Unlocking Antibacterial Potential: Thiophene-2-carbaldehyde Modification of Acertannin from African Leaves as MurA Enzyme Inhibitors

Abstract

The global rise of antimicrobial resistance underscores the need for novel inhibitors targeting essential bacterial enzymes such as UDP-N-acetylglucosamine enolpyruvyl transferase (MurA). This study evaluates the antibacterial potential of three natural polyphenols—Acertannin from African leaves and structurally modified with Thiophene-2-carbaldehyde (TC) to enhance MurA inhibition. A validated QSAR model, incorporating hydrophobic, electronic, and steric descriptors, predicted significantly lower EC₅₀ values for TC-modified compounds, with TC-acertannin showing the highest predicted potency (EC₅₀ = 0.382 µM). Molecular docking revealed strong binding affinity to MurA, with ΔG = −7.8 kcal/mol and Ki = 1.88 µM, involving key interactions such as hydrogen bonding, π-anion, and π-sulfur contacts with residues CYS115, ARG120, ASN23, ARG91, LYS22 and GLU188. PASS prediction further indicated enhanced antibacterial activity and membrane-related mechanisms, with TC-Acertannin showing a Pa of 0.923 for membrane integrity agonism. These results highlight TC-modified tannin as promising MurA-targeted antibacterial agents and support the rational design of natural product-based inhibitors to combat antibiotic-resistant bacteria