Quorum sensing is the bacterial communication that regulates biofilm formation, virulence, and drug resistance development. The misuse of antibiotics accelerates the emergence of resistant pathogens, highlighting the urgent need for alternative anti-virulence strategies. In this context, LasR, a key transcriptional regulator in the QS network of Pseudomonas aeruginosa, was targeted to disrupt bacterial communication and biofilm development. In the present study, we designed a library of glycinate and propanoate derivatives (n = 30), and carried out molecular docking, MM-GBSA studies, synthesized and characterized. Their QS inhibitory activity was evaluated against the P. aeruginosa MH602 reporter strain at concentrations ranging from 250 to 8 µM. The compounds exhibited 79-35% inhibition at 250 µM, retaining moderate to low activity (28-7%) at 8 µM. SAR studies indicated that the electron-withdrawing phenyl substituents on the triazole ring enhanced activity, with 11b and 10o (3-nitrophenyl) showing the highest inhibition. In silico ADME, molecular dynamics studies supported favorable LasR binding. The most active compounds were evaluated for cytotoxicity, biofilm inhibition, and suppression of pyocyanin and protease production. 10o emerged as the most promising, demonstrating strong anti-biofilm activity and significant reduction of pyocyanin, suggesting thiolactone-based triazoles as potential QS inhibitors to combat bacterial resistance.

INTRODUCTION:Microbial keratitis is a serious complication of contact lens wear, occurring in 2-24 cases per 10,000 wearers annually. Increasing lens use, especially for myopia control in children, highlights the need for safer designs. Antimicrobial coatings and films offer a promising strategy to reduce infection risk. Recent approaches include metallic and polymeric nanocoatings, antimicrobial peptides (AMPs), peptidomimetics, and hybrid systems that prevent microbial adhesion and biofilm formation while maintaining lens biocompatibility. AREAS COVERED:This review examines advances in antimicrobial nanocoatings for contact lenses, focusing on metallic nanoparticles (silver, zinc oxide, titanium dioxide), organo-selenium coatings, polymeric layers, AMPs such as melimine and Mel4, and emerging peptidomimetics. Literature from PubMed, Scopus, and Web of Science (2008-2025) was analyzed. Key topics include coating techniques (surface grafting, dip-coating, plasma treatment), antimicrobial mechanisms, and outcomes from preclinical and clinical trials. Limitations such as nanoparticle toxicity, peptide degradation, and regulatory hurdles are discussed. EXPERT OPINION/COMMENTARY:Antimicrobial nanocoatings show strong potential, achieving >3-log10 bacterial reductions and reducing corneal infiltrative events in trials. Future work should focus on hybrid, stimuli-responsive coatings that activate under infection-specific conditions, ensure long-term safety, and meet manufacturing and regulatory requirements.

Background/objectives: Multidrug-resistant and extensively drug-resistant Gram-negative pathogens are a major cause of severe ocular infections, yet treatment options are increasingly compromised by escalating antibiotic resistance. Membrane-active peptides (colistin and Mel4) offer the potential to restore antibiotic susceptibility. This study investigated the efficacy of peptide- and colistin-based adjuvant strategies in enhancing the activity of conventional antibiotics. Methods: Antibacterial activity was assessed using MIC/MBC testing, checkerboard assays, time-kill kinetics, and biofilm disruption studies, supported by confocal microscopy. Toxicity was assessed using L929 fibroblasts and red blood cells. A mechanistic study was performed with a membrane permeability assay. Results: Clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae showed high resistance to six antibiotic classes (up to MICs > 2048 mg/L), while polymyxin B and colistin remained active (MIC ≤ 2 mg/L). Mel4 displayed variable activity (MIC 7.8-500 mg/L). A total of 102 antibiotic-antibiotic, antibiotic-Mel4, and antibiotic-colistin combination tests were performed, of which 45 showed synergistic interactions. Combining traditional antimicrobials with either colistin or Mel4 restored antibiotic susceptibility, reducing MICs up to 2048-fold. Aminoglycoside-colistin combinations significantly lowered MICs, especially against K. pneumoniae. Time-kill assays confirmed rapid bactericidal effects (>3 log10 reduction in 3 h). The ciprofloxacin-Mel4 combination effectively disrupted biofilms (62-92%) with low toxicity and high cell viability. Membrane permeability assays showed that ciprofloxacin has limited activity, whereas both Mel4 and the ciprofloxacin-Mel4 combination showed enhanced activity across concentration gradients and over time. Conclusions: Membrane-active antimicrobials, colistin and Mel4, enhance conventional antibiotics against multidrug- and extensively drug-resistant ocular Gram-negative pathogens by restoring susceptibility, accelerating bactericidal effects, and disrupting biofilms. With low toxicity, these combinations represent promising therapeutic strategies for severe multidrug-resistant ocular infections.

Approximately 150 million people worldwide wear contact lenses, and most wear them successfully. However, contact lens wear is a major risk factor for developing infections and inflammation of the eye. This review outlines the need for antimicrobial contact lenses to help reduce the incidence of infection and inflammation. Antimicrobial peptides (AMPs) have been probably the best researched as antimicrobial coatings for contact lenses, with one of these (Mel4) progressing to a successful stage III clinical trial. Other antimicrobials including metals such as silver and selenium, and quorum sensing inhibitors have also progressed through to clinical trials. Currently only the Mel4 coated lenses have been shown to reduce the incidence of contact lens-associated inflammation. Unfortunately, no antimicrobial lens is yet available for sale, but the need is clear, and researchers, manufacturers and contact lens wearers are encouraged to continue their efforts in this space.

Chronic inflammation accounts for more than half of all global deaths, and is associated with many diseases including cancer, heart disease or diabetes. Here a novel series of TANK-binding kinase 1 (TBK1) inhibitors based on isoflavonoid derivatives was synthesised via the multicomponent Petasis reaction. TBK1 is a key mediator of several inflammatory pathways, and its inhibition shows great promise for overcoming autoimmune diseases, hyper-inflammatory diseases, neurodegenerative diseases, and cancer resistance. Molecular modelling and SAR studies were conducted on isoflavonoid derivatives with established anti-inflammatory activity to generate a library of novel analogues with improved biological activity. A series of TBK1 inhibitors were synthesised, with the lead compound 7a exhibiting potent inhibitory activity against NF-κB and type I IFN inflammatory signalling pathways (IC50 = 0.13 µM), representing a 6.7-fold improvement compared to the parent isoflavene compound.

The emergence of antimicrobial resistance (AMR) poses a critical threat to public health worldwide, making conventional antibiotics ineffective against multidrug-resistant (MDR) pathogens. This literature review examines the potential therapeutic applications of nano-antimicrobial peptides (Nano-AMPs), with a focus on multidrug-resistant pathogens prioritized by the World Health Organisation (WHO). Antimicrobial peptides (AMPs) are essential components of the innate immune system with broad-spectrum bactericidal and immunomodulatory properties, and have emerged as promising alternatives to conventional antibiotics because of their unique mechanisms of action (e.g., membrane disruption, pore formation, and immunomodulation). Currently, the clinical translation of AMPs is hindered by several challenges, including enzymatic and non-enzymatic degradation, poor bioavailability, and biocompatibility issues, as well as local and systemic adverse events. To address these concerns, recent advancements in nanocarrier delivery systems offer novel solutions, enabling selected and targeted drug delivery, enhanced bioavailability, and controlled and sustained AMP release. Lipid-based nanocarriers (e.g., liposomes), polymeric and other nanocarrier systems improve peptide solubility and limit off-target events, while inorganic carriers like gold, silver, and silica nanoparticles facilitate functionalization and synergism to combat MDR Gram-negative infections. Despite promising findings, challenges such as production, long-term efficacy and safety, and regulatory approval persist. Therefore, interdisciplinary efforts, such as advanced machine learning methods alongside conventional pharmacological approaches, may be needed to optimize nanocarrier designs and validate clinical efficacy and safety in preclinical and clinical trials. This review critically analyses the latest evidence on different nanocarriers and their synergistic effects, highlighting their transformative potential to combat AMR, thereby offering insights to develop next-generation antibiotics, particularly against Gram-negative pathogens.

Antimicrobial peptides (AMPs) and their synthetic mimics are emerging as promising alternatives to conventional antibiotics, particularly in response to the growing threat of antimicrobial resistance. Naturally occurring AMPs are essential components of the innate immune system and display broad-spectrum activity against diverse microbial pathogens, while their synthetic mimics, including peptidomimetics and polymer-based analogs, are designed to enhance stability, reduce toxicity, and improve pharmacokinetics. This study aims to demonstrate the production, characterization, and biological evaluation of AMPs and small-molecule peptide mimics. AMPs are generated using recombinant expression systems or solid-phase peptide synthesis, enabling precise control over amino acid sequence and structural properties. Small-molecule peptide mimics are synthesized using chemical strategies, including an anthranilic acid (2-aminobenzoic acid) scaffold to enhance structural stability and pharmacological performance. Following synthesis, compounds are purified and chemically characterized prior to biological testing. Antimicrobial activity is evaluated using in vitro minimum inhibitory concentration (MIC) assays, and cytotoxicity is assessed against mammalian cell lines to determine selectivity. Representative results demonstrate that both AMPs and their mimics exhibit potent activity against Klebsiella pneumoniae and Escherichia coli, highlighting their broad-spectrum antibacterial potential. Overall, this protocol provides a comprehensive and reproducible framework for the development and systematic evaluation of antimicrobial peptides and their mimics as next-generation anti-infective agents.

Pseudomonas aeruginosa is a major global health concern due to its multidrug resistance (MDR), necessitating the urgent development of novel therapeutic strategies. Understanding the molecular basis of resistance in clinical isolates is critical for designing next-generation antimicrobials. This study analysed recent clinical isolates of P. aeruginosa obtained from the NCBI for their resistance gene and virulence factor profiles. Among the virulence-associated targets, MvfR, a key transcriptional regulator of quorum sensing and biofilm formation, was prioritized based on its functional relevance. AI modelling of MvfR identified from the genome analysis was performed, followed by molecular docking against library of compounds, phylogenetic comparisons to compare with previously identified homologs, ADMET-profiling, 500 ns molecular dynamics (MD) simulations, binding free energy, and Density Functional Theory (DFT). Genes critical for antimicrobial resistance, drug targeting, and virulence factors were identified across multiple databases. The antimicrobial resistance genes and receptors revealed key resistance mechanisms, including antibiotic-inactivating enzymes, efflux pumps, quorum sensing, and alterations in cell wall charge or permeability. Notably, (S)-1-(2-(difluoromethyl)-1 H-benzo[d]imidazol-5-yl)-3-(2-hydroxy-2-(pyridin-4-yl)ethyl)urea exhibited the highest docking score against MvfR. DFT and MD simulations over 500 ns demonstrated stability of the top ligands, supported by favourable molecular stability parameters such as RMSD, SASA, RMSF, and Rg plots. Furthermore, the top-ranking ligands satisfied Lipinski’s rule of five, suggesting favourable drug-like properties. This study provides an integrated computational characterization of MvfR in recent P. aeruginosa isolates and identifies genetic variations that may influence disease manifestation. It further demonstrates an integrative computational strategy to accelerate discovery of promising antimicrobial agents against multidrug-resistant bacteria.

Antimicrobial peptides show promise as broad-spectrum agents and are less likely to induce rapid resistance. However, protease sensitivity limits their potential as antibiotic alternatives. Non-canonical amino acid incorporation may enhance stability but could impact other properties. The activities of four peptides (oligoarginine (PLR10), oligohomoarginine (PLHR10), Mel4, and Mel4HArg) were tested against strains of S. aureus, P. aeruginosa and E. coli. Circular dichroism (CD) was used to determine their secondary structure. Their MICs against E. coli and P. aeruginosa were re-examined after protease treatment. Cytotoxicities against L929 cell line were determined. MICs for the four AMPs ranged from 31.25 to > 500 µM. Total substitution of arginine with homoarginine had minimal effect on MICs of PLR10, but increased the MICs of Mel4, e.g., against S. aureus ATCC 6538 from 31.25 to > 250 µM. In 30 mM SDS, substitution with homoarginine resulted in the loss of α-helical structures. Trypsin reduced PLR10 activity against E. coli and P. aeruginosa but had less effect on PLHR10. At 62.5 µM, PLR10 reduced E. coli growth by 20

Fatty acid synthase (FASN) is overexpressed in many cancers and has therefore emerged as a potential target for anticancer drug development, particularly through inhibition of the thioesterase domain. In this study, 21 N-aryl oleamide derivatives were rationally designed and screened via molecular docking against the thioesterase (TE) domain of FASN. N-phenyloleamide (OA2) and N-(o-tolyl)oleamide (OA3) emerged as the top candidates and were further evaluated in their epoxidized forms: 8-(3-octyloxiran-2-yl)-N-phenyloctanamide (EOA2) and 8-(3-octyloxiran-2-yl)-N-(o-tolyl) octanamide (EOA3). The epoxide derivatives exhibited enhanced binding affinities (OA2 = − 5.49, OA3 = − 5.36, EOA2 = − 5.85, and EOA3 = − 5.84 kcal/mol), with EOA2 showing interactions with the catalytic triad (Ser2308, Asp2338, His2481), suggesting a favorable binding orientation. The selected compounds (OA2, OA3, EOA2, and EOA3) were synthesized and evaluated for cytotoxic activity. EOA2 demonstrated the most potent activity against HeLa cells (IC50 = 6.16 µg/mL) and showed notable selectivity over normal Vero cells. Molecular dynamics simulations over 300 ns confirmed stable binding, as evidenced by consistent root mean square deviation, root mean square fluctuation, radius of gyration, solvent-accessible surface area, and hydrogen-bond profiles. Molecular mechanics Poisson-Boltzmann surface area analysis showed a favorable binding free energy of − 27.62 ± 2.44 kcal/mol, indicating that hydrophobic and electrostatic interactions stabilize the complex. Protein secondary structure and Ramachandran analyses further confirmed preservation of protein structural integrity throughout the simulation, while ADMET predictions indicated acceptable drug-likeness. These findings suggest EOA2 as a promising anticancer lead compound with cytotoxic activity against HeLa cells and good selectivity toward cancer cells.

The advancement of antimicrobial contact lenses presents a promising strategy for mitigating microbial keratitis. This study investigated the antimicrobial activity of four guanidine-substituted anthranilic amide peptidomimetics (GAMPs), identifying RK1083 as the most potent candidate. The minimum inhibitory concentrations ranged from 20 to 86 µM, with therapeutic indices between 2 and 22. All tested GAMPs exhibited resistance to proteolytic degradation. RK1083 was covalently immobilized onto contact lenses using carbodiimide chemistry, oxazoline plasma deposition, and plasma immersion ion implantation (PIII). The modified lenses demonstrated increased nitrogen content (≥3

BACKGROUND:Antimicrobial peptides and peptidomimetics have emerged as promising alternatives to traditional antibiotics for MDR bacterial infections. Their advancement, however, is often limited by toxicity and poor pharmacokinetics. In this review, we apply a rigorous quantitative framework to evaluate the therapeutic balance of potency and safety for these agents, offering new perspectives that extend beyond previous descriptive analyses. METHODS:We systematically searched key biomedical databases (January 2000 to May 2025) for studies reporting antimicrobial potency, cytotoxicity, selectivity index, stability and in vivo efficacy. Bias was assessed using an adapted laboratory animal experimentation quality tool. Data were synthesized using a pooled geometric mean approach to compare therapeutic windows across compound. RESULTS:Of 136 peptides from 47 studies, natural antimicrobial peptides were most potent in vitro against Gram-negative bacteria but frequently caused significant host toxicity. Limited cytotoxicity data prevented robust selectivity analysis for these natural compounds. Peptidomimetics generally provided a wider safety margin than synthetic peptides, though toxicity was context dependent. Major translational barriers, including protein binding and cation effects, diminished in vivo efficacy. Notably, some rationally designed compounds achieved therapeutic benefit in animal models without acute toxicity, unlike traditional agents such as polymyxin B. CONCLUSIONS:Advancing antimicrobial peptides and peptidomimetics into clinical use will require overcoming the fundamental trade-off between potency and safety. Natural compounds remain restricted by toxicity, while synthetic agents and peptidomimetics promise better safety but face pharmacokinetic challenges. Future research should prioritize innovative delivery approaches to enhance efficacy and reduce toxicity, enabling these novel therapies to address MDR infections.

Proton gradients across membranes are central to modern bioenergetics and are thought to have played a pivotal role in life’s emergence. We report that the autocatalytic formaldehyde-sulfite (FS) pH-clock reaction can generate such gradients when encapsulated in unilamellar phospholipid vesicles. POPC/POPG vesicles (~100 nm) containing sodium (bi)sulfite and the fluorescent pH probe HPTS were prepared by the thin-film hydration method, extruded and purified via size exclusion chromatography. Upon aqueous formaldehyde addition, a rapid rise in lumen pH was observed, resulting in a transmembrane pH gradient whose magnitude and kinetics were sensitive to initial lumen pH. Vesicles with lumen pH near 7.5 exhibited an increase to ~8.8 followed by a gradual decrease toward neutrality. 13 C NMR spectroscopy confirmed encapsulation of the final FS product, hydroxymethanesulfonate. Vesicles doped with small percentages of oleic acid afforded faster proton transport, demonstrating the spike in pH can be controlled through membrane composition. These findings establish a simple, nonenzymatic route to transmembrane pH gradients and provide a rare experimental example of an autocatalytic reaction network confined within protocell-like vesicles.

Abstract Background Deregulated MYC signalling is a central oncogenic driver in high-risk medulloblastoma (MB) and diffuse intrinsic pontine glioma (DIPG), where it promotes aggressive tumour growth and treatment resistance. Somatic H3K27M mutations occur in DIPG tumours and drive epigenetic reprogramming that sustains oncogenic transcriptional programs, including MYC and MYCN signalling. Methods We developed a series of small-molecule MYC inhibitors (UNSW-SC compounds) derived from the lead scaffold SE486-11 (Cheung, Oncogene, 2021), with improved potency. The lead compound, UNSW-SC-22, was evaluated in MYC-driven MB and DIPG models using pharmacology, genetic dependency assays, target-engagement studies (SPR and CETSA), transcriptomic profiling, and in vivo efficacy studies in orthotopic and transgenic mouse models. Results UNSW-SC-22 demonstrated potent and selective cytotoxicity in MYC-high MB and DIPG cells (IC50: 0.02-2.6 μM) and a wide therapeutic index. Sensitivity correlated strongly with MYC expression levels, confirming MYC- and MYCN-dependent activity. Mechanistically, UNSW-SC-22 directly bound full-length c-MYC and MYCN, reduced their protein half-life by approximately two-fold, and promoted phosphorylation-dependent proteasomal degradation without affecting MYC mRNA levels. Transcriptomic analyses revealed suppression of MYC-regulated and activation of p53-associated stress responses. Most importantly, UNSW-SC-22 effetely crossed the blood–brain barrier, achieving brain concentrations exceeding in vitro IC50 values (brain Cmax 10.8 μM), and showed a favourable in vitro safety pharmacology profile. In vivo, UNSW-SC-22 significantly reduced tumour burden and prolonged survival in MYCN-driven MB transgenic (p = 0.0004) and orthotopic xenografts models. In orthotopic DIPG models, SC-22 significantly reduces tumour burden, extends median survival by 10.5 days. UNSW-SC-22 synergised with clinically relevant histone deacetylase inhibitor, Entinostat, resulting in survival benefit compared with either agent alone. Conclusions These findings establish MYC as a therapeutically actionable vulnerability in lethal childhood brain tumours and support dual targeting of MYC and epigenetic regulators as a promising strategy for high-risk MB and incurable DIPG.

Targeting quorum-sensing inhibitors (QSIs) is a promising strategy to combat antibiotic-resistant bacteria by disrupting biofilm formation without imposing direct lethal pressure. In this study, we designed and synthesized a library of 30 2-phenylindole-based 1,2,3-triazole derivatives (11a-g, 12a-i, 13a-h, and 14a-f), which were structurally characterized using HRMS, IR, and 1H and 13C NMR spectroscopy. These compounds were evaluated for their in vitro QS inhibitory activity against the Pseudomonas aeruginosa MH602 reporter strain at concentrations ranging from 250 to 8 μM. All compounds demonstrated good to excellent QS inhibition (> 60%) at 250 μM and moderate inhibition (> 30%) at 8 μM. Structure-activity relationship (SAR) analysis indicated that halogen substitution had a positive influence on QS inhibitory potency. Among the series, compound 12a showed the most potent activity, with 82.6% and 38.9% inhibition at 250 and 8 μM, respectively. Further studies, including in silico ADME prediction, molecular docking, molecular dynamics simulations, and binding free energy analysis, were performed for 12a. The most active compounds from each series were also assessed for cytotoxicity against the HEK 293 T cell line, showing IC₅₀ values in the range of 83.7-168.7 μM. Antimicrobial evaluation revealed that the top seven compounds exhibited minimal or no antibacterial activity at 125 μM; however, compounds 12h, 13a, and 14c showed significant biofilm inhibition addition to pyocyanin and QS suppression, highlighting their potential as promising leads to combat antimicrobial resistance.

American foulbrood (AFB), caused by Paenibacillus larvae, remains one of the most devastating bacterial diseases affecting honeybee populations worldwide, posing a serious threat to pollination services and global food security. Current antibiotic-based control strategies are limited by inefficacy against persistent spores and the emergence of antimicrobial resistance, highlighting the urgent need for alternative therapeutic approaches. In this study, we developed an integrated in silico pipeline combining quantitative structure–activity relationship (QSAR) modeling, virtual screening, molecular docking, ADMET profiling, and molecular dynamics (MD) simulations to identify novel phytochemical inhibitors targeting β-ketoacyl-acyl carrier protein synthase III (FabH), a key enzyme in bacterial fatty acid biosynthesis absent in eukaryotic hosts. QSAR models built from curated ChEMBL datasets (n = 360 compounds) demonstrated satisfactory predictive performance (R² = 0.643, RMSE = 0.587 pIC₅₀ units, AUC = 0.780), with Y-randomization (100 permutations) and applicability domain analysis (Williams plot) confirming model robustness and the absence of chance correlations, supporting their suitability for virtual screening applications. Virtual screening of an in-house phytochemical library identified hinokiflavone as the most promising candidate, exhibiting strong binding affinity toward FabH (− 9.398 kcal/mol) and forming a stable network of hydrogen bonding and hydrophobic interactions within the catalytic pocket. Density functional theory (DFT) calculations further confirmed the electronic stability and reactivity profile of hinokiflavone, supporting its favorable interaction potential with the target protein. ADMET analysis revealed an acceptable pharmacokinetic profile with notable limitations in solubility and bioavailability. Subsequent 200 ns molecular dynamics simulations confirmed the stability of the FabH–hinokiflavone complex, as evidenced by low structural deviation (RMSD ≈ 0.23 nm), limited residue fluctuations, stable radius of gyration, and consistent solvent-accessible surface area, indicating a well-maintained compact structure and stable binding interface. Overall, hinokiflavone emerges as a computationally identified potential FabH-binding compound. These results provide theoretical insights that may guide future experimental investigations and the development of alternative strategies for controlling P. larvae infections in apiculture.

This study reports the synthesis of a range of novel peptide-mimicking antimicrobials with conjugated ortho-hindered nitroarenes (CONAs) for nitric oxide release. These peptide-mimics were rationally designed, building from a previously established anthranilamide peptide-mimicking scaffold and synergistically substituting aromatic capping groups for aromatic CONAs. CONAs were synthesised via a novel synthetic pathway, avoiding the use of highly toxic CrO3 and red fuming nitric acid, in fewer steps and good-excellent yields compared to previously reported methods. Of the synthesised peptide-mimics, one formed a self-assembling low molecular weight hydrogel, and their gel properties were characterised by rheology, atomic force microscopy and circular dichroism. The synthesised compounds released NO when exposed to 530 nm light, and their antimicrobial activity was measured via a minimum inhibitory concentration assay, with one compound exhibiting activity against Gram-positive Staphylococcus aureus at 8 µg mL-1.

The accelerating antimicrobial resistance (AMR) crisis continues to render more and more conventional antibiotics ineffective. Antimicrobial peptides (AMPs) are promising alternatives to traditional antibiotics due to their broad-spectrum activity, diverse mechanisms of action, and lower propensity for resistance. Traditional discovery approaches face limitations arising from the vast sequence space and the challenge of balancing efficacy with low toxicity. Addressing these challenges is critical for developing next-generation antimicrobial agents, and computational methods are increasingly driving progress. Public repositories, and techniques such as molecular docking enable in silico evaluation of peptide target interactions, identifying candidates with strong binding potential. Molecular dynamics (MD) simulations offer deeper insights into how AMPs disrupt membranes, form pores, or act synergistically, while Steered MD extends this to probing membrane penetration. Artificial intelligence (AI) methods, including machine learning and deep learning, capture complex sequence activity relationships, predict novel AMPs from genomic and metagenomic data, and design new peptides de novo using generative models. Despite rapid advances, most existing reviews treat these approaches in isolation, leaving a fragmented understanding of their interplay. This paper addresses that gap by unifying computational strategies, highlighting synergies, and critiquing limitations. Ultimately, integrating these methodologies offers a path toward more efficient AMP discovery to fight AMR.

Various N-protected amino acids were coupled to isatin forming N-amino acylisatins. These novel N-acylisatins participate in a ring-opening reaction with either alcohols or amines to give the corresponding N-glyoxylesters or amides. Upon deprotection, cyclization under basic conditions produces 1,4-benzodiazepin-2-ones bearing ester or amide functionalities at the C5 position. This method provides an effective approach for the construction of benzodiazepine derivatives with diverse substituents at C3 and C5.