Aug 2026· European journal of medicinal chemistry· Vol 319, pp.
119245
· 0 citations· 68 references
Medicine
TL;DR
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.
Abstract
Synthetic mimetics of antimicrobial peptides (AMPs) typically rely on amine or guanidine groups to provide an overall cationic charge, often overlooking the metal-binding functionalities that influence AMP-membrane interactions. Here, we report three coumarin amphiphiles incorporating hydrophilic metal-binding headgroups and demonstrate that this design strategy yields improved potency and selectivity. All three compounds displayed strong antibacterial activity against methicillin-resistant S. aureus (MRSA), and a diethylenetriamine (DETA) derivative was also active against the Gram-negative bacteria, A. baumannii and E. coli. The compounds also showed moderate activity against MRSA biofilms, reducing the biomass of established MRSA biofilms by 40-50%. Mechanistic investigations revealed that the DETA and cyclen derivatives increased the outer-membrane permeability of E. coli and potentiated the activity of minocycline and rifampicin. All three amphiphiles also exhibited potent antifungal activity against C. neoformans, surpassing the activity of the clinical control fluconazole, with the DETA analogue also displaying activity against C. albicans. Collectively, these 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.
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
The rise of antimicrobial resistance has necessitated the urgent development of new and effective antimicrobial agents. One promising class of compounds is antimicrobial peptides (AMPs) and their mimics, although this type of membrane-active agent is also prone to cause toxicity issues. To circumvent the associated toxicities of AMPs, we herein developed a novel AMP mimic prodrug where the cationic ammonium residues are caged with trans-cyclooctene (TCO) units that can be bioorthogonally activated by tetrazine via an inverse-electron-demand Diels–Alder click-to-release reaction. The prodrug, TCO-Dendron, was inactive but exhibited antimicrobial activity against Gram-negative pathogens, especially Pseudomonas aeruginosa, in the presence of dimethyl tetrazine. Crucially, through detailed correlation of NMR, MS and antimicrobial assays, we obtained strong indications that the intermediate dihydropyridazine tautomer that persists due to incomplete release of the original AMP mimic also demonstrates antimicrobial activity, thus overcoming the often rate-limiting step in many click-to-release systems. In addition, TCO-Dendron was significantly less toxic to red blood cells and mouse embryonic fibroblast cells than the original AMP mimic, further demonstrating the on-demand control of toxicity enabled by the bioorthogonal trigger. Overall, this study thus not only reports the development of a new click chemistry-responsive AMP mimic prodrug but also reveals important mechanistic insights that help to inform the development of future antimicrobial prodrug systems.
Hao Luo, Rhiannon P. Kuchel, K. Neumann et al.· Chemical Science· 0 citations
Carboranes are boron-rich polyhedral clusters with unique physicochemical properties, including high hydrophobicity, three-dimensional structure, and the ability to act as bioisosteres of aromatic groups. These features make them attractive building blocks in medicinal chemistry. This chapter summarizes recent advances in the design of carborane-containing derivatives of biologically active scaffolds, including 1,8-naphthalimides, acridines, penicillin G, and isoniazid.The incorporation of carborane clusters significantly influenced the biological activity of parent compounds by modulating DNA interactions, anticancer mechanisms, antibacterial activity, lipophilicity, and membrane permeability. In anticancer conjugates, carborane modification affected DNA binding, reactive oxygen species generation, apoptosis induction, and cellular localization. In antibacterial agents, carborane incorporation improved the activity of selected penicillin G and isoniazid derivatives, including activity against resistant bacterial strains.These examples demonstrate that carboranes are versatile pharmacophores capable of enhancing the biological properties of established drug scaffolds and represent promising tools for the development of novel anticancer and antimicrobial agents.
Agnieszka B. Olejniczak· Handbook of Experimental Pha...· 0 citations
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.
Suzuri Miyoshi, K. Obata, Hiroto Murata et al.· ACS Applied Materials and In...· 0 citations
The spread of antibiotic resistance has become a major challenge in global public health, and there is an urgent need to develop novel antibacterial agents with low resistance. Peptide-based antibacterial agents have attracted increasing attention for their membrane-targeting mechanisms, which may reduce the risk of the development of resistance. Herein, a series of quaternary ammonium-modified cyclic dipeptides (named cHHn-m) were designed and synthesized through a quaternization reaction and their antibacterial activity and cytotoxicity were systematically investigated. The optimal cyclic dipeptides (cHH8-6) demonstrated the best antibacterial ability with MIC values of 2.0 and 3.9 μg mL-1 against S. aureus and E. coli, respectively. Antibacterial mechanism studies indicate that cHH8-6 can bind to a negatively charged bacterial membrane through electrostatic interactions, subsequently disrupting the integrity of the bacterial membrane. Due to its unique mechanism, cHH8-6 is less likely to induce bacterial resistance compared to clinical antibiotics. In addition, cHH8-6 effectively inhibited bacterial biofilm formation and eradicated mature bacterial biofilms. In bacterial-induced mouse models of epidermal and keratitis infections, cHH8-6 effectively reduces the bacterial count at the infection site with negligible in vivo toxicity. This study provides a novel approach for treating clinical bacterial infections.
Zhe Zong, Guowenlie Gao, Pengqi Wan et al.· Biomaterials Science· 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.