TL;DR
Molecular docking results provided a molecular basis for the conjugate's interaction with target proteins (PDB IDs: 4LFU and 4TQX), suggesting its potential as a quorum-sensing modulator.
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.
Antimicrobial resistance (AMR) continues to challenge global healthcare by reducing the effectiveness of existing antibacterial therapies. Resistant organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) pose significant therapeutic challenges, underscoring the need for new antimicrobial candidates with improved antibacterial potential. The present study aimed to design, synthesize, characterize, and biologically evaluate a series of novel imidazole-thiol conjugates containing aminopyridine, chlorinated aromatic, nitroaromatic, and heteroaromatic moieties. The chemical structures of the synthesized compounds were characterized using FTIR, 1H NMR, 13C NMR, and mass spectrometry. The synthesized derivatives exhibited antibacterial activity against both Gram-positive and Gram-negative bacteria, including resistant strains such as MRSA and VRE. Among the synthesized derivatives, BS2 and BS3 exhibited the lowest minimum inhibitory concentration (MIC) values against the tested resistant strains. Computational studies, including molecular docking against Staphylococcus aureus enoyl-acyl carrier protein reductase (SaFabI; PDB ID: 4ALL), molecular dynamics (MD) simulations, and MM/GBSA analyses, supported the predicted interaction of BS3 with the active site of SaFabI under the simulated conditions. In addition, BS3 exhibited moderate antioxidant activity, protected plasmid DNA against oxidative damage in the Fenton reagent-mediated DNA nicking assay, and demonstrated concentration-dependent cytotoxicity with acceptable cell viability at lower concentrations. In silico ADMET and toxicity analyses indicated acceptable drug-like and toxicity characteristics. Overall, BS3 was identified as a potential lead compound for further optimization as an antimicrobial agent.
A series of novel haloarene-decorated tetrahydropyridine derivatives B(1a–1f) were synthesized via a simple, environmentally benign one-pot multicomponent reaction employing ethanol as a green solvent and [Et₃NH][HSO₄] as a Brønsted acid ionic liquid catalyst. The reaction utilized methyl acetoacetate (1 mmol), substituted aromatic aldehydes (2 mmol), and substituted anilines (2 mmol) at 60 °C to afford the desired compounds. All compounds were evaluated for their in vitro antimicrobial activity against three fungal strains (Candida albicans, Aspergillus niger, and Aspergillus clavatus), two Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and two Gram-positive bacteria (Staphylococcus aureus and Streptococcus pyogenes), using the serial broth dilution method. Additionally, their antimalarial potential was assessed against chloroquine- and quinine-sensitive 3D7 and multidrug-resistant Dd2 strains of Plasmodium falciparum. Among the synthesized derivatives, compounds B1a, B1b, and B1b exhibited the most potent antimicrobial and antimalarial activities. Molecular docking studies revealed that compound B1f showed the highest binding affinity toward S. aureus nucleoside diphosphate kinase, with a predicted free binding energy of − 913 kcal/mol. Pharmacological profiling suggested favorable drug-like properties and non-toxic behavior. These findings highlight haloarene-decorated tetrahydropyridine derivatives as promising dual-action candidates with potential to combat both bacterial and malarial infections.
The antibacterial activities of numerous medium and long-chain unsaturated fatty acids are well documented. However, the natural short-chain unsaturated fatty acid, 4-pentenoic acid (C5:1 Δ4) has not been systematically evaluated for its antibacterial activity, mechanism of action, or application potential. This study investigated these to provide a basis for novel preservatives. 4-Pentenoic acid showed broad-spectrum activity against 21 strains of pathogenic bacteria, with MICs 1.5-3 mg/mL, MBCs 3-6 mg/mL, and low resistance risk. It disrupted bacterial membrane integrity, inhibited biofilm formation, and regulated the pdu, nar and RND efflux pump genes, thereby affecting bacterial metabolism and stress responses. Checkerboard broth microdilution susceptibility assays confirmed that the combination of 4-pentenoic acid with antibiotics (such as meropenem) exerted additive antibacterial effects. At effective antibacterial concentrations, oral administration of 4-pentenoic acid caused no observable toxicity. It can markedly inhibit the proliferation of pathogenic bacteria in milk, beef, and peanut butter, while dosages close to the minimum inhibitory concentration exerted minimal adverse effects on the sensory properties and pH of these foods. In summary, this study provides theoretical and experimental basis for the development of new food preservatives and antibacterial agents.
The experimental and computational findings suggest that cFP is a promising antimicrobial lead and warrant further mechanistic and translational investigation.
Background: Antimicrobial resistance (AMR) was directly attributable to an estimated 1.27 million deaths in 2019 and is projected to cause 1.91 million attributable deaths annually by 2050, creating sustained demand for antibacterial scaffolds that act through mechanisms distinct from conventional target inhibition. Anthraquinone–delocalised lipophilic cation (DLC) conjugates, in which a triphenylphosphonium (TPP⁺) or related cationic group drives electrostatic, membrane-targeted accumulation, are one such scaffold. SH1 (1-[(5-triphenylphosphonium-pentyl)oxy]anthraquinone) was previously synthesised and shown to accumulate selectively in the mitochondria of PC-3 prostate cancer cells, but its antibacterial activity has not previously been reported. Aim: To our knowledge, following a structured search of PubMed and Scopus that identified no prior antibacterial data for this compound, this study presents the first antibacterial evaluation of SH1. Methods: SH1 was assessed by broth microdilution in accordance with EUCAST guidelines against sensitive and drug-resistant strains of Staphylococcus aureus and Escherichia coli. Results: SH1 demonstrated a minimum inhibitory concentration (MIC) of 1.6 mg/L against both antibiotic-sensitive (NCTC 6571) and methicillin-resistant (NCTC 13616) S. aureus, with a minimum bactericidal concentration (MBC) of 3.2 mg/L, indicating equipotent bactericidal activity against MRSA. Against E. coli (ATCC 47055, sensitive; LIB213, resistant), SH1 showed an MIC and MBC of 25.6 mg/L for both strains. Conclusion: These results identify SH1 as a previously uncharacterised antibacterial agent active against MRSA and support the anthraquinone–DLC pharmacophore as a membrane-active scaffold warranting further structural optimisation. Halogenated analogues, including the arginine-conjugated derivative VO6 synthesised as part of this programme, remain candidates for future evaluation once solubility constraints are addressed. The study was limited to four bacterial strains, and comparator antibiotics were considered using published breakpoint data rather than side-by-side testing; these constraints are discussed further in the Limitations section.
