It is demonstrated that antibacterial activity in vancoresmycin cannot be attributed to isolated substructures but instead depends on the integrated molecular architecture, providing a framework for future design strategies that preserve global structural properties rather than focusing on discrete motifs.
Abstract
Vancoresmycin is a structurally complex tetramic‐acid‐containing natural product with potent activity against Gram‐positive bacteria, yet its structure–activity relationships remain poorly defined. In particular, it is unclear whether discrete substructures contribute independently to antibacterial activity or whether biological function depends on the integrity of the full molecular framework. Here, we report the synthesis and biological evaluation of a series of structurally defined fragments derived from vancoresmycin and its aglycon amycomycin, including the tetramic acid core, eastern and western polyketide segments, and the mycosamine residue. Despite preserving key structural motifs, the fragments did not exhibit considerable antibacterial activity. Only the western fragment displayed weak activity accompanied by indications of membrane‐associated stress. These results demonstrate that antibacterial activity in vancoresmycin cannot be attributed to isolated substructures but instead depends on the integrated molecular architecture. These results provide a framework for future design strategies that preserve global structural properties rather than focusing on discrete motifs.
Actinomycins constitute a class of bioactive compounds known for their potent cytotoxic properties. Among them, actinomycin D, isolated in the 1940s from Streptomyces antibioticus, is the most extensively studied derivative. Structurally, actinomycins are characterized by a planar phenoxazinone chromophore flanked by two cyclic pentapeptides. They exert their biological effects primarily through DNA intercalation and transcription inhibition. Despite its remarkable bioactivity, the clinical application of actinomycin D is limited by significant adverse effects, including hepatotoxicity and restricted selectivity. These limitations underscore the need for structurally optimized analogs with improved therapeutic profiles and reduced toxicity. Over the decades, natural product discovery, precursor‐directed biosynthesis, and synthetic modification have yielded more than 70 structurally distinct derivatives, incorporating variations in both the peptide rings and the chromophore core. These structural modifications have resulted in diverse antibacterial, antiviral, and cytotoxic activities. Thus, this review critically examines the historical development, chemical diversity, and in vitro and preclinical bioactivity of actinomycin derivatives, highlighting key structural modifications over time and discussing their implications for future drug development.
Simplification of the complex macrolide UK-2A delivers florylpicoxamid, while optimization of its synthetically challenging pyridinyl acid remained underdeveloped. Scaffold hopping with 14 structurally distinctive heterocyclic acids in the molecular evolution of florylpicoxamid led to thiazole amide as a novel antifungal chemotype. The concomitant antifungal optimization achieved a structurally unique candidate, LEX-K02 (9al, EC50 = 0.140 μM), exhibiting 49-fold higher activity against Gaeumannomyces graminis than florylpicoxamid (EC50 = 7.06 μM). It was demonstrated to possess a unique mechanism in view of both antifungal phenotypes and molecular docking simulation. This antifungal candidate can disrupt the cell membrane. Transcriptomics and metabolomics analysis suggested that compound LEX-K02 may affect the synthesis of N-glycans by targeting the map00510 pathway, and is safe for wheat. Pyridinyl acid optimization of UK-2A-related molecules was validated as a viable fungicide discovery strategy.
Wenlong Kong, Pengzhi Sun, Xian Ming et al.· Journal of Agricultural and...· 0 citations
The development of antibacterials with unique mechanisms of action is key to addressing the threat posed by antibiotic resistance. Among the wide array of natural products that target bacterial cell wall biosynthesis, bacitracin A is the preeminent example of an antibiotic that functions by selectively targeting and sequestering the key bacterial phospholipid undecaprenyl pyrophosphate (C55PP). Historically, the bacitracins have been isolated from fermentations of Bacillus species. We recently discovered a series of structurally distinct bacitracin-like peptide antibiotics produced by members of the Paenibacillus genus, termed the paenitracins. Here, we report the total synthesis of paenitracin B (1), enabling definitive stereochemical validation of the previously proposed structure and delivering quantities of material suitable for more extensive antibacterial testing. The synthetic route developed was also applied to the preparation of paenitracin analogues, with some showing significantly enhanced antibacterial activity, particularly against VanA-type vancomycin-resistant Enterococcus faecium clinical isolates.
Yunhao Duan, Lucas Jongman, Vladyslav Lysenko et al.· ACS Infectious Diseases· 0 citations
The rapid emergence of antimicrobial resistance necessitates the development of novel antimicrobial agents with improved efficacy and selectivity. In this study, a dermatoxin-like peptide, dermatoxin-PD1, was identified from the skin secretion of Pachymedusa dacnicolor, and its structure–activity relationship was investigated through a rational truncation strategy based on predicted proteolytic cleavage sites. A series of truncated analogues was generated, among which a shortened peptide fragment (T1) retained potent antimicrobial activity, particularly against Gram-negative bacteria, whereas further truncation resulted in a marked loss of function. Structural analysis revealed that both dermatoxin-PD1 and T1 adopted amphipathic α-helical conformations under membrane-mimicking conditions. Functional assays demonstrated that bacterial killing was associated with membrane permeabilisation and depolarisation, with additional evidence supporting interactions with lipopolysaccharide (LPS). Notably, T1 exhibited remarkably reduced haemolytic and cytotoxic effects compared with the parent peptide, resulting in an improved selectivity profile. These findings provide additional insight into the structure–activity relationship of dermatoxin-like peptides and suggest that protease cleavage-guided truncation may represent a useful strategy for developing shorter and safer antimicrobial peptides.
This study presents the design, synthesis, and evaluation of a novel series of covalent broad-spectrum inhibitors targeting the coronavirus main protease (3CLpro). The designed compounds feature a tetrahydroquinoline (THQ) scaffold functionalized with a chloroacetamide warhead. The most potent of this series in the primary screening assay, 4bf and 5bf, exhibited low micromolar IC₅₀ values against 3CLpro of SARS-CoV-2, SARS-CoV, and MERS-CoV, thereby demonstrating significant cross-reactivity. Structural analysis via X-ray crystallography confirmed covalent binding to the catalytic Cys145 residue. Complementary molecular dynamics simulations revealed stable binding modes and key interactions, highlighting differences in flexibility and residue contacts between the top inhibitors. While in vitro cytotoxicity was observed in Vero E6 cells, acute toxicity studies in mice revealed an LD₅₀ exceeding 1000 mg/kg for the lead compounds, indicating a promising in vivo safety profile. These findings establish substituted tetrahydroquinolines as a viable scaffold for the development of broad-spectrum anticoronaviral agents.
Anastasia A. Pronina, D. Shcherbakov, A. P. Sanchez-Pimentel et al.· Bioorganic chemistry (Print)· 0 citations
The global escalation of antimicrobial resistance poses a critical threat to public health, emphasizing the need for innovative therapeutic scaffolds with novel mechanisms of action. Among various heterocyclic frameworks, the indole nucleus has attracted significant attention due to its structural versatility and extensive pharmacological profile. The discussion systematically examines diverse biological targets, including bacterial cell wall biosynthesis, FtsZ‐mediated cytokinesis, DNA gyrase, dihydrofolate reductase, glutathione S‐transferase, and CYP51 enzymes. For each target, recent synthetic analogs, their mechanistic implications, and structure–activity relationships are examined to highlight the molecular determinants responsible for enhanced efficacy and selectivity. Classical and contemporary synthetic strategies, such as the Fischer, Bartoli, and Madelung methods, as well as metal‐catalyzed cyclisation methods, are outlined to provide a foundation for rational drug design. Furthermore, molecular docking and structure‐based drug design studies are reviewed to correlate binding affinities with observed bioactivities. The inclusion of FDA‐approved indole‐containing drugs and ongoing clinical evaluations underscores the translational relevance of this scaffold. Overall, this review accentuates the versatility of the indole core as a privileged pharmacophore and its promise in the development of next‐generation antimicrobial agents capable of overcoming multidrug resistance. Continued efforts to optimize indole hybrids and elucidate their mechanistic pathways are anticipated to yield potent, safe, and clinically viable therapeutics.
Vidyasagar, J. Yadav, Meenakshi Singh· Drug development research (P...· 1 citation
