Murepavadin is a novel peptide antibiotic that exhibits potent antibiofilm activity and enhances the efficacy of conventional antibiotics against Pseudomonas aeruginosa

Mocravimod as a repurposing drug against clinical isolates of Staphylococcus aureus by targeting cell membrane

ABSTRACT Staphylococcus aureus infections, particularly those caused by multidrug-resistant strains and associated with biofilm formation, pose a major therapeutic challenge in clinical practice. The objective of this study was to evaluate the antibacterial and antibiofilm activity of mocravimod (KRP-203), an FDA-approved S1P receptor modulator, against clinical S. aureus isolates and to explore its underlying mechanism of action. The antibacterial activity of KRP-203 was assessed against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) using MIC determination, time-kill assays, and biofilm inhibition models. KRP-203 exhibited strong bactericidal activity against planktonic MSSA and MRSA, with MIC values ranging 6.25–50μM. Time-kill assays demonstrated rapid bacterial eradication at 8× MIC within 2 h, showing superior killing kinetics compared with vancomycin. At sub-inhibitory concentrations, KRP-203 inhibited biofilm formation by up to 70% and reduced viable bacterial counts in mature biofilms by >2.5 logs. To elucidate the antibacterial mechanism, whole-genome sequencing and quantitative proteomic analyses were performed. These analyses revealed mutations in membrane-associated genes, including glnQ and BCAT, and significant alterations in proteins related to membrane integrity and redox regulation. Consistently, functional assays confirmed that KRP-203 disrupts bacterial cell membrane, as evidenced by dose-dependent membrane depolarization, increased permeability, and direct binding to cardiolipin and phosphatidylglycerol. Molecular docking further predicted a favorable interaction between KRP-203 and GlnQ. In conclusion, KRP-203 demonstrated notable antibacterial and antibiofilm activity against S. aureus, likely through membrane integrity disruption. While these findings highlight its potential as a repurposed antibacterial agent, further studies are required to fully elucidate its molecular targets, optimize antibacterial efficacy, and evaluate its in vivo safety profile. IMPORTANCE Antibiotic resistance and the formation of biofilms, which protect bacteria from medications and immunological responses, present the significant challenges for the clinical treatment of Staphylococcus aureus infections. This study reveals mocravimod hydrochloride (KRP-203), a clinically approved drug initially intended to treat leukemia, as a viable new candidate against S. aureus infection. KRP-203 quickly kills both drug-susceptible and resistant S. aureus, including difficult-to-treat biofilm-associated cells. Its membrane-disrupting activity quickly kills drug-resistant bacteria while also destroying biofilm formations, presenting a dual action rarely accomplished by conventional antibiotics. Critically, KRP-203’s established safety profile in human studies may hasten its repurposing as a new weapon against biofilm-associated infections, providing possible solutions for chronic and drug-resistant S. aureus infections where existing treatments commonly fail. Antibiotic resistance and the formation of biofilms, which protect bacteria from medications and immunological responses, present the significant challenges for the clinical treatment of Staphylococcus aureus infections. This study reveals mocravimod hydrochloride (KRP-203), a clinically approved drug initially intended to treat leukemia, as a viable new candidate against S. aureus infection. KRP-203 quickly kills both drug-susceptible and resistant S. aureus, including difficult-to-treat biofilm-associated cells. Its membrane-disrupting activity quickly kills drug-resistant bacteria while also destroying biofilm formations, presenting a dual action rarely accomplished by conventional antibiotics. Critically, KRP-203’s established safety profile in human studies may hasten its repurposing as a new weapon against biofilm-associated infections, providing possible solutions for chronic and drug-resistant S. aureus infections where existing treatments commonly fail.

Investigation of the antimicrobial, antibiofilm, and immunomodulatory activities of cranberry (Vaccinium macrocarpon L.) proanthocyanidins against multidrug-resistant pathogens

The increasing emergence of multidrug-resistant (MDR) pathogens poses a significant challenge to global healthcare, necessitating the development of alternative antimicrobial strategies. In the present study, cranberry extract was evaluated for its antimicrobial, antibiofilm, antioxidant, and anti-inflammatory activities against a panel of clinically relevant microorganisms, including Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA). The extract demonstrated notable antimicrobial activity, with minimum inhibitory concentration (MIC) values ranging from 32 to 512 µg/mL, exhibiting relatively higher efficacy against Gram-positive bacteria. Significant antibiofilm activity was observed at sub-inhibitory concentrations, where cranberry extract reduced biofilm formation by up to 75–80% at 1/2 MIC and 50–65% at 1/4 MIC (p < 0.05) across tested isolates. Scanning electron microscopy (SEM) further supported these findings by revealing alterations in biofilm architecture following treatment. In addition, the extract exhibited strong antioxidant activity, achieving more than 85% free radical scavenging activity at higher concentrations. Cytotoxicity assessment revealed an IC50 of approximately 450–500 µg/mL, with selectivity indices indicating a favorable therapeutic window, particularly against Gram-positive bacteria. Furthermore, in vivo evaluation using an infection model demonstrated improved survival rates (> 90%) and significant reductions in pro-inflammatory markers, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), nuclear factor kappa B (NF-κB), and cyclooxygenase-2 (COX-2), compared with untreated infected controls (p < 0.05). Collectively, these findings highlight the potential of cranberry extract as a multifunctional therapeutic agent with antimicrobial, antibiofilm, antioxidant, and anti-inflammatory properties. The observed efficacy against MDR pathogens suggests its potential application as a complementary or alternative strategy for the management of resistant infections.

Antimicrobial properties of postbiotics of different LAB against multidrug resistance bacteria

It was shown the comparative antimicrobial activity of postbiotics (bacteriocins and exopolysaccharides) isolated from lactic acid bacteria (LAB) strains of genus Enterococcus and Lactobacillus against three broad panelsof human pathogens. The antimicrobial activity was assessed in a concentration-dependent manner and compared with that of conventional antibiotics. Selected and purified bacteriocins from strains of L. rhamnosus 2012 and E. faecium KE5, for which an MIC of 5 mg/mL was established against S. typhimurium G-38 via the serial dilution method, exhibited the strongest antimicrobial activity across a broad panel of pathogens when tested at this concentration using agar diffusion assays. Postbiotics displayed strain-specific inhibitory effects, highlighting their narrower antimicrobial spectrum relative to antibiotics. It was shown that conventional antibiotics demonstrated broad-spectrum efficacy against susceptible strains but known failures against multidrug-resistant (MDR) isolates. Differences in antimicrobial effects between postbiotics may depend on their interaction with the cell membrane of pathogens. These findings suggest that LAB-derived postbiotics could serve as complementary antimicrobial agents (with antibiotics or another bioactive substance), which may have applications in nutritional and preventive frameworks.

Antibiofilm potential of biogenic magnesium oxide nanoparticles against multidrug resistant gram-negative bacteria.

It is suggested that biogenically synthesized MgO NPs hold considerable promise as antibacterial and antibiofilm agents against MDR Gram-negative pathogens.

Assessment of the efficacy of diosmin against methicillin-resistant Staphylococcus aureus and the underlying mechanism of action

Objective: To investigate the antibacterial and antibiofilm activities of diosmin, a plant-derived flavonoid glycoside, against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), in response to the growing challenge of multidrug-resistant bacterial infections. Methods: The antibacterial activity of diosmin was assessed against five clinical MRSA isolates using broth microdilution method to determine minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Antibiofilm activity was evaluated using crystal violet biofilm assay. Additionally, cell viability within biofilms was measured using a triphenyl tetrazolium chloride (TTC) assay. Results: Diosmin demonstrated a consistent MIC of 1.0 mg/mL and MBC of 2.0 mg/mL across all tested MRSA isolates, indicating primarily bacteriostatic activity at lower concentrations. Biofilm formation was significantly inhibited in a dose-dependent manner, with reductions ranging from 52% to 79% at 1.5 mg/mL. The minimum biofilm inhibitory concentration (MBIC50) values ranged from 0.0048 mg/mL to 0.0350 mg/mL. TTC assay results showed that diosmin significantly reduced viable biofilm-embedded cells at concentrations equal to or above the MIC, while sub-MIC concentrations exhibited minimal cytotoxic effects, suggesting non-lethal antibiofilm mechanisms. Conclusion: Diosmin exhibits promising antibacterial and antibiofilm activities against MRSA, with effective inhibition of biofilm formation and reduction of viable cells. These findings support its potential as a natural alternative or adjunct therapeutic agent for managing MRSA infections.

Gramicidin D as a Multi-Target Antimicrobial Against Staphylococcus aureus: Biofilm Disruption, Virulence Attenuation, Antibiotic Potentiation, and Protein-Peptide Docking Insight.