Aug 2026· Chemical Science· 0 citations· 53 references
Medicine
TL;DR
A novel AMP mimic prodrug where the cationic ammonium residues are caged with trans-cyclooctene units that can be bioorthogonally activated by tetrazine via an inverse-electron-demand Diels–Alder click-to-release reaction is developed, demonstrating the on-demand control of toxicity enabled by the bioorthogonal trigger.
Abstract
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.
The growing threat of antimicrobial resistance (AMR) underscores the need for antibacterial scaffolds that act through mechanisms distinct from those of conventional antibiotics. Conjugated oligoelectrolytes (COEs) are membrane-active antimicrobials, although stilbene-containing representatives can present scaffold-specific challenges associated with alkene stability and synthetic accessibility. Here, we report a naphthalene-based rigid-core electrolyte (RCE) platform that removes the phenylene-vinylene linker while retaining potent antibacterial activity. The RCEs were accessed through a two-step, transition-metal-free route, and the lead compound N6P displayed activity against the tested ESKAPE representatives (MICs = 1-8 μg/mL), Mycobacterium abscessus (MIC = 4 μg/mL), and Streptococcus pneumoniae (MIC = 1 μg/mL). DiSC3(5) depolarization, ANS uptake, TEM imaging and DAPI/PI imaging were consistent with bacterial membrane perturbation. N6P was rapidly bactericidal against MRSA, retained activity in serum-supplemented medium, produced only a fourfold maximum MIC increase during 14 passages, and reduced viable bacteria in established MRSA biofilms. In a murine MRSA wound model, N6P and N6-Br reduced bacterial burden by 3.2-4.8 log10 CFU at doses of 0.05-0.25 mg/kg. Serum biochemical profiling at 0.25 mg/kg showed no consistent treatment-related changes, while histological examination at doses up to 0.75 mg/kg revealed no overt abnormalities under the conditions evaluated. These findings identify compact scaffold rigidity, linker length, and cation identity as important design variables for this RCE series and support further pharmacokinetic, formulation, and tolerability studies.
Aniket Kulkarni, T. J. M. Jim, V. Lotocki et al.· European journal of medicina...· 0 citations
In the context of rapid rise of resistant pathogen strains, antimicrobial peptides (AMPs) represent promising scaffolds that complement conventional antibiotics, especially given the specific toxicities that limit classic drugs like fluoroquinolones and nitroimidazoles. AMP monotherapy faces major drawbacks, primarily due to inherent host-cell toxicity and a short half-life.
To overcome these limitations, this study details the design and synthesis of dual-mechanism prodrugs by conjugating the membrane-active AMPs scaffolds of urechistachykinin I and decoralin to norfloxacin and metronidazole via a pathogen-cleavable ester linker. To minimize off-target toxicity, both AMP sequences were synthesized with a C-terminal carboxyl group, as these variants exhibit negligible hemolytic and neurotoxic activity compared to their amidated analogues. The designed antibiotic-peptide conjugates were synthesized on solid support starting from the C-terminus, followed by N-terminal chain elongation to attach the antibiotics. Specific derivatization methods ensured the covalent ester linkage of norfloxacin and metronidazole to the N-termini of urechistachykinin I (resulting in conjugates
1a
and
1b
) and decoralin (resulting in conjugates
2a
and
2b
). Structural behavior was assessed by 200 ns molecular dynamics simulations in water. Antimicrobial activity was evaluated by broth microdilution against Gram-negative, Gram-positive bacteria and fungi, and compared to parent peptides and reference antibiotics as positive controls.
All conjugates exhibited increased flexibility and solvent exposure relative to their parent peptides, as evidenced by increased RMSD, radius of gyration, H-bonding with water and higher solvent accessible surface area. In vitro screening identified
1a
,
2a
and
2b
as the most active conjugates. Norfloxacin conjugate
1a
exhibited potent activity against
Escherichia coli
ATCC 8739 (MIC 0.56 μM) and
Candida parapsilosis
(MIC 2.26 μM). Norfloxacin conjugate
2a
showed broad-spectrum inhibition, including
Escherichia coli
ATCC 8739 (MIC 8.64 μM),
Salmonella enterica
ATCC BAA-2162 (MIC 8.64 μM) and
Listeria
monocytogenes
DSMZ 115292 (MIC 4.32 μM), with improved activity over unmodified decoralin. Metronidazole conjugate
2b
was active against
Listeria monocytogenes
DSMZ 115292 (MIC 11.86 μM) and
Enterococcus faecalis
ATCC 29212 (MIC 23.12 μM).
These in vitro assays demonstrate retained peptide membrane-disrupting properties and synergistic effects with the antibiotics. The dual-mechanism design represents a promising strategy to reduce toxicity and overcome antimicrobial resistance.
Denisa Leonte, Clemence Fartaoui, Ioana Ionuț et al.· Frontiers in Pharmacology· 0 citations
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
Synthetic mimics of antimicrobial peptides (SMAMPs) have emerged as a promising alternative to conventional antibiotics in the fight against antimicrobial resistance. Here, a new class of poly(diitaconamide)-based SMAMPs featuring facially amphiphilic repeat units is presented. Copolymers with systematically varied hydrophobicity and charge density are obtained by free radical copolymerization combining diitaconamide and acrylamide-based repeat units, each bearing different alkyl substituents. These polymers have good hydrolytic stability over a wide pH range. They exhibit structure-bioactivity relationships typical for facially amphiphilic antimicrobial polymers, including selectivity for bacteria over mammalian cells: increasing the hydrophobicity enhances the antimicrobial activity, particularly against Escherichia coli bacteria, but also leads to increased haemolytic activity. Copolymers with pentyl-substituted co-repeat units display overall higher antimicrobial activity, whereas their propyl-substituted analogues exhibit improved selectivity towards bacterial cells over mammalian cells. These trends are consistent with previously reported facially amphiphilic SMAMP systems. They indicate that the facial amphiphilicity design concept was successfully translated to this polymer type and highlight the critical role of balanced amphiphilicity on the repeat unit level. Interestingly, one of the poly(diitaconamide) SMAMPs is selective for Gram-negative over Gram-positive bacteria, and the combination of precise hydrophobic balance and suitable molar mass is proposed as a tool to achieve such Gram-selectivity. As a demonstrator for clinical applications, SMAMP ointments with high antimicrobial activity and a pot stability of at least 8 weeks are presented, which are also selective for Gram-negative over Gram-positive bacteria.
Lea Sollka, Diana Lorena Guevara Solarte, S. Rau et al.· Journal of materials chemist...· 0 citations
The rising global concerns for antimicrobial resistance (AMR) urgently demands novel antimicrobial agents. Conventional antibiotics, which are purely based on organic moieties, are failing against multidrug-resistant (MDR) and pan-drug-resistant (PDR) pathogens, necessitating innovative therapeutic approaches. However, metallodrugs, compounds incorporating metal ions, have re-emerged as a promising class of antimicrobials. Historically used in medicine, their application declined with conventional antibiotics. However, metallodrugs offer unique chemical diversity, diverse mechanisms of action, and the ability to overcome established resistance pathways. This review explores their multifaceted actions, including membrane disruption, oxidative stress induction, and enzyme inhibition. Key metal ions like silver, copper, gold, gallium, bismuth, and ruthenium are highlighted for their antimicrobial applications and therapeutic potential. Advanced strategies for enhancing metallodrug efficacy include rational ligand design, combination therapies, nanotechnology-driven delivery systems, and photoactivation. While significant opportunities exist, challenges such as toxicity concerns, pharmacokinetic optimization, potential resistance mechanisms, and regulatory pathways must be addressed. This article provides a foundation for researchers and clinicians, emphasizing metallodrugs’ transformative potential in combating the AMR crisis and shaping infectious disease treatment.
L. Usman, Dailami S. A. Masokano, Patrick I. Ahuruonye· Discover Chemistry· 0 citations
Peptide dendrimers, characterized by their branched structure and densely arrayed surface amino acids or peptides, offer enhanced multivalency and unimolecular stability that collectively improve receptor engagement and bioactivity. Despite these advantages, broad application remains limited due to synthetic complexity, high production costs, and increased toxicity associated with larger dendrimer generations. To address these limitations, this study presents a streamlined design for peptide dendrimers featuring one or two branched heptapeptides tethered to a linear nonapeptide scaffold, with lauric acid introduced to the dendrimer core to drive self-assembly and enhance molecular stability. The resulting construct, designated Lau-IL-9-C2, demonstrated potent and broad-spectrum antibacterial activity against multidrug-resistant strains, alongside high biocompatibility in both in vitro and in vivo models. Mechanistic investigations revealed that Lau-IL-9-C2 exerted bactericidal effects through dual modes of action, not only disrupting bacterial membranes by targeting lipoteichoic acid (LTA), lipopolysaccharide (LPS), and phosphatidylglycerol but also inhibiting intracellular biological processes. Lau-IL-9-C2 also eradicated bacterial biofilms and persister cells and exhibited sustained efficacy without resistance development. In a murine wound infection model, Lau-IL-9-C2 achieved significant therapeutic outcomes, effectively clearing bacterial burden and accelerating wound healing. These findings support the rational design of structurally accessible peptide dendrimers as a promising platform for next-generation antimicrobial therapeutics. STATEMENT OF SIGNIFICANCE: Peptide dendrimers with enhanced multivalency and unimolecular stability that collectively improve bioactivity. However, higher dendrimer generations substantially increase synthetic complexity and production costs. To address these limitations, we present a minimal yet functionally robust branching strategy to construct peptide dendrimers featuring with one or two branched heptapeptides tethered to a linear nonapeptide scaffold, with lauric acid introduced to the dendrimer core to drive self-assembly and enhance molecular stability. The lead peptide dendrimer Lau-IL-9-C2 was identified with potent and broad-spectrum antimicrobial activity against multidrug-resistant bacteria and high biocompatibility in both in vitro and in vivo systems. These findings advance understanding of peptide dendrimer structure-activity relationships and support the development of simplified dendrimer-based antibiotics for the treatment of multidrug-resistant bacterial infections.
An Yan, Tianyu Zhang, Xing-Yu Wang et al.· Acta Biomaterialia· 0 citations
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