A Study of the Antibacterial Activities and the Mode of Action of L-Methionine and L-Cystine Based Surfactants and their Interaction with Bovine Serum Albumin Using Fluorescence Spectroscopy and in Silico Modelling

Abstract

Surfactants are versatile excipients that are commonly employed in diverse pharmaceutical formulations given their broad range of antimicrobial activities. Sulfur-based amino acid surfactants are promising candidates as substitutes for conventional antibacterial agents in light of the current antibiotic resistance crisis. Dodecyl esters of the free amine (SURF1), cationic ester hydrochloride (SURF2), and quaternary ammonium (QUAT3) derivatives of methionine, and the Gemini diester of cystine (GEM4) were synthesized and evaluated for antibacterial activity against Gram-positive and Gram-negative pathogens. All surfactants displayed moderate to high antibacterial activities, particularly on Gram-positive bacteria, with QUAT3 showing the highest activity. Among Gram-negative bacteria, QUAT3, GEM4, and SURF2 were mostly active towards K. pneumoniae with minimum inhibitory concentrations (MIC) ranging from 0.004 to 0.441 mM. QUAT3 and GEM4 displayed a bacteriostatic behavior similar to that of tetracycline, as assessed by broth macrodilution assays. Fluorescence binding studies with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) revealed that the antibacterial activities could be attributed to a combination of electrostatic and hydrophobic interactions. Bovine serum albumin (BSA) fluorescence and molecular docking studies indicated that SURF1 and QUAT3 interact mainly via van der Waals' forces and hydrogen bonding while SURF2 binds through hydrophobic interactions. QUAT3, which displays broad-spectrum activity, has the potential to combat drug-resistant bacteria.