Structural and biochemical insights into the antibiofilm activity of cationic lipoamino acid ester against methicillin-resistant Staphylococcus aureus

Underexplored Ligand‐Binding Features of FabI From Staphylococcus aureus and Escherichia coli: A Comparative Pharmacophoric Modeling and Surface Mapping Approach

The rapid spread of antimicrobial resistance, particularly among pathogens such as Staphylococcus aureus and Escherichia coli, highlights the urgent need for novel antibacterial agents with new mechanisms of action. The bacterial enoyl‐acyl carrier protein reductase (FabI), an essential enzyme in fatty acid biosynthesis, represents a promising target for narrow‐spectrum antimicrobials. This study aimed to define consensus pharmacophore models and interaction profiles for FabI through an integrated computational approach. ConPhar and FTMap analyses were applied to experimental structures and molecular dynamics (MD) simulations, while protein–ligand interactions from crystallographic complexes were evaluated using PLIP. Results revealed a conserved binding core involving residues Y156/Y157 and A95 in both species. We also assessed the reliability of residues located in flexible regions by comparing MD snapshots and experimental structures, as well as the contribution of inhibitor–cofactor interactions. Surface mapping identified Y146/Y147 as a key residue, consistent with its reported role in resistance mutations. Additionally, residues I200 (E. coli), V201 (S. aureus), and F203/F204 were identified as potential unexplored interaction sites. Finally, validated consensus pharmacophore models were proposed for future virtual screening and inhibitor design.

Cationic metal-binding coumarin amphiphiles as membrane-active antimicrobial agents.

Synthetic mimetics of antimicrobial peptides (AMPs) typically rely on amine or guanidine groups to provide an overall cationic charge, often overlooking the metal-binding functionalities that influence AMP-membrane interactions. Here, we report three coumarin amphiphiles incorporating hydrophilic metal-binding headgroups and demonstrate that this design strategy yields improved potency and selectivity. All three compounds displayed strong antibacterial activity against methicillin-resistant S. aureus (MRSA), and a diethylenetriamine (DETA) derivative was also active against the Gram-negative bacteria, A. baumannii and E. coli. The compounds also showed moderate activity against MRSA biofilms, reducing the biomass of established MRSA biofilms by 40-50%. Mechanistic investigations revealed that the DETA and cyclen derivatives increased the outer-membrane permeability of E. coli and potentiated the activity of minocycline and rifampicin. All three amphiphiles also exhibited potent antifungal activity against C. neoformans, surpassing the activity of the clinical control fluconazole, with the DETA analogue also displaying activity against C. albicans. Collectively, these results suggest that incorporating metal-binding headgroups into amphiphilic scaffolds may engage a distinct mode of action compared to traditional small-molecule AMP mimetics, resulting in increased antimicrobial potency and selectivity over mammalian membranes.

Synthesis, antibacterial, and antibiofilm activities of an adenosine-benzoic acid conjugate against Streptococcus mutans and Escherichia coli: insights from molecular docking.

Aromatic Fluorination Enhances the Hydrophobicity and Antimicrobial Activity of Magainin 2.

Inspired by the structure of the natural antimicrobial peptide magainin 2 (MG), we developed a series of fluorinated magainin 2 analogues (FMGs) incorporating pentafluorophenylalanine residue and systematically studied their physicochemical properties and antimicrobial activities. Analytical reverse-phase high-performance liquid chromatography and circular dichroism spectroscopy demonstrated that incorporation of pentafluorophenylalanines effectively modulates the hydrophobicity and secondary structure of peptides. Membrane-disruption assays using model lipid bilayers, together with evaluations of antibacterial activity assays against Escherichia coli (E. coli) and hemolytic toxicity assays toward red blood cells, revealed that FMGs exhibit enhanced antimicrobial activity, with minimum inhibitory concentration values reduced by up to an order of magnitude relative to MG, without a substantial increase in toxicity. Notably, FMGs also retained superior antibacterial activity against a drug-resistant E. coli strain harboring the RP4 multidrug-resistance plasmid. Molecular dynamics simulations suggested that the preferential membrane-disruptive activity arises from selective binding to negatively charged bacterial membranes. These findings provide detailed structure-activity relationships for fluorinated antimicrobial peptides and highlight the introduction of fluorinated aromatic units as a powerful strategy to enhance hydrophobicity and antimicrobial activity.

From Antibacterial to Antifungal: Structure, Safety, and Serum Albumin Binding of Zn(II)-Nalidixate Complexes with Phenanthroline and Bipyridine.

Synthesis, characterization, crystallography insights, and larvicidal activity of 4-substituted-8-(trifluoromethyl)quinoline derivatives against Anopheles arabiensis

A new series of 8-trifluoromethyl quinoline derivatives bearing substituted saturated amines has been synthesized by standard conventional reflux methods. The structures of the novel saturated amine derivatives 4a–4h were characterized by 1H and 13C-NMR and mass spectrometry. Among the designed compounds 4a–4h, compound 4a was subjected to the single-crystal X-ray diffraction technique (SCXRD). According to the SCXRD analysis, the compound crystallized in a monoclinic lattice structure with the space group P21/n. The crystal structure is stabilized through intermolecular C–H⋯O interactions. Hirshfeld surface analysis is performed to validate the intermolecular interactions of compound 4a. Density functional theory (DFT) calculations are performed to study the optimized structure, molecular geometry, and molecular electrostatic potential (MEP) of compound 4a using the B3LYP/6–311++G(d,p) level of theory in the gas phase. We evaluated the title compounds for larvicidal activity using Temephos as the standard reference against Anopheles arabiensis. Compound 4b exhibited the highest larval mortality, at 97%, after 48 h of exposure. The synthesized compounds were generally non-toxic to normal fibroblasts. To further validate the biological activity, molecular docking studies were performed on the designed title compounds 4a–4h against five malaria vectors (PDB IDs: 1ZP4, 2CH2, 4JBV, 5V13, and 6ARY). In silico ADMET profiles were also screened to evaluate the drug-likeness and toxicity of the tested compounds.