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29 pages, 6672 KiB  
Article
Discovery of a Novel Antimicrobial Peptide from Paenibacillus sp. Na14 with Potent Activity Against Gram-Negative Bacteria and Genomic Insights into Its Biosynthetic Pathway
by Nuttapon Songnaka, Adisorn Ratanaphan, Namfa Sermkaew, Somchai Sawatdee, Sucheewin Krobthong, Chanat Aonbangkhen, Yodying Yingchutrakul and Apichart Atipairin
Antibiotics 2025, 14(8), 805; https://doi.org/10.3390/antibiotics14080805 - 6 Aug 2025
Abstract
Background/Objectives: Antimicrobial resistance (AMR) contributes to millions of deaths globally each year, creating an urgent need for new therapeutic agents. Antimicrobial peptides (AMPs) have emerged as promising candidates due to their potential to combat AMR pathogens. This study aimed to evaluate the antimicrobial [...] Read more.
Background/Objectives: Antimicrobial resistance (AMR) contributes to millions of deaths globally each year, creating an urgent need for new therapeutic agents. Antimicrobial peptides (AMPs) have emerged as promising candidates due to their potential to combat AMR pathogens. This study aimed to evaluate the antimicrobial activity of an AMP from a soil-derived bacterial isolate against Gram-negative bacteria. Method: Soil bacteria were isolated and screened for antimicrobial activity. The bioactive peptide was purified and determined its structure and antimicrobial efficacy. Genomic analysis was conducted to predict the biosynthetic gene clusters (BGCs) responsible for AMP production. Results: Genomic analysis identified the isolate as Paenibacillus sp. Na14, which exhibited low genomic similarity (61.0%) to other known Paenibacillus species, suggesting it may represent a novel species. The AMP from the Na14 strain exhibited heat stability up to 90 °C for 3 h and retained its activity across a broad pH range from 3 to 11. Structural analysis revealed that the Na14 peptide consisted of 14 amino acid residues, adopting an α-helical structure. This peptide exhibited bactericidal activity at concentrations of 2–4 µg/mL within 6–12 h, and its killing rate was concentration-dependent. The peptide was found to disrupt the bacterial membranes. The Na14 peptide shared 64.29% sequence similarity with brevibacillin 2V, an AMP from Brevibacillus sp., which also belongs to the Paenibacillaceae family. Genomic annotation identified BGCs associated with secondary metabolism, with a particular focus on non-ribosomal peptide synthetase (NRPS) gene clusters. Structural modeling of the predicted NRPS enzymes showed high similarity to known NRPS modules in Brevibacillus species. These genomic findings provide evidence supporting the similarity between the Na14 peptide and brevibacillin 2V. Conclusions: This study highlights the discovery of a novel AMP with potent activity against Gram-negative pathogens and provides new insight into conserved AMP biosynthetic enzymes within the Paenibacillaceae family. Full article
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51 pages, 1874 KiB  
Review
Parkinson’s Disease: Bridging Gaps, Building Biomarkers, and Reimagining Clinical Translation
by Masaru Tanaka
Cells 2025, 14(15), 1161; https://doi.org/10.3390/cells14151161 - 28 Jul 2025
Viewed by 808
Abstract
Parkinson’s disease (PD), a progressive neurodegenerative disorder, imposes growing clinical and socioeconomic burdens worldwide. Despite landmark discoveries in dopamine biology and α-synuclein pathology, translating mechanistic insights into effective, personalized interventions remains elusive. Recent advances in molecular profiling, neuroimaging, and computational modeling have broadened [...] Read more.
Parkinson’s disease (PD), a progressive neurodegenerative disorder, imposes growing clinical and socioeconomic burdens worldwide. Despite landmark discoveries in dopamine biology and α-synuclein pathology, translating mechanistic insights into effective, personalized interventions remains elusive. Recent advances in molecular profiling, neuroimaging, and computational modeling have broadened the understanding of PD as a multifactorial systems disorder rather than a purely dopaminergic condition. However, critical gaps persist in diagnostic precision, biomarker standardization, and the translation of bench side findings into clinically meaningful therapies. This review critically examines the current landscape of PD research, identifying conceptual blind spots and methodological shortfalls across pathophysiology, clinical evaluation, trial design, and translational readiness. By synthesizing evidence from molecular neuroscience, data science, and global health, the review proposes strategic directions to recalibrate the research agenda toward precision neurology. Here I highlight the urgent need for interdisciplinary, globally inclusive, and biomarker-driven frameworks to overcome the fragmented progression of PD research. Grounded in the Accelerating Medicines Partnership-Parkinson’s Disease (AMP-PD) and the Parkinson’s Progression Markers Initiative (PPMI), this review maps shared biomarkers, open data, and patient-driven tools to faster personalized treatment. In doing so, it offers actionable insights for researchers, clinicians, and policymakers working at the intersection of biology, technology, and healthcare delivery. As the field pivots from symptomatic relief to disease modification, the road forward must be cohesive, collaborative, and rigorously translational, ensuring that laboratory discoveries systematically progress to clinical application. Full article
(This article belongs to the Special Issue Exclusive Review Papers in Parkinson's Research)
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19 pages, 3290 KiB  
Article
Identification and Screening of Novel Antimicrobial Peptides from Medicinal Leech via Heterologous Expression in Escherichia coli
by Maria Serebrennikova, Ekaterina Grafskaia, Daria Kharlampieva, Ksenia Brovina, Pavel Bobrovsky, Sabina Alieva, Valentin Manuvera and Vassili Lazarev
Int. J. Mol. Sci. 2025, 26(14), 6903; https://doi.org/10.3390/ijms26146903 - 18 Jul 2025
Viewed by 287
Abstract
The growing threat of infectious diseases requires novel therapeutics with different mechanisms of action. Antimicrobial peptides (AMPs), which are crucial for innate immunity, are a promising research area. The medicinal leech (Hirudo medicinalis) is a potential source of bioactive AMPs that [...] Read more.
The growing threat of infectious diseases requires novel therapeutics with different mechanisms of action. Antimicrobial peptides (AMPs), which are crucial for innate immunity, are a promising research area. The medicinal leech (Hirudo medicinalis) is a potential source of bioactive AMPs that are vital while interacting with microorganisms. This study aims to investigate the antimicrobial properties of peptides found in the H. medicinalis genome using a novel high-throughput screening method based on the expression of recombinant AMP genes in Escherichia coli. This approach enables the direct detection of AMP activity within cells, skipping the synthesis and purification steps, while allowing the simultaneous analysis of multiple peptides. The application of this method to the first identified candidate AMPs from H. medicinalis resulted in the discovery of three novel peptides: LBrHM1, NrlHM1 and NrlHM2. These peptides, which belong to the lumbricin and macin families, exhibit significant activity against E. coli. Two fragments of the new LBrHM1 homologue were synthesised and studied: a unique N-terminal fragment (residues 1–23) and a fragment (residues 27–55) coinciding with the active site of lumbricin I. Both fragments exhibited antimicrobial activity in a liquid medium against Bacillus subtilis. Notably, the N-terminal fragment lacks homologues among previously described AMPs. Full article
(This article belongs to the Section Molecular Biology)
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29 pages, 366 KiB  
Article
Video-Driven Artificial Intelligence for Predictive Modelling of Antimicrobial Peptide Generation: Literature Review on Advances and Challenges
by Jielu Yan, Zhengli Chen, Jianxiu Cai, Weizhi Xian, Xuekai Wei, Yi Qin and Yifan Li
Appl. Sci. 2025, 15(13), 7363; https://doi.org/10.3390/app15137363 - 30 Jun 2025
Viewed by 581
Abstract
How video-based methodologies and advanced computer vision algorithms can facilitate the development of antimicrobial peptide (AMP) generation models should be further reviewed, structural and functional patterns should be elucidated, and the generative power of in silico pipelines should be enhanced. AMPs have drawn [...] Read more.
How video-based methodologies and advanced computer vision algorithms can facilitate the development of antimicrobial peptide (AMP) generation models should be further reviewed, structural and functional patterns should be elucidated, and the generative power of in silico pipelines should be enhanced. AMPs have drawn significant interest as promising therapeutic agents because of their broad-spectrum efficacy, low resistance profile, and membrane-disrupting mechanisms. However, traditional discovery methods are hindered by high costs, lengthy synthesis processes, and difficulty in accessing the extensive chemical space involved in AMP research. Recent advances in artificial intelligence—especially machine learning (ML), deep learning (DL), and pattern recognition—offer game-changing opportunities to accelerate AMP design and validation. By integrating video analysis with computational modelling, researchers can visualise and quantify AMP–microbe interactions at unprecedented levels of detail, thereby informing both experimental design and the refinement of predictive algorithms. This review provides a comprehensive overview of these emerging techniques, highlights major breakthroughs, addresses critical challenges, and ultimately emphasises the powerful synergy between video-driven pattern recognition, AI-based modelling, and experimental validation in the pursuit of next-generation antimicrobial strategies. Full article
(This article belongs to the Section Computing and Artificial Intelligence)
18 pages, 2398 KiB  
Review
The Therapeutic Potential of Antimicrobial Peptides Isolated from the Skin Secretions of Anurans of the Genus Boana in the Face of the Global Antimicrobial Resistance Crisis
by Priscila Mendes Ferreira, Fabiano Fagundes Moser da Silva, Joyce Silva dos Santos, Brunna de Oliveira Silva, Carlos José Correia de Santana, Osmindo Rodrigues Pires Júnior, Wagner Fontes and Mariana S. Castro
Toxins 2025, 17(7), 312; https://doi.org/10.3390/toxins17070312 - 20 Jun 2025
Viewed by 1067
Abstract
Microorganisms play a dual role in human health, serving as both essential allies and serious threats. Their association with infections led to the development of antimicrobials like penicillin, which revolutionized medicine. However, the emergence of antimicrobial resistance (AMR) has created a global health [...] Read more.
Microorganisms play a dual role in human health, serving as both essential allies and serious threats. Their association with infections led to the development of antimicrobials like penicillin, which revolutionized medicine. However, the emergence of antimicrobial resistance (AMR) has created a global health crisis, rendering many treatments ineffective due to pathogen mutations and acquired resistance mechanisms, particularly among ESKAPE pathogens. This resistance increases morbidity, mortality, and healthcare costs, exacerbated by antibiotic overuse and globalization. Biofilms and sepsis further complicate treatment. Addressing AMR requires new therapies, rational antibiotic use, and innovative approaches for drug discovery. Coordinated global action is essential to ensure future access to effective treatments. Antimicrobial peptides (AMPs) derived from Boana species (Anura, Hylidae) represent a promising alternative in the fight against AMR. These peptides exhibit activity against multidrug-resistant pathogens. Unlike conventional antibiotics, Boana peptides act through a broad mechanism that limits resistance development. Their ability to disrupt bacterial membranes and modulate immune responses makes them ideal candidates for the development of new treatments. These peptides may offer valuable alternatives for treating resistant infections and addressing the global AMR crisis. Full article
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20 pages, 7525 KiB  
Article
Heterologous Expression and Antimicrobial Mechanism of a Cysteine-Rich Peptide from Barnacle Pollicipes pollicipes
by Zhicheng He, Zixun Fei, Huishao Shi, Meichuan Huang, Liumi Wei, Junjian Wang, Peng He and Wei Zhang
Microorganisms 2025, 13(6), 1381; https://doi.org/10.3390/microorganisms13061381 - 13 Jun 2025
Viewed by 489
Abstract
The escalating crisis of antimicrobial resistance in aquaculture, driven by the indiscriminate use of antibiotics, underscores the urgent need to develop novel anti-infective agents. This study addresses this requirement by investigating cysteine-rich antimicrobial peptides (AMPs) in understudied crustacean species. A cysteine-rich AMP, designated [...] Read more.
The escalating crisis of antimicrobial resistance in aquaculture, driven by the indiscriminate use of antibiotics, underscores the urgent need to develop novel anti-infective agents. This study addresses this requirement by investigating cysteine-rich antimicrobial peptides (AMPs) in understudied crustacean species. A cysteine-rich AMP, designated PpRcys1, was identified and characterized from the genome of Pollicipes pollicipes. PpRcys1 comprises 104 amino acids, with 85 residues forming the mature peptide region, and exhibits random coils, a CSαβ-fold, and one β-sheet. Our findings demonstrated that recombinant PpRcys1 (rPpRcys1) possesses broad-spectrum antimicrobial activity against three Gram-positive bacteria (Staphylococcus aureus, Bacillus sp. T2, and Streptococcus agalactiae) and four Gram-negative bacteria (Aeromonas hydrophila, Escherichia coli, Vibrio alginolyticus, and Acinetobacter sp. L3), with minimum inhibitory concentrations ranging from 8 to 32 μM. It exerts antimicrobial effects by inducing membrane disruption without impacting bacterial protease activity, DNA migration, or respiratory chain reductase activity. Further investigation is warranted to determine whether it can target and interfere with intracellular bacterial processes. Our discovery and characterization of this novel AMP provide a promising foundation for its development as an alternative to antibiotics. Full article
(This article belongs to the Special Issue Therapeutic Potential of Antimicrobial Peptides)
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24 pages, 1312 KiB  
Review
Targeting Phosphodiesterase 4 in Gastrointestinal and Liver Diseases: From Isoform-Specific Mechanisms to Precision Therapeutics
by Can Chen, Mei Liu and Xiang Tao
Biomedicines 2025, 13(6), 1285; https://doi.org/10.3390/biomedicines13061285 - 23 May 2025
Viewed by 834
Abstract
Phosphodiesterase 4 (PDE4) serves as a crucial regulator of cyclic adenosine monophosphate (cAMP) signaling and has been identified as a significant therapeutic target for inflammatory and metabolic disorders impacting the gastrointestinal (GI) tract and liver. Although pan-PDE4 inhibitors hold therapeutic promise, their clinical [...] Read more.
Phosphodiesterase 4 (PDE4) serves as a crucial regulator of cyclic adenosine monophosphate (cAMP) signaling and has been identified as a significant therapeutic target for inflammatory and metabolic disorders impacting the gastrointestinal (GI) tract and liver. Although pan-PDE4 inhibitors hold therapeutic promise, their clinical use has been constrained by dose-dependent adverse effects. Recent progress in the development of isoform-specific PDE4 inhibitors, such as those selective for PDE4B/D, alongside targeted delivery systems like liver-targeting nanoparticles and probiotic-derived vesicles, is reshaping the therapeutic landscape. This review consolidates the latest insights into PDE4 biology, highlighting how the structural characterization of isoforms informs drug design. We conduct a critical evaluation of preclinical and clinical data across various diseases, including inflammatory bowel diseases (IBDs), alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), liver fibrosis, and digestive tract tumors, with an emphasis on mechanisms extending beyond cAMP modulation, such as microbiota remodeling and immune reprogramming. Additionally, we address challenges in clinical translation, including biomarker discovery and the heterogeneity of trial outcomes, and propose a roadmap for future research directions. Full article
(This article belongs to the Section Drug Discovery, Development and Delivery)
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19 pages, 1973 KiB  
Article
Characterization of Novel and Known Activators of Cannabinoid Receptor Subtype 2 Reveals Mixed Pharmacology That Differentiates Mycophenolate Mofetil and GW-842,166X from MDA7
by Alice L. Rodriguez, Aidong Qi, Allie Han, Haley E. Kling, Marc C. Quitalig, Aaron M. Bender, Lisa Barbaro, David Whomble, Craig W. Lindsley and Colleen M. Niswender
Int. J. Mol. Sci. 2025, 26(10), 4956; https://doi.org/10.3390/ijms26104956 - 21 May 2025
Viewed by 775
Abstract
CB1 and CB2 cannabinoid receptors are members of the GPCR superfamily that modulate the effects of endocannabinoids. CB1 is the most abundant CB receptor in the central nervous system, while CB2 is present both peripherally and in the brain. [...] Read more.
CB1 and CB2 cannabinoid receptors are members of the GPCR superfamily that modulate the effects of endocannabinoids. CB1 is the most abundant CB receptor in the central nervous system, while CB2 is present both peripherally and in the brain. CB2 plays a role in inflammation, as well as neurodegenerative and psychiatric disorders. To identify new ligands for CB2, we screened a library of FDA-approved drugs for activity at the receptor using a thallium flux assay, resulting in the discovery of the immunosuppressant mycophenolate mofetil as a potent, selective activator of CB2. Further characterization of the compound confirmed agonist activity in a variety of complementary assays, including PI hydrolysis, cAMP inhibition, and β-arrestin recruitment. Radioligand binding assays established a non-competitive interaction with the site occupied by [3H]CP55,940. CB2 agonists GW-842,166X and MDA7 were also profiled, revealing that GW-842,166X exhibits a similar activity profile to mycophenolate mofetil, whereas MDA7 presents a distinct profile. These differences provide insight into the complex CB2 pharmacology impacting preclinical and clinical studies, and ultimately, new treatment strategies for brain disorders. Full article
(This article belongs to the Special Issue Molecular Advances on Cannabinoid and Endocannabinoid Research 2.0)
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33 pages, 25820 KiB  
Article
Novel Anti-MRSA Peptide from Mangrove-Derived Virgibacillus chiguensis FN33 Supported by Genomics and Molecular Dynamics
by Namfa Sermkaew, Apichart Atipairin, Phetcharat Boonruamkaew, Sucheewin Krobthong, Chanat Aonbangkhen, Jumpei Uchiyama, Yodying Yingchutrakul and Nuttapon Songnaka
Mar. Drugs 2025, 23(5), 209; https://doi.org/10.3390/md23050209 - 14 May 2025
Viewed by 884
Abstract
Antimicrobial resistance (AMR) is a global health threat, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the major resistant pathogens. This study reports the isolation of a novel mangrove-derived bacterium, Virgibacillus chiguensis FN33, as identified through genome analysis and the discovery of a [...] Read more.
Antimicrobial resistance (AMR) is a global health threat, with methicillin-resistant Staphylococcus aureus (MRSA) being one of the major resistant pathogens. This study reports the isolation of a novel mangrove-derived bacterium, Virgibacillus chiguensis FN33, as identified through genome analysis and the discovery of a new anionic antimicrobial peptide (AMP) exhibiting anti-MRSA activity. The AMP was composed of 23 amino acids, which were elucidated as NH3-Glu-Gly-Gly-Cys-Gly-Val-Asp-Thr-Trp-Gly-Cys-Leu-Thr-Pro-Cys-His-Cys-Asp-Leu-Phe-Cys-Thr-Thr-COOH. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) for MRSA were 8 µg/mL and 16 µg/mL, respectively. FN33 AMP induced cell membrane permeabilization, suggesting a membrane-disrupting mechanism. The AMP remained stable at 30–40 °C but lost activity at higher temperatures and following exposure to proteases, surfactants, and extreme pH. All-atom molecular dynamics simulations showed that the AMP adopts a β-sheet structure upon membrane interaction. These findings suggest that Virgibacillus chiguensis FN33 is a promising source of novel antibacterial agents against MRSA, supporting alternative strategies for drug-resistant infections. Full article
(This article belongs to the Special Issue Research on Marine Antimicrobial Peptides)
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27 pages, 7160 KiB  
Review
Inhibitors of Cyclic Dinucleotide Phosphodiesterases and Cyclic Oligonucleotide Ring Nucleases as Potential Drugs for Various Diseases
by Christopher S. Vennard, Samson Marvellous Oladeji and Herman O. Sintim
Cells 2025, 14(9), 663; https://doi.org/10.3390/cells14090663 - 30 Apr 2025
Viewed by 671
Abstract
The phosphodiester linkage is found in DNA, RNA and many signaling molecules, such as cyclic mononucleotide, cyclic dinucleotides (CDNs) and cyclic oligonucleotides (cONs). Enzymes that cleave the phosphodiester linkage (nucleases and phosphodiesterases) play important roles in cell persistence and fitness and have therefore [...] Read more.
The phosphodiester linkage is found in DNA, RNA and many signaling molecules, such as cyclic mononucleotide, cyclic dinucleotides (CDNs) and cyclic oligonucleotides (cONs). Enzymes that cleave the phosphodiester linkage (nucleases and phosphodiesterases) play important roles in cell persistence and fitness and have therefore become targets for various diseased states. While various inhibitors have been developed for nucleases and cyclic mononucleotide phosphodiesterases, and some have become clinical successes, there is a paucity of inhibitors of the recently discovered phosphodiesterases or ring nucleases that cleave CDNs and cONs. Inhibitors of bacterial c-di-GMP or c-di-AMP phosphodiesterases have the potential to be used as anti-virulence compounds, while compounds that inhibit the degradation of 3′,3′-cGAMP, cA3, cA4, cA6 could serve as antibiotic adjuvants as the accumulation of these second messengers leads to bacterial abortive infection. In humans, 2′3′-cGAMP plays critical roles in antiviral and antitumor responses. ENPP1 (the 2′3′-cGAMP phosphodiesterase) or virally encoded cyclic dinucleotide phosphodiesterases, such as poxin, however, blunt this response. Inhibitors of ENPP1 or poxin-like enzymes have the potential to be used as anticancer and antiviral agents, respectively. This review summarizes efforts made towards the discovery and development of compounds that inhibit CDN phosphodiesterases and cON ring nucleases. Full article
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21 pages, 2443 KiB  
Review
Antimicrobial Peptides and Their Potential Applications in Plant Protection
by Deming Sun, Zhaohui Jia, Junjie Zhu, Jinhua Liu, Yichao Chen, Zhi Xu and Haijie Ma
Agronomy 2025, 15(5), 1113; https://doi.org/10.3390/agronomy15051113 - 30 Apr 2025
Viewed by 1100
Abstract
The overuse of pesticides has led to resistance in phytopathogens, posing significant threats to global food security and environmental health. Antimicrobial peptides (AMPs), small molecules produced by various organisms as part of their innate immune defense, exhibit broad-spectrum antimicrobial activity with a lower [...] Read more.
The overuse of pesticides has led to resistance in phytopathogens, posing significant threats to global food security and environmental health. Antimicrobial peptides (AMPs), small molecules produced by various organisms as part of their innate immune defense, exhibit broad-spectrum antimicrobial activity with a lower risk of resistance development. These properties make AMPs promising candidates for sustainable agricultural practices. However, challenges such as high production costs, instability, and potential toxicity to plant cells have hindered their widespread application. This review provides a comprehensive overview of the discovery, classification, and antimicrobial mechanisms of AMPs, focusing on their roles in plant protection. It also explores strategies for identifying and optimizing AMPs, including structural modifications, targeted delivery systems, and production methods using plant- and microbe-based expression systems. Additionally, the review highlights the potential of transgenic approaches to enhance crop resistance by expressing AMP genes in plants. Despite the challenges, AMPs offer a transformative opportunity for modern agriculture, providing innovative solutions to combat plant diseases while reducing reliance on conventional pesticides. Continued research and technological advancements are essential to fully realize the potential of AMPs in sustainable plant protection. Full article
(This article belongs to the Special Issue Research Progress on Pathogenicity of Fungi in Crops—2nd Edition)
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21 pages, 6505 KiB  
Article
Discovery of Boronic Acids-Based β-Lactamase Inhibitors Through In Situ Click Chemistry
by Nicolò Santi, Alessandra Piccirilli, Federico Corsini, Magdalena A. Taracila, Mariagrazia Perilli, Robert A. Bonomo, Francesco Fini, Fabio Prati and Emilia Caselli
Int. J. Mol. Sci. 2025, 26(9), 4182; https://doi.org/10.3390/ijms26094182 - 28 Apr 2025
Viewed by 1149
Abstract
In this study, we evaluated in situ click chemistry as a platform for discovering boronic acid-based β-lactamase inhibitors (BLIs). Unlike conventional drug discovery approaches requiring multi-step synthesis, protection strategies, and extensive screening, the in situ method can allow for the generation and identification [...] Read more.
In this study, we evaluated in situ click chemistry as a platform for discovering boronic acid-based β-lactamase inhibitors (BLIs). Unlike conventional drug discovery approaches requiring multi-step synthesis, protection strategies, and extensive screening, the in situ method can allow for the generation and identification of potent β-lactamase inhibitors in a rapid, economic, and efficient way. Using KPC-2 (class A carbapenemase) and AmpC (class C cephalosporinase) as templates, we demonstrated their ability to catalyse azide-alkyne cycloaddition, facilitating the formation of triazole-based β-lactamase inhibitors. Initial screening of various β-lactamases and boronic warheads identified compound 3 (3-azidomethylphenyl boronic acid) as the most effective scaffold for kinetic target-guided synthesis (KTGS). KTGS experiments with AmpC and KPC-2 yielded triazole inhibitors with Ki values as low as 140 nM (compound 10a, AmpC) and 730 nM (compound 5, KPC-2). Competitive inhibition studies confirmed triazole formation within the active site, while an LC–MS analysis verified that the reversible covalent interaction of boronic acids did not affect detection of the in situ-synthesised product. While KTGS successfully identified potent inhibitors, limitations in amplification coefficients and spatial constraints highlight the need for optimised warhead designs. This study validates KTGS as a promising strategy for BLI discovery and provides insights for further refinement in fighting β-lactamase-mediated antibiotic resistance. Full article
(This article belongs to the Section Molecular Pharmacology)
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18 pages, 8998 KiB  
Article
Synthesis and Evaluation of Aquatic Antimicrobial Peptides Derived from Marine Metagenomes Using a High-Throughput Screening Approach
by Kaiyue Wu, Guangxin Xu, Yin Tian, Guizhen Li, Zhiwei Yi and Xixiang Tang
Mar. Drugs 2025, 23(4), 178; https://doi.org/10.3390/md23040178 - 20 Apr 2025
Cited by 1 | Viewed by 794
Abstract
Bacterial diseases cause high mortality and considerable losses in aquaculture. The rapid expansion of intensive aquaculture has further increased the risk of large-scale outbreaks. However, the emergence of drug-resistant bacteria, food safety concerns, and environmental regulations have severely limited the availability of antimicrobial. [...] Read more.
Bacterial diseases cause high mortality and considerable losses in aquaculture. The rapid expansion of intensive aquaculture has further increased the risk of large-scale outbreaks. However, the emergence of drug-resistant bacteria, food safety concerns, and environmental regulations have severely limited the availability of antimicrobial. Compared to traditional antibiotics, antimicrobial peptides (AMPs) offer broad spectrum activity, physicochemical stability, and lower resistance development. However, their low natural yield and high extraction costs along with the time-consuming and expensive nature of traditional drug discovery, pose a challenge. In this study, we applied a machine-learning macro-model to predict AMPs from three macrogenomes in the water column of South American white shrimp aquaculture ponds. The AMP content per megabase in the traditional earthen pond (TC1) was 1.8 times higher than in the biofloc pond (ZA1) and 63% higher than in the elevated pond (ZP11). A total of 1033 potential AMPs were predicted, including 6 anionic linear peptides, 616 cationic linear peptides, and 411 cationic cysteine-containing peptides. After screening based on structural, and physio-chemical properties, we selected 10 candidate peptides. Using a rapid high-throughput cell-free protein expression system, we identified nine peptides with antimicrobial activity against aquatic pathogens. Three were further validated through chemical synthesis. The three antimicrobial peptides (K-5, K-58, K-61) showed some inhibitory effects on all four pathogenic bacteria. The MIC of K-5 against Vibrio alginolyticus was 25 μM, the cell viability of the three peptides was higher than 70% at low concentrations (≤12.5 μM), and the hemolysis rate of K-5 and K-58 was lower than 5% at 200 μM. This study highlights the benefits of machine learning in AMP discovery, demonstrates the potential of cell-free protein synthesis systems for peptide screening, and provides an efficient method for high-throughput AMP identification for aquatic applications. Full article
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28 pages, 723 KiB  
Review
Novel Antibacterial Approaches and Therapeutic Strategies
by Gustavo A. Niño-Vega, Jorge A. Ortiz-Ramírez and Everardo López-Romero
Antibiotics 2025, 14(4), 404; https://doi.org/10.3390/antibiotics14040404 - 15 Apr 2025
Viewed by 1901
Abstract
The increase in multidrug-resistant organisms worldwide is a major public health threat driven by antibiotic overuse, horizontal gene transfer (HGT), environmental drivers, and deficient infection control in hospitals. In this article, we discuss these factors and summarize the new drugs and treatment strategies [...] Read more.
The increase in multidrug-resistant organisms worldwide is a major public health threat driven by antibiotic overuse, horizontal gene transfer (HGT), environmental drivers, and deficient infection control in hospitals. In this article, we discuss these factors and summarize the new drugs and treatment strategies suggested to combat the increasing challenges of multidrug-resistant (MDR) bacteria. New treatments recently developed involve targeting key processes involved in bacterial growth, such as riboswitches and proteolysis, and combination therapies to improve efficacy and minimize adverse effects. It also tackles the challenges of the Gram-negative bacterial outer membrane, stressing that novel strategies are needed to evade permeability barriers, efflux pumps, and resistance mechanisms. Other approaches, including phage therapy, AMPs, and AI in drug discovery, are also discussed as potential alternatives. Finally, this review points out the urgency for continued research and development (R&D), industry–academic partnerships, and financial engines to ensure that MDR microbes do not exceed the value of antibacterial therapies. Full article
(This article belongs to the Special Issue Evaluation of Emerging Antimicrobials)
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15 pages, 4198 KiB  
Article
Chemical Space Exploration and Machine Learning-Based Screening of PDE7A Inhibitors
by Yuze Li, Zhe Wang, Shengyao Ma, Xiaowen Tang and Hanting Zhang
Pharmaceuticals 2025, 18(4), 444; https://doi.org/10.3390/ph18040444 - 21 Mar 2025
Cited by 1 | Viewed by 608
Abstract
Background/Objectives: Phosphodiesterase 7 (PDE7), a member of the PDE superfamily, selectively catalyzes the hydrolysis of cyclic adenosine 3′,5′-monophosphate (cAMP), thereby regulating the intracellular levels of this second messenger and influencing various physiological functions and processes. There are two subtypes of PDE7, PDE7A [...] Read more.
Background/Objectives: Phosphodiesterase 7 (PDE7), a member of the PDE superfamily, selectively catalyzes the hydrolysis of cyclic adenosine 3′,5′-monophosphate (cAMP), thereby regulating the intracellular levels of this second messenger and influencing various physiological functions and processes. There are two subtypes of PDE7, PDE7A and PDE7B, which are encoded by distinct genes. PDE7 inhibitors have been shown to exert therapeutic effects on neurological and respiratory diseases. However, FDA-approved drugs based on the PDE7A inhibitor are still absent, highlighting the need for novel compounds to advance PDE7A inhibitor development. Methods: To address this urgent and important issue, we conducted a comprehensive cheminformatics analysis of compounds with potential for PDE7A inhibition using a curated database to elucidate the chemical characteristics of the highly active PDE7A inhibitors. The specific substructures that significantly enhance the activity of PDE7A inhibitors, including benzenesulfonamido, acylamino, and phenoxyl, were identified by an interpretable machine learning analysis. Subsequently, a machine learning model employing the Random Forest–Morgan pattern was constructed for the qualitative and quantitative prediction of PDE7A inhibitors. Results: As a result, six compounds with potential PDE7A inhibitory activity were screened out from the SPECS compound library. These identified compounds exhibited favorable molecular properties and potent binding affinities with the target protein, holding promise as candidates for further exploration in the development of potent PDE7A inhibitors. Conclusions: The results of the present study would advance the exploration of innovative PDE7A inhibitors and provide valuable insights for future endeavors in the discovery of novel PDE inhibitors. Full article
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