Introductory Chapter: Bacterial Biofilms in Human Infection – An Urgent Problem That Needs to Be Solved

1. Introduction

Infectious diseases pose continuous and increasing risks to human health and welfare along with the development of human society [1]. Even nowadays, in the twenty-first century when individuals, communities, and hospitals have easy access to effective disinfectants, abundant antibiotics, and advanced medical technologies, infectious disease outbreaks are still able to cause severe consequences on lives and livelihoods all over the world [2]. In fact, according to a recent comprehensive demographic analysis for the Global Burden of Disease Study, around seven million people died of infectious diseases in 2019, representing approximately 12% of all deaths globally [3]. As one of the five major infectious agents, that is, viruses, bacteria, fungi, protozoa, and helminths [4], bacteria have a significant impact on public health since their infections can occur at any part of human body and can be transmitted to human beings via many apparent and hidden routes, making their control and prevention extremely difficult [5]. Bacterial infections have caused many devastating pandemics in human history such as the Black Death caused by Yersinia pestis, Cholera caused by Vibrio cholerae, and so forth, leading to tens of millions deaths all over the world [6]. In addition, there are many other bacterial pathogens that are able to cause infectious diseases with severe consequences like leprosy (Mycobacterium leprae), tuberculosis (Mycobacterium tuberculosis), anthrax (Bacillus anthracis), syphilis (Treponema pallidum), and so on, making clinical treatment of bacterial infection difficult and complex. Since the discovery of penicillin in 1928 and other antibiotics after that, due to the high effectiveness of antibiotics in bacterial infection control, it was once thought that antibiotics were one of the most successful chemotherapies in the history of medicine [7]. However, with the arm race between bacterial evolution and the development of antibiotics, drug-resistant and multidrug-resistant bacterial pathogens keep emerging, leading to the emergence of hard-to-treat multiple antibiotic-resistant infections and the failure of last-line antibiotics [7]. In clinical settings, formation of bacterial biofilms could significantly enhance antibiotic resistance from 10- to 1000-fold increment when compared to similar bacteria living in a planktonic state [8]. In addition, bacterial biofilms are closely associated with chronic infections like pneumoniae in cystic fibrosis patients and are extremely difficult to eradicate once formed [9]. Therefore, it is important to understand bacterial biofilm formations and regulations at molecular level so as to facilitate the development of novel drugs and discovery of drug targets for disrupting biofilms, leading to the effective improvement of clinical treatment of antibiotics-resistant bacterial pathogens and biofilm-related bacterial chronic infections.

2. Bacterial biofilm formation and regulation

In specificity, bacterial biofilm is a highly complex, well-organized, three-dimension-structural consortium of bacteria that are embedded in a self-produced extracellular matrix, containing polysaccharides, proteins and nucleic acids, and so on [10]. Despite the structural complexity of bacterial biofilms, a classical five-step model was previously proposed to explain its formation: (1) reversible attachment phase, (2) irreversible attachment phase, (3) extracellular polymeric substances (EPS) production, (4) maturation, and (5) dispersal and detachment [11]. Recently, Sauer et al. have revised the conceptual model and proposed a simple three-step biofilm formation model, that is, aggregation, growth, and disaggregation, in order to represent a broader range of biofilm system [12]. Biofilm formation is sophisticatedly regulated and is involved in complex network of regulatory cascades such as quorum sensing (QS) system (communications of bacterial cells within biofilm), regulatory small RNAs (sRNAs), second messengers (cyclic-di-guanosine monophosphate, c-di-GMP), and so forth [13], while elucidation of the regulatory mechanisms of biofilm formation will promote the development of effective strategies to biofilm inhibition and control [14].

3. Bacterial biofilm prevention, inhibition, and eradication

Biofilm infections are persistent and recalcitrant, are tightly associated with the rise of antibiotic resistance, and show heterogeneous features with diverse nature [15]. Due to the harmfulness of bacterial biofilms in human infections, effective strategies for preventing, inhibiting, and eradicating biofilms are urgently needed. As the proverb runs, prevention is better than cure [16]. Therefore, it is always the priority to prevent the formation of bacterial biofilm rather than to inhibit and eradicate it, which requires less effort on biofilm control. Multiple strategies are currently available for biofilm prevention, which most frequently involve treating abiotic surfaces (smoothness, wettability, or hydrophilicity) and coating surfaces (salivary proteins, 2-methacryloyloxyethyl phosphorylcholine, monomeric trimethylsilane, antimicrobial peptide) [17]. These methods are able to greatly reduce microbial attachment to device surface, hence preventing biofilm formation and reducing bacterial infection. As for the inhibition of bacterial biofilms, there are also many effective combating tactics like quorum-sensing blockage, hindering the biosynthesis of N-acyl-homoserine lactones (AHL) signal molecule, biodegradation or alteration of AHL signal molecule, interference with receptor proteins by analog compounds, and so on [18]. Further in-depth studies are needed to elucidate the effects and mechanisms of these biofilm inhibition tactics so that they could be used in the host, proving their applicability to humans in clinical settings. Although prevention and inhibition of bacterial biofilms provide some clinical premise, these methods do not represent a direct treatment for established biofilms while eradication agents and approaches are efficient to remove mature biofilms [19]. Several representative methods include electrochemical methods, antimicrobial compounds, biofilm architecture modulation, and drug delivery methods, all of which aim to eradicate bacterial biofilms when applied alone or synergistically [20]. However, the eradication of mature bacterial biofilms is extraordinarily difficult. More strategies and novel compounds need to be developed for a more effective fight against biofilms.

4. Summary

With the development of prevention, inhibition, and eradication methods of bacterial biofilms, the mortality rate of chronic and fatal bacterial infections is expected to be greatly reduced in future.

Acknowledgments

This study was financially supported by Research Foundation for Advanced Talents of Guandong Provincial People’s Hospital [Grant No. KY012023293].

Author contributions

LW and BG conceived the framework of the manuscript, provided platform and resources, and contributed to project administration and funding acquisitions. All the authors contributed to the writing and revision of the manuscript and approved the submission of the final version of the manuscript.

Declaration of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Inclusion and diversity

We support inclusive, diverse, and equitable conduct of research.