A Bakuchiol-Linked Tetrazole Exhibits Narrow-spectrum Activity Against Streptococcus pneumoniae

Abstract

Natural product-based amphiphilic phenolic terpenoid antimicrobial agents were rationally designed by integrating the meroterpenoid bakuchiol with a tetrazole moiety through a fragment-based drug design strategy. A library of 30 bakuchiol-linked tetrazole derivatives was synthesized via chemical transformation of bakuchiol, followed by comprehensive structural characterization using 1D and 2D NMR spectroscopy. The compounds were screened for antibacterial activity against different bacterial strains. Among the synthesized compounds, lead molecule 11m demonstrated selective narrow-spectrum antibacterial activity against Streptococcus species. It significantly reduces bacterial growth and inhibits biofilm formation. Mechanistic study indicates that 11m induces alterations in cell envelope architecture, leading to leakage of intracellular content, elevated autolysis, and noticeable morphological changes. These effects occur without membrane depolarization, suggesting the bactericidal activity of the compound may be associated with perturbations in the cell envelope. This study highlights the potential of semisynthetic natural product derivatives (bakuchiol) as a promising platform for developing narrow-spectrum antibacterial agents. Furthermore, the selectivity of 11m provides a strategic advantage in overcoming bacterial resistance, offering a valuable therapeutic approach against multidrug-resistant pathogens.