bacterial adhesion and biofilm formation. Ag-, Cu-, Zn-, and Ga-containing HA systems show the most consistently reported antibacterial effects, although their efficacy and cytocompatibility depend strongly on dopant concentration and ion-release kinetics. Co-substituted HA may combine antibacterial activity with angiogenic and osteogenic stimulation, whereas Sr-substituted HA is primarily osteogenic and anti-resorptive, with variable antibacterial performance. Ti-modified HA and TiO₂/HA composites exhibit predominantly photoactive antibacterial behavior, while Ce-substituted HA shows concentration-, oxidation-state-, and synthesis-dependent biological effects. The review also evaluates protein adsorption, osteogenic and angiogenic signaling, macrophage-mediated immunomodulation, biological safety, and representative commercial and translational applications. Overall, metal-substituted HA represents a versatile platform for infection-resistant and regenerative hard-tissue biomaterials, provided that composition, phase structure, ion release, antibacterial efficacy, and cytocompatibility are systematically co-optimized before clinical translation. Full article

Background/Objectives: Antimicrobial resistance is a critical threat to global public health. Eugenol is a bioactive compound with broad-spectrum antimicrobial activity that has attracted increasing interest as a naturally derived antimicrobial agent with potential complementary applications to conventional antibiotics, but its clinical application is severely limited by its high volatility, low water solubility and thermo-oxidative instability. The main objective of this study was to develop eugenol-loaded microparticles using a ternary biopolymer matrix, to characterise their main physicochemical properties, and to evaluate their in vitro antimicrobial efficacy against clinically relevant bacterial reference strains. Methods: The microparticles were formulated from an emulsion of maltodextrin, gum arabic and soy lecithin, and encapsulated using a spray-drying technique. Product recovery, particle morphology assessed by scanning electron microscopy (SEM), particle size distribution determined by laser diffraction, and encapsulation efficiency quantified by GC-FID were analysed. Subsequently, antimicrobial activity was evaluated by comparing the microparticles with free eugenol using agar well diffusion and broth microdilution assays to determine the minimum inhibitory concentration (MIC) against eight bacterial strains. Results: The spray-drying process achieved a product recovery of 61.88% and an encapsulation efficiency of 52.45%. The resulting microparticles exhibited a smooth, spherical morphology with diameters of less than 20 µm. In microbiological assays, microencapsulation significantly reduced MIC values by 4- to 16-fold compared with free eugenol for susceptible strains. The formulation exhibited potent activity against most of the Gram-positive and Gram-negative pathogens tested, except for Pseudomonas aeruginosa, which remained resistant to both formulations. Conclusions: The encapsulation of eugenol in this optimised biopolymer matrix substantially improved its antimicrobial efficacy against the tested bacterial strains. These findings highlight the potential of spray-dried eugenol microparticles as a promising antimicrobial formulation and provide a basis for their further development for topical applications. Further studies are warranted to evaluate their pharmaceutical performance and antimicrobial mechanisms. Full article

Background/Objectives: Antimicrobial peptides (AMPs) have emerged as promising alternatives to conventional antibiotics in response to the escalating global threat of antimicrobial resistance (AMR), owing to their potent antimicrobial activity and low propensity for resistance development. However, their clinical application remains limited by poor selectivity and undesirable toxicity toward mammalian cells. Methods: In this study, the naturally occurring frog-derived AMP Dermaseptin-A4 (A4) was selected as a template for rational design. Guided by the principle that optimising the balance between peptide hydrophobicity and cationicity could improve bacterial membrane targeting while reducing interactions with mammalian membranes, three analogues were designed through the targeted modulation of these physicochemical properties. Results: Among the designed analogues, A4-3 exhibited the best overall biological profile. A4-3 maintained a stable α-helical conformation in membrane-mimicking environments and displayed potent antimicrobial activity against tested Gram-positive and Gram-negative bacteria while exhibiting lower haemolytic and cytotoxic effects than the parent peptide. As a result, A4-3 showed improved selectivity, achieving a selectivity index of up to 34.5. A4-3 rapidly eradicated bacterial cells through a membrane-targeting mechanism, leading to membrane disruption and the loss of cellular integrity, and exhibited a low propensity for resistance development following prolonged exposure. A4-3 also retained its antimicrobial activity under physiologically relevant conditions. Conclusions: Collectively, these findings demonstrate that achieving an optimal balance between peptide hydrophobicity and cationicity is an effective strategy for enhancing antimicrobial selectivity without compromising antibacterial activity, highlighting A4-3 as a promising lead candidate for the development of novel antimicrobial therapeutics against drug-resistant bacterial infections. Full article