Combating Bacterial Biofilms: Current and Emerging Antibiofilm Strategies for Treating Persistent Infections

Abstract

Biofilms are intricate multicellular structures created by microorganisms on living (biotic) or nonliving (abiotic) surfaces. Medically, biofilms often lead to persistent infections, increased antibiotic resistance, and recurrence of infections. In this review, we highlighted the clinical problem associated with biofilm infections and focused on current and emerging antibiofilm strategies. These strategies are often directed at disrupting quorum sensing, which is crucial for biofilm formation, preventing bacterial adhesion to surfaces, impeding bacterial aggregation in viscous mucus layers, degrading the extracellular polymeric matrix, and developing nanoparticle-based antimicrobial drug complexes which target persistent cells within the biofilm core. It is important to acknowledge, however, that the use of antibiofilm agents faces obstacles, such as limited effectiveness in vivo, potential cytotoxicity to host cells, and propensity to elicit resistance in targeted biofilm-forming microbes. Emerging next generation antibiofilm strategies, which rely on multipronged approaches, were highlighted, and these benefit from current advances in nanotechnology, synthetic biology, and antimicrobial drug discovery. The assessment of current antibiofilm mitigation approaches, as presented here, could guide future initiatives toward innovative antibiofilm therapeutic strategies. Enhancing the efficacy and specificity of some emerging antibiofilm strategies via careful investigations, under conditions that closely mimic biofilm characteristics within the human body, could bridge the gap between laboratory research and practical application.

Keywords: antibiofilm agents; antibiofilm nanoparticles; antimicrobial peptides; bacterial biofilm; biofilm infection; quorum sensing.

Figure 1

Infections linked to surface- and tissue-located biofilms. These include infections resulting from biofilm formation on surfaces such as catheters, teeth, and kidney stones, or on tissues such as cystic fibrosis lungs, chronic wounds, and tonsils. The figure was adapted from [11] and created using biorender.com, accessed on 28 May 2023.

Figure 2

Development of biofilm on abiotic surfaces triggering human infections. Medical devices, such as catheters, are ideal abiotic surfaces for biofilm formation. The process begins with individual cells attaching to the device surface, followed by the secretion of extracellular polymeric substances (EPSs) and the aggregation of biofilm cells (microcolony formation). Subsequently, the full maturation of the biofilm structure occurs via an increased production of EPSs and a rise in biofilm population density. Eventually, biofilm dispersal takes place, causing recurring infections by restarting the biofilm development process. The figure was created using biorender.com, accessed on 28 May 2023.

Figure 3

Biofilm-associated infections within cystic fibrosis airways. The biofilm development is a multistep process starting with planktonic P. aeruginosa cells inhibiting the host immune responses including neutrophiles and macrophages (step 1) within the thickened mucus accumulated in cystic fibrosis airways (CFTR deficient). Bacterial survivors lose motility, accumulate extracellular polymeric substances, and form biofilm aggregates with heterogeneous populations (step 2). The biofilm populations exhibit genotypic and phenotypic convergence (step 3) to yield a fully mature biofilm with tolerance to antibiotics and persistent populations, which can cause recurring infections (step 4). CFTR, cystic fibrosis transmembrane conductance regulator; ROS, reactive oxygen species; PA, P. aeruginosa. The figure was created using biorender.com, accessed on 28 May 2023.

Figure 4

A comprehensive overview of biofilm eradication strategies for overcoming infection scenarios. These strategies include targeting biofilm extracellular polymeric substances (EPSs) via degradation enzymes (e.g., DNases or glucanohydrolases), EPS-specific antibodies, and cyclic-di-guanosine monophosphate (c-di-GMP) inhibitors that subsequently reduce EPS production. Additional approaches facilitate biofilm dispersal by employing nitric oxide to activate proteins that hydrolyze c-di-GMP, thereby boosting biofilm cell dispersal and motility. These dispersed cells become susceptible to destruction by innate immune cells (such as macrophages and neutrophils) via phagocytosis and free radical release, or due to antibiotic treatment. The diagram also depicts antibiofilm agents (e.g., small peptides) that specifically target persister cells within the biofilm core to eradicate recurring biofilm-associated infections. The figure was created using biorender.com, accessed on 28 May 2023.