Biofilms harbour complex structural and biological attributes, such as the presence of an extracellular polymeric matrix, physical and chemical heterogeneity and drug tolerance, which provide remarkable therapeutic challenges.
Biofilm drug tolerance is a consequence of complex physicochemical and biological properties with multiple microbial genetic and molecular factors, often involving polymicrobial interactions.
The challenges to existing antimicrobial or monotherapeutic approaches by the multifactorial nature of biofilm development, combined with drug tolerance, requires robust effective multitargeted or combinatorial therapies.
Combinatorial strategies are needed to eliminate existing biofilms by targeting vital structural and functional traits of biofilms, such as the EPS matrix and dormant cells, as well as approaches exploiting host–pathogen interactions.
Promising technologies based on 'smart release' or 'on-demand activation' of bioactive agents when triggered by biofilm-derived cues can degrade the matrix and kill resident bacteria, and have the potential to eradicate the pathogenic niche with precision and minimal cytotoxicity to surrounding tissues.
Validation of proof-of-concept studies using clinically relevant animal models, as well as clinical trials, are needed for rigorous evaluation.
Biofilm formation is a key virulence factor for a wide range of microorganisms that cause chronic infections. The multifactorial nature of biofilm development and drug tolerance imposes great challenges for the use of conventional antimicrobials and indicates the need for multi-targeted or combinatorial therapies. In this Review, we focus on current therapeutic strategies and those under development that target vital structural and functional traits of microbial biofilms and drug tolerance mechanisms, including the extracellular matrix and dormant cells. We emphasize strategies that are supported by in vivo or ex vivo studies, highlight emerging biofilm-targeting technologies and provide a rationale for multi-targeted therapies aimed at disrupting the complex biofilm microenvironment.
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Work in the authors' laboratory is supported, in part, by the US National Institute for Dental and Craniofacial Research grants DE018023, DE025220 and DE025848 (H.K.); The Ohio State University Infectious Disease Discovery Theme- Public Health Preparedness for Infectious Disease Transdisciplinary Team Grant (P.S.). The authors also thank the helpful comments of the reviewers. In addition, the authors regret that several important studies could only indirectly be acknowledged through review articles owing to space and reference number limitations.
P.S. has received research funding from and/or has consulted from Philips Oral Healthcare, Smith & Nephew, Biocomposites Ltd., Zimmer-Biomet, Colgate-Palmolive. H.K. has received funding from Johnson & Johnson, Colgate–Palmolive and Dentsply. R.P.H. has consulted for Biocomposites Ltd. R.N.A and L.H.-S. declare no competing interests.
Supplementary information S1 (table)
Overview of Current and Prospective Anti-Biofilm Strategies (DOCX 75 kb)
- Extracellular polymeric substance
(EPS). The EPS can contain exopolysaccharides, fibrous and globular proteins (including extracellular enzymes), lipids and nucleic acids (eDNA). These components form a matrix that can be surface-associated or secreted locally, or deposited on abiotic and biotic surfaces. The EPS matrix functions as a 'multifunctional scaffold' that supports and protects embedded bacteria.
- Antimicrobial chemotherapy
The clinical treatment of microbial infections with antimicrobial agents.
- Lock therapy
An approach whereby high concentrations of antibiotics are injected into the catheter lumen for an extended period of time to eradicate bacteria. Catheter locks have been used to treat sepsis since the 1980s; however, with the understanding that infecting microorganisms are present as biofilms on medical device materials, this approach is now specifically tailored to improve efficacy.
Bacterial or fungal surface-associated determinants that mediate adherence to living cells or attachment to abiotic surfaces and can promote virulence.
A mannose glycoside consisting of a carbohydrate bound to the hydroxyl group of another compound by O-, N-, S- or C-glycosidic bonds, each with different susceptibilities to hydrolysis.
A class of bacterial amyloid (aggregates of proteins that form insoluble fibres) produced by many members of the Enterobacteriaceae and a major component of the extracellular matrix, promoting surface adhesion, cell aggregation and biofilm formation.
- Type I pili
Filamentous surface structures that have a FimH adhesin at the pilus tip, mediating adherence to host cells and uropathogenic Escherichia coli invasion of bladder epithelial cells.
- Antimicrobial peptides
A subset of host defence peptides with antibiotic activity. Peptides such as LL-37 (cathelicidin) and human β-defensins are rapidly acting, small-molecule effectors that are part of the innate immune response of the host.
- Nitric oxide
(NO). A ubiquitous signalling molecule found in both prokaryotic and eukaryotic systems. NO is toxic in the millimolar range, but in the picomolar and nanomolar range it can be used to form reactive oxidative and nitrosative species that interact with proteins, DNA and metabolic enzymes. As NO is labile, the optimal concentration to disperse biofilms is difficult to measure; however, NO microelectrodes are highly sensitive and may provide excellent spatial and temporal resolution in tissues or body fluids.
- Cystic fibrosis transmembrane conductance regulator
(CFTR). A transmembrane protein and ion transport channel that regulates epithelial fluid homeostasis central to airway mucociliary clearance and defence against inhaled pathogens.
Class of organic compounds (C2H7N5) used as oral antihyperglycaemic drugs. Derivatives of this compound with bactericidal activity are commonly used as antiseptic and disinfecting agents such as chlorhexidine.
Structures with a size range between 1–1000 nm. They can be classified as organic or inorganic and can exhibit antibacterial properties or can be used as drug delivery systems.
Compounds that lower the surface tension between liquids and solids. Surfactants are used as cleaning detergents, and some biofilm bacteria produce their own surfactants in order to disperse from a surface.
- Topographic surface patterns
Patterns, including protruding squares, cone-shapes, wrinkle and ridge-like patterning or nanopores, that disrupt bacterial adhesion.
The unwanted accumulation of microorganisms and macroorganisms on surfaces. Microbial biofilms are often considered 'biofouling', particularly in the context of manmade industrial surfaces.
- Super-hydrophobic surfaces
Surfaces that maintain air at the solid–liquid interface when hydrated. This leads to improved functionality through water repellency or reduced drag.
- Smart surfaces
Surfaces that elicit their effect only upon contact with certain physiological, physical or physiochemical cues to provide targeted application, thus increasing therapeutic precision and reducing the risk of cytotoxity.
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Koo, H., Allan, R., Howlin, R. et al. Targeting microbial biofilms: current and prospective therapeutic strategies. Nat Rev Microbiol 15, 740–755 (2017). https://doi.org/10.1038/nrmicro.2017.99
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