Jul 2026· Biomaterials Science· Vol 14, pp. 4704-4713· 0 citations
Medicine
TL;DR
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, and due to its unique mechanism, cHH8-6 is less likely to induce bacterial resistance compared to clinical antibiotics.
Abstract
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.
The increasing prevalence of multidrug-resistant bacteria underscores the need for antibacterial agents with mechanisms distinct from those of conventional antibiotics. Inspired by the amphiphilic organization and membrane-active properties of host defense peptides (HDPs), we synthesized 22 salicylanilide derivatives and related analogues by systematically varying the ortho-phenolic hydroxyl group and substituents on the aromatic rings to modulate structural features associated with molecular polarity and hydrophobicity. Structure-activity relationship (SAR) analysis identified D2, bearing 3,5-dibromo and 2,5-bis(trifluoromethyl) substitutions, as the lead compound. D2 exhibited potent activity against Gram-positive pathogens, with MIC values of 0.2 - 12.5 μg/mL and MICs of 0.8 - 1.6 μg/mL against multiple MRSA strains. Mechanistic studies showed that D2 induced membrane depolarization and reduced intracellular ATP levels without detectable gross membrane permeabilization under the tested conditions, consistent with a membrane-associated antibacterial effect. No detectable increase in the MIC of D2 was observed over 21 serial passages, and D2 also showed substantial activity against established biofilms. In murine models of MRSA pneumonia and keratitis, D2 reduced bacterial burdens at the sites of infection and attenuated infection-associated pathological damage. Collectively, these findings identify D2 as a promising salicylanilide-based antibacterial lead and provide a structure-activity framework for further optimization of this chemotype against drug-resistant Gram-positive pathogens.
Pan-Pan Wang, Min Li, Yu-Hang He et al.· European journal of medicina...· 0 citations
Microorganisms such as bacteria, viruses, fungi, and parasites cause serious infections in humans. The misuse of antimicrobial treatments in humans, animals, and agriculture has led to the development of resistant pathogens that can survive and multiply even in the presence of antibiotics. The rise of antibiotic-resistant pathogens has caused significant loss of life and impacted social and economic conditions. Antimicrobial peptides exert antibacterial activity through multiple modes of action. Cyclic peptides are known for greater stability and bioavailability than linear peptides. Among them, cyclic depsipeptides represent a distinct subclass characterized by the presence of an ester bond in addition to peptide bonds. Because of the distinct molecular structure of cyclic depsipeptides, particularly their amino acid components, they demonstrate robust antimicrobial efficacy. Cyclic depsipeptides demonstrate antimicrobial efficacy by targeting various components of the cell wall, including lipid II, menaquinone, lipopolysaccharides, and the DNA polymerase β sliding clamp, as well as by inhibiting biofilm formation and quorum sensing. Additionally, it demonstrated a lower likelihood of resistance development, emphasizing its ability to fight multidrug-resistant pathogens. Given these promising findings, cyclic depsipeptides offer a promising molecular framework for addressing a range of human infections, particularly in an era of increasing antibiotic resistance. This review summarises the recently identified cyclic depsipeptide-based antimicrobial candidates for the treatment of bacterial, fungal, and parasitic infections.
Antimicrobial resistance has become a serious global health challenge, increasing the need for new therapeutic strategies beyond conventional antibiotics. In this study, FL18 and its chimeric derivatives, FL18–TAT8 and FL18–Ahx–TAT8, were designed to combine antimicrobial activity with the cell-associated advantages of a cell-penetrating peptide motif and were synthesized by Fmoc-based solid-phase peptide synthesis. Their molecular masses were confirmed by MALDI-MS analysis. The antibacterial activities of the peptides were evaluated against representative Gram-negative and Gram-positive bacterial strains, including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecium. The tested peptides exhibited minimum inhibitory concentration values in the range of 4–64 μM depending on the peptide sequence and bacterial strain, while TAT8 alone showed no significant antibacterial activity under the tested conditions. Among the constructs, FL18–Ahx–TAT8 displayed the most favorable overall antibacterial profile, particularly against P. aeruginosa and E. faecium. Biocompatibility studies further showed that FL18 and its chimeric derivatives maintained approximately 75–90% HaCaT cell viability across the tested concentration range and exhibited generally low hemolytic activity. In addition, confocal microscopy and flow cytometry revealed peptide-associated fluorescence in HaCaT cells, with the TAT8-containing chimeras showing a broader and more pronounced fluorescence distribution than FL18 alone. Overall, these findings demonstrate that FL18-based chimerization provides a modular and effective strategy for tuning antibacterial activity, biocompatibility, and peptide–cell interaction behavior, underscoring their promise as building blocks for the design of next-generation antimicrobial peptide platforms.
N. Zencirci, Busra Kilic, Öznur Akbal Vural et al.· ACS Omega· 0 citations
ABSTRACT Antibiotic-resistant bacteria are a global public health threat that is becoming increasingly difficult to address with conventional therapeutics. Consequently, there is much interest in studying alternative biologics that circumvent antibiotic resistance. The Brevinin-2 family of antimicrobial peptides (AMPs) is a group of naturally occurring molecules that have the potential for high activity and low toxicity. Herein, we investigated the potential of a consensus-sequence-driven approach to Brevinin-2 peptide synthesis and evaluated their action against a panel of multidrug-resistant (MDR) bacteria, including carbapenemase-resistant Escherichia coli. We used the positional frequency of amino acids to generate novel synthetic peptides representative of the Brevinin-2 family. Four templates—G30, G33, S33, and G37—were synthesized by standard fluorenylmethyloxycarbonyl (FMOC) chemistry, purified by reverse-phase fast protein liquid chromatography (RP-FPLC), and tested for antibacterial activity and hemolytic toxicity. The results demonstrated a broadly applicable chemical peptide synthesis pipeline for the Brevinin-2 family with a high degree of purity (>90%). Two peptides—S33 and G33—exhibited activity consistent with potential selectivity toward gram-positive and -negative bacteria, respectively, while G37 displays broad-spectrum activity, with growth of a Class B carbapenemase-resistant E. coli inhibited at 16 µM and a Class A carbapenemase-resistant K. pneumoniae inhibited at 64 µM. G37 acts rapidly, slowing growth within 30 min and fully killing targeted bacteria within 150 min. Although moderate levels of hemolytic toxicity pose a challenge for future development, the consensus-sequence approach toward novel Brevinin-2 AMP discovery via alignment combined with in vitro antimicrobial analysis shows promise to test and initially validate other peptides. IMPORTANCE The escalating threat of antimicrobial resistance (AMR) demands innovative therapeutic strategies beyond traditional antibiotics. This study demonstrates a systematic, consensus-sequence-driven approach to designing antimicrobial peptides (AMPs) from the naturally occurring Brevinin-2 family, offering a replicable framework for accelerated drug discovery. Our novel peptide G37 exhibits bactericidal activity against carbapenemase-resistant Escherichia coli within 150 min while maintaining low hemolytic activity at therapeutic concentrations. The potential preferential activity shown by peptides S33 and G33 for gram-positive versus gram-negative bacteria provides prospective valuable insights into structure-activity relationships that can guide further peptide optimization. By combining computational sequence analysis, standardized solid-phase peptide synthesis, and comprehensive in vitro validation, this work establishes a streamlined pipeline for Brevinin-2 peptide development. This methodology addresses the urgent need for alternative antimicrobials while providing a scalable approach to combat multidrug-resistant (MDR) pathogens. The escalating threat of antimicrobial resistance (AMR) demands innovative therapeutic strategies beyond traditional antibiotics. This study demonstrates a systematic, consensus-sequence-driven approach to designing antimicrobial peptides (AMPs) from the naturally occurring Brevinin-2 family, offering a replicable framework for accelerated drug discovery. Our novel peptide G37 exhibits bactericidal activity against carbapenemase-resistant Escherichia coli within 150 min while maintaining low hemolytic activity at therapeutic concentrations. The potential preferential activity shown by peptides S33 and G33 for gram-positive versus gram-negative bacteria provides prospective valuable insights into structure-activity relationships that can guide further peptide optimization. By combining computational sequence analysis, standardized solid-phase peptide synthesis, and comprehensive in vitro validation, this work establishes a streamlined pipeline for Brevinin-2 peptide development. This methodology addresses the urgent need for alternative antimicrobials while providing a scalable approach to combat multidrug-resistant (MDR) pathogens.
Colin M. McDowell, Jessica D. Carder, J. Brozik et al.· Applied and Environmental Mi...· 0 citations
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.
Hao Luo, Rhiannon P. Kuchel, Kevin Neumann et al.· Chemical Science· 0 citations
The rapid emergence of multidrug-resistant bacterial pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA), underscores the critical discovery for new antibiotics with novel scaffolds. We identified lead compound LXW933, which exhibits promising anti-MRSA activity and features a unique 1,2,4-oxadiazole scaffold, from our phidianidine-based compound library. Based on this structure, a Function-Oriented Synthesis (FOS) strategy had been conducted to afford a series of phidianidine derivatives for their antibacterial activity evaluation. Compounds 24a exhibited excellent anti-MRSA efficacy with an MIC value of 1.5 μg/mL and low toxicity against HeLa cells. Further mechanistic study showed that 24a effectively inhibits biofilm formation and exerts its antibacterial effect by disrupting the bacterial cell membrane. This research provides valuable insights for the discovery of antibacterial drug leads derived from oxadiazole-containing marine alkaloids, paving the way for new strategies to combat antimicrobial resistance.
Qiong Wu, Bing-Yuan Yan, Chen Qu et al.· Chinese Journal of Natural M...· 0 citations
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