Jul 2026· ACS Applied Materials and Interfaces· Vol 18 31, pp.
42323-42331
· 0 citations· 42 references
Medicine
TL;DR
Analysis of reverse-phase high-performance liquid chromatography and circular dichroism spectroscopy demonstrated that incorporation of pentafluorophenylalanines effectively modulates the hydrophobicity and secondary structure of peptides.
Abstract
Inspired by the structure of the natural antimicrobial peptide magainin 2 (MG), we developed a series of fluorinated magainin 2 analogues (FMGs) incorporating pentafluorophenylalanine residue and systematically studied their physicochemical properties and antimicrobial activities. Analytical reverse-phase high-performance liquid chromatography and circular dichroism spectroscopy demonstrated that incorporation of pentafluorophenylalanines effectively modulates the hydrophobicity and secondary structure of peptides. Membrane-disruption assays using model lipid bilayers, together with evaluations of antibacterial activity assays against Escherichia coli (E. coli) and hemolytic toxicity assays toward red blood cells, revealed that FMGs exhibit enhanced antimicrobial activity, with minimum inhibitory concentration values reduced by up to an order of magnitude relative to MG, without a substantial increase in toxicity. Notably, FMGs also retained superior antibacterial activity against a drug-resistant E. coli strain harboring the RP4 multidrug-resistance plasmid. Molecular dynamics simulations suggested that the preferential membrane-disruptive activity arises from selective binding to negatively charged bacterial membranes. These findings provide detailed structure-activity relationships for fluorinated antimicrobial peptides and highlight the introduction of fluorinated aromatic units as a powerful strategy to enhance hydrophobicity and antimicrobial activity.
The results suggest that incorporating metal-binding headgroups into amphiphilic scaffolds may engage a distinct mode of action compared to traditional small-molecule AMP mimetics, resulting in increased antimicrobial potency and selectivity over mammalian membranes.
Samuel O. Nitschke, Anteneh Amsalu, Muhammed Awad et al.· European journal of medicina...· 0 citations
As essential flavoring substances in the food industry, γ/δ-lactones and chiral monoterpenoid ketones are known for broad-spectrum antibacterial activity, yet systematic studies on their structure-activity relationships and mechanisms remain limited. This study evaluated the antibacterial activity and mechanisms of these compounds against foodborne pathogens. D-Carvone and L-carvone exhibited the strongest activity, with minimum inhibitory concentrations (MIC) of 0.5 mg/mL and minimum bactericidal concentrations (MBC) of 1.0 mg/mL against Escherichia coli and Staphylococcus aureus. Growth curve analysis revealed that chiral ketones bearing an α,β-unsaturated carbonyl moiety exhibited superior inhibitory effects over saturated analogs and lactones. Mechanistic studies demonstrated that these active compounds primarily disrupted the bacterial cell membrane, as evidenced by increased extracellular conductivity, leakage of proteins and nucleic acids, dissipation of membrane potential, and irreversible morphological alterations including cell shrinkage, membrane collapse, and pore formation observed by scanning electron microscopy (SEM). Molecular docking showed D- and L-carvone had the highest binding affinities to target proteins, correlating with their lowest MICs. Both the electrophilic α,β-unsaturated carbonyl and hydrophobic monoterpene skeleton likely drive membrane disruption. Time-resolved assays revealed slightly faster kinetics for D-carvone, though without affecting MICs. Overall, both enantiomers exhibit potent in vitro antibacterial activity via membrane disruption, warranting further evaluation in food systems.
Tianhao Xie, Shu-Ping Niu, Jinhao Zou et al.· Food microbiology· 0 citations
Methicillin-resistant Staphylococcus aureus (MRSA) remains a major threat owing to limited therapeutic options and increasing antimicrobial resistance. In this study, a new honokiol-derived amphiphilic compound, 5D, was developed and evaluated for its anti-MRSA activity. 5D exhibited potent activity against clinical MRSA isolates (MIC = 0.5-1 μg/mL), and rapidly killed MRSA N315 in both early and late growth phases. It also disrupted established biofilms, retained activity after plasma exposure, and showed a low propensity for resistance development. Mechanistic analyses revealed that 5D damages bacterial morphology, dissipates membrane potential, increases membrane permeability, and causes leakage of intracellular DNA and proteins. Untargeted metabolomics indicated that 5D markedly perturbs glycerophospholipid metabolism, while phospholipid supplementation and isothermal titration calorimetry suggested preferential interaction with phosphatidylglycerol. In a Galleria mellonella infection model, 5D improved 7-day survival to approximately 33% and reduced bacterial burdens by 0.7-1.2 log10 CFU/mL compared with untreated larvae. In a murine sepsis model, 5D increased survival to 83.3-100% and significantly reduced organ bacterial burdens. These findings identify 5D as a promising honokiol-derived anti-MRSA lead compound that acts mainly by disrupting membrane integrity and phospholipid homeostasis.
Muchen Zhang, Yan Wang, Jing Pan et al.· Bioorganic chemistry (Print)· 0 citations
The global infection rates caused by multidrug-resistant bacteria continue to rise, while the pipeline for novel antibiotics is increasingly drying up, highlighting the urgent need to develop new antimicrobial agents. Drawing inspiration from the amphiphilic structure of cationic antimicrobial peptides (AMPs), a collection of amphiphilic guanidinium salts incorporating cinnamic acid skeleton was designed and prepared. Bioactivity screening revealed that compound 10c exhibited excellent inhibitory effects against Gram-positive bacteria, with MIC values ranging from 1 to 2 μg/mL, comparable to the clinically used drug vancomycin. Further evaluation demonstrated that 10c possessed negligible hemolytic activity, infrequent resistance acquisition, low cytotoxicity, fast bactericidal action, and good plasma stability, indicating strong potential for further development. Additionally, 10c not only effectively prevented biofilm formation but also significantly disrupted pre-formed biofilms. Mechanistic studies revealed that 10c achieved selective membrane targeting by specifically interacting with phosphatidylglycerol present in the bacterial cell membrane. This interaction triggered membrane depolarization, increased membrane permeability, leading to elevated intracellular ROS levels and escape of cellular contents, ultimately accelerating bacterial death. More importantly, 10c significantly reduced bacterial burden and mitigated tissue inflammation, outperforming vancomycin in a murine skin abscess model. In summary, these results indicated that compound 10c was a membrane-active antimicrobial candidate with promising potential for further development.
Fen Zhou, Ping Zhao, Mengqi Liu et al.· Frontiers in Microbiology· 0 citations
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.
Mucin-derived peptides constitute attractive antimicrobial candidates, but their clinical application is restricted by limited stability and moderate efficacy. To address these limitations, we modified d-amino-acid-containing peptidomimetics and investigated their Cu(ii) and Zn(ii) complexes with respect to coordination chemistry, structure, proteolytic resistance, and antimicrobial activity. Potentiometric, spectroscopic, and DFT studies revealed that metal binding donor sets are analogous to those of the native peptide, producing only minor local conformational effects without significant global structural rearrangement, as confirmed by circular dichroism analysis. In contrast to the modest structural changes, biological activity was strongly influenced by chirality and metal coordination. The fully d-configured analogue displayed the highest antimicrobial potency, particularly at pH 5.5, and its Zn(ii) and Cu(ii) complexes showed enhanced antibacterial and antifungal effects relative to the native system. Proteolytic assays demonstrated rapid plasma degradation of the native peptide and the partially modified analogue, whereas the fully d-substituted peptidomimetic remained largely intact after 2 h. All compounds exhibited minimal hemolytic and cytotoxic effects. These findings demonstrate that d-amino-acid incorporation combined with metal coordination significantly improves both enzymatic stability and antimicrobial performance of mucin-derived peptides.
A. Ślusarczyk, D. Bellotti, Silvia Leveraro et al.· RSC Advances· 0 citations
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