Multiple Strategies for the Application of Medicinal Plant-Derived Bioactive Compounds in Controlling Microbial Biofilm and Virulence Properties

Abstract

Biofilms are complex microbial communities encased within a self-produced extracellular matrix, which plays a critical role in chronic infections and antimicrobial resistance. These enhance pathogen survival and virulence by protecting against host immune defenses and conventional antimicrobial treatments, posing substantial challenges in clinical contexts such as device-associated infections and chronic wounds. Secondary metabolites derived from medicinal plants, such as alkaloids, tannins, flavonoids, phenolic acids, and essential oils, have gained attention as promising agents against biofilm formation, microbial virulence, and antibiotic resistance. These natural compounds not only limit microbial growth and biofilm development but also disrupt communication between bacteria, known as quorum sensing, which reduces their ability to cause disease. Through progress in nanotechnology, various nanocarriers such as lipid-based systems, polymeric nanoparticles, and metal nanoparticles have been developed to improve the solubility, stability, and cellular uptake of phytochemicals. In addition, the synergistic use of plant-based metabolites with conventional antibiotics or antifungal drugs has shown promise in tackling drug-resistant microorganisms and revitalizing existing drugs. This review comprehensively discusses the efficacy of pure secondary metabolites from medicinal plants, both as individuals and in nanoformulated forms or in combination with antimicrobial agents, as alternative strategies to control biofilm-forming pathogens. The molecular mechanisms underlying their antibiofilm and antivirulence activities are discussed in detail. Lastly, the current pitfalls, limitations, and emerging directions in translating these natural compounds into clinical applications are critically evaluated.

Keywords: antimicrobial resistance; biofilm inhibition; drug combination; medicinal plant secondary metabolites; nanoformulations for biofilm control; virulence attenuation.

Figure 3

Multiple action mechanisms in the inhibitory role of medicinal plant products towards the biofilm (inhibition at the initial stage and eradication of mature biofilm), QS signaling systems, virulence factors, and EPS production. Reprinted with permission [65], Copyright © 2023 by the authors. Published by Elsevier GmbH.

Figure 1

Stages of microbial biofilm formation and the composition of the biofilm matrix. Reprinted from [33], Copyright © 2024 by the authors. Licensee MDPI, Basel, Switzerland under the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Figure 2

Transcriptomic analysis revealed a complex quorum sensing (QS) system in P. aeruginosa, involving the two well-studied QS systems (las and rhl), which are crucial for producing virulence factors, antibiotic resistance, and biofilm development. Modified figure from [56] with Copyright © 2004 Elsevier Ltd.

Figure 4

Antimicrobial activity of RLs-CSp towards S. aureus. RLs can be adsorbed to the surface of RLs-CSp (A₂) when encapsulated onto RLs-CSp (A₁), which is another option. Through electrostatic attraction (B₁,B₂), first, the negatively charged S. aureus membranes are drawn to the positively charged RLs-CSp. RLs are discharged from the RLs-CSp delivery system and penetrate membranes over time, ultimately killing and destroying these cells (B₃). The experimental in vitro RLs’ cumulative release profile (C) shows that all chemicals can be released from the RLs-CSp. Reprinted with permission [181], Copyright © 2020 Elsevier Ltd.

Figure 5

Antibiofilm inhibition role of the smart nanogel carrageenan nanogels (CAR NGs) based on carrageenan and green coffee extract against (a) E. coli, (b) S. enterica, (c) S. aureus, and (d) L. monocytogenes on the surface of the stainless steel. Reprinted with permission from [192], Copyright © 2024 Elsevier Ltd.

Figure 6

Metallic nanoparticles (MNPs) have antibiofilm and antivirulence properties.