The indiscriminate use of antibiotics and biofilm formation have contributed to the emergence of resistant infections. Natural compounds such as limonene and its derivatives have gained attention due to their therapeutic potential and lower risk of resistance. This study evaluated the antibacterial and antibiofilm activity of limonene isomers ((R)- and (S)-limonene) and their derivatives ((S)-perillyl alcohol and (S)-perillaldehyde), as well as their combined effects with β-lactam antibiotics against Gram-positive and Gram-negative strains of clinical and food relevance. Disk diffusion, MIC, MBC, growth curve, biofilm quantification (biomass and cell viability), and checkerboard assays were performed. (S)-limonene, (S)-perillyl alcohol, and (S)-perillaldehyde showed bactericidal activity, whereas (R)-limonene was bacteriostatic. Structural and electronic analyses indicated that oxygenation and substituents modify electron density, polarity, and reactivity, influencing biological activity. All compounds delayed bacterial growth and significantly reduced biofilm biomass and cell viability, with S-isomers achieving reductions of up to 90%. Combinatory analysis revealed synergistic and additive effects with oxacillin, benzylpenicillin, ampicillin, and ceftriaxone, particularly against MRSA and Klebsiella pneumoniae. In silico docking suggested potential inhibition of Gyrase B, thymidylate kinase, and topoisomerase through interactions with active-site residues. ADMET predictions indicated favorable permeability and absorption, especially for S-PA and R-LMN. These findings highlight the potential of limonene derivatives as alternative or adjunct antimicrobial agents against biofilm-associated infections.
Cavalcante et al. (Mon,) studied this question.