Rational Design of Thiophene-2-Carbaldehyde Modified Petunidin-3-Glucoside as a Novel MurA-Targeted Antibacterial Candidate

Abstract

The global rise of antimicrobial resistance highlights the urgent need for novel inhibitors targeting essential bacterial enzymes such as UDP-N-acetylglucosamine enolpyruvyl transferase (MurA). This study investigates the antibacterial potential of Petunidin-3-glucoside, a natural polyphenol isolated from African leaves, and its structural modification with Thiophene-2-carbaldehyde (TC) to enhance MurA inhibition. A validated QSAR model using hydrophobic, electronic, and steric descriptors predicted significantly lower EC₅₀ values for TC-modified compounds, with TC–Petunidin-3-glucoside showing the highest predicted potency (EC₅₀ = 0.070 µM). Molecular docking revealed strong binding affinity to MurA (ΔG = −8.5 kcal/mol, Ki = 0.689 µM), involving key interactions such as hydrogen bonding, π-anion, and π-sulfur contacts with residues CYS115, ARG120, and ASP305. Additionally, π-alkyl and π-sigma interactions with LEU370, VAL163, and PHE328 stabilized the aromatic moieties within the enzyme’s active site. PASS prediction indicated enhanced antibacterial activity and membrane-related mechanisms, with a Pa of 0.910 for membrane integrity agonism. Overall, TC-modified Petunidin-3-glucoside exhibits promising characteristics as a MurA-targeted antibacterial candidate, supporting the rational design of natural product-derived inhibitors to combat antibiotic-resistant pathogens.