Approaches to Dispersing Medical Biofilms.
01 Apr 2017-Vol. 5, Iss: 2, pp 15
TL;DR: This review addresses the current state of research into medical biofilm dispersal and focuses on three major classes of dispersal agents: enzymes, antibiofilm peptides, and dispersal molecules (including dispersal signals, anti-matrix molecules, and sequestration molecules).
Abstract: Biofilm-associated infections pose a complex problem to the medical community, in that residence within the protection of a biofilm affords pathogens greatly increased tolerances to antibiotics and antimicrobials, as well as protection from the host immune response. This results in highly recalcitrant, chronic infections and high rates of morbidity and mortality. Since as much as 80% of human bacterial infections are biofilm-associated, many researchers have begun investigating therapies that specifically target the biofilm architecture, thereby dispersing the microbial cells into their more vulnerable, planktonic mode of life. This review addresses the current state of research into medical biofilm dispersal. We focus on three major classes of dispersal agents: enzymes (including proteases, deoxyribonucleases, and glycoside hydrolases), antibiofilm peptides, and dispersal molecules (including dispersal signals, anti-matrix molecules, and sequestration molecules). Throughout our discussion, we provide detailed lists and summaries of some of the most prominent and extensively researched dispersal agents that have shown promise against the biofilms of clinically relevant pathogens, and we catalog which specific microorganisms they have been shown to be effective against. Lastly, we discuss some of the main hurdles to development of biofilm dispersal agents, and contemplate what needs to be done to overcome them.
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TL;DR: The events involved in bacterial biofilm formation are described, the negative and positive aspects associated with bacterial biofilms are listed, the main strategies currently used to regulate establishment of harmful bacterial bioFilms are elaborated as well as certain strategies employed to encourage formation of beneficial bacterialBiofilms.
Abstract: Bacterial biofilms are complex surface attached communities of bacteria held together by self-produced polymer matrixs mainly composed of polysaccharides, secreted proteins, and extracellular DNAs. Bacterial biofilm formation is a complex process and can be described in five main phases: (i) reversible attachment phase, where bacteria non-specifically attach to surfaces; (ii) irreversible attachment phase, which involves interaction between bacterial cells and a surface using bacterial adhesins such as fimbriae and lipopolysaccharide (LPS); (iii) production of extracellular polymeric substances (EPS) by the resident bacterial cells; (iv) biofilm maturation phase, in which bacterial cells synthesize and release signaling molecules to sense the presence of each other, conducing to the formation of microcolony and maturation of biofilms; and (v) dispersal/detachment phase, where the bacterial cells depart biofilms and comeback to independent planktonic lifestyle. Biofilm formation is detrimental in healthcare, drinking water distribution systems, food, and marine industries, etc. As a result, current studies have been focused toward control and prevention of biofilms. In an effort to get rid of harmful biofilms, various techniques and approaches have been employed that interfere with bacterial attachment, bacterial communication systems (quorum sensing, QS), and biofilm matrixs. Biofilms, however, also offer beneficial roles in a variety of fields including applications in plant protection, bioremediation, wastewater treatment, and corrosion inhibition amongst others. Development of beneficial biofilms can be promoted through manipulation of adhesion surfaces, QS and environmental conditions. This review describes the events involved in bacterial biofilm formation, lists the negative and positive aspects associated with bacterial biofilms, elaborates the main strategies currently used to regulate establishment of harmful bacterial biofilms as well as certain strategies employed to encourage formation of beneficial bacterial biofilms, and highlights the future perspectives of bacterial biofilms.
306 citations
TL;DR: The current understanding of biofilm antibiotic tolerance mechanisms is reviewed and an overview ofBiofilm remediation strategies is provided, focusing primarily on the most promising biofilm eradication agents and approaches.
Abstract: Most free-living bacteria can attach to surfaces and aggregate to grow into multicellular communities encased in extracellular polymeric substances called biofilms. Biofilms are recalcitrant to antibiotic therapy and a major cause of persistent and recurrent infections by clinically important pathogens worldwide (e.g., Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus). Currently, most biofilm remediation strategies involve the development of biofilm-inhibition agents, aimed at preventing the early stages of biofilm formation, or biofilm-dispersal agents, aimed at disrupting the biofilm cell community. While both strategies offer some clinical promise, neither represents a direct treatment and eradication strategy for established biofilms. Consequently, the discovery and development of biofilm eradication agents as comprehensive, stand-alone biofilm treatment options has become a fundamental area of research. Here we review our current understanding of biofilm antibiotic tolerance mechanisms and provide an overview of biofilm remediation strategies, focusing primarily on the most promising biofilm eradication agents and approaches. Many of these offer exciting prospects for the future of biofilm therapeutics for a large number of infections that are currently refractory to conventional antibiotics.
294 citations
Cites background from "Approaches to Dispersing Medical Bi..."
...These constituents not only assist in securing the biofilm to the surface, but also trap nutrients, provide structural support, and shield against host immune responses and antimicrobial treatments (Flemming et al., 2007)....
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TL;DR: This review presents some of the anti-virulence strategies that are currently being developed and will cover strategies focused on quench pathogen quorum sensing (QS) systems, disassemble of bacterial functional membrane microdomains (FMMs), disruption of biofilm formation and bacterial toxin neutralization.
Abstract: Antimicrobial resistance constitutes one of the major challenges facing humanity in the Twenty-First century. The spread of resistant pathogens has been such that the possibility of returning to a pre-antibiotic era is real. In this scenario, innovative therapeutic strategies must be employed to restrict resistance. Among the innovative proposed strategies, anti-virulence therapy has been envisioned as a promising alternative for effective control of the emergence and spread of resistant pathogens. This review presents some of the anti-virulence strategies that are currently being developed, it will cover strategies focused on quench pathogen quorum sensing (QS) systems, disassemble of bacterial functional membrane microdomains (FMMs), disruption of biofilm formation and bacterial toxin neutralization.
170 citations
TL;DR: The aim of this review is to highlight the most promising combination strategies developed so far to enhance the therapeutic potential of AMPs against bacterial biofilms.
Abstract: The great clinical significance of biofilm-associated infections and their inherent recalcitrance to antibiotic treatment urgently demand the development of novel antibiofilm strategies. In this regard, antimicrobial peptides (AMPs) are increasingly recognized as a promising template for the development of antibiofilm drugs. Indeed, owing to their main mechanism of action, which relies on the permeabilization of bacterial membranes, AMPs exhibit a strong antimicrobial activity also against multidrug-resistant bacteria and slow-growing or dormant biofilm-forming cells and are less prone to induce resistance compared to current antibiotics. Furthermore, the antimicrobial potency of AMPs can be highly increased by combining them with conventional (antibiotics) as well as unconventional bioactive molecules. Combination treatments appear particularly attractive in the case of biofilms since the heterogeneous nature of these microbial communities requires to target cells in different metabolic states (e.g., actively growing cells, dormant cells) and environmental conditions (e.g., acidic pH, lack of oxygen or nutrients). Therefore, the combination of different bioactive molecules acting against distinct biofilm components has the potential to facilitate biofilm control and/or eradication. The aim of this review is to highlight the most promising combination strategies developed so far to enhance the therapeutic potential of AMPs against bacterial biofilms. The rationale behind and beneficial outcomes of using AMPs in combination with conventional antibiotics, compounds capable of disaggregating the extracellular matrix, inhibitors of signaling pathways involved in biofilm formation (i.e., quorum sensing), and other peptide-based molecules will be presented and discussed.
135 citations
Cites background from "Approaches to Dispersing Medical Bi..."
...…in potentiating the antibiofilm activity of AMPs by combining them with compounds capable of inhibiting the synthesis of EPS components in forming biofilms (Table 1 and Figure 1D) and/or promoting matrix disaggregation in preformed biofilms (Table 1 and Figure 1E) (Fleming and Rumbaugh, 2017)....
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TL;DR: This review is a brief overview of biofilm research and provides updates on recent understandings on biofilm development, antibiotic resistance and transmission, and importance of QS mechanisms.
Abstract: Biofilm is a mode of living employed by many pathogenic and environmental microbes to proliferate as multicellular aggregates on inert inanimate or biological substrates. Several microbial diseases are associated with biofilms that pose challenges in treatment with antibiotics targeting individual cells. Bacteria in biofilms secrete exopolymeric substances that contribute to architectural stability and provide a secure niche to inhabiting cells. Quorum sensing (QS) plays essential roles in biofilm development. Pathogenic bacteria in biofilms utilize QS mechanisms to activate virulence and develop antibiotic resistance. This review is a brief overview of biofilm research and provides updates on recent understandings on biofilm development, antibiotic resistance and transmission, and importance of QS mechanisms. Strategies to combat biofilm associated diseases including anti-biofilm substances, quorum quenching molecules, bio-surfactants and competitive inhibitors are briefly discussed. The review concludes with updates on recent approaches utilized for biofilm inhibition and provides perspectives for further research in the field.
124 citations
References
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TL;DR: The functions, properties and constituents of the EPS matrix that make biofilms the most successful forms of life on earth are described.
Abstract: The microorganisms in biofilms live in a self-produced matrix of hydrated extracellular polymeric substances (EPS) that form their immediate environment. EPS are mainly polysaccharides, proteins, nucleic acids and lipids; they provide the mechanical stability of biofilms, mediate their adhesion to surfaces and form a cohesive, three-dimensional polymer network that interconnects and transiently immobilizes biofilm cells. In addition, the biofilm matrix acts as an external digestive system by keeping extracellular enzymes close to the cells, enabling them to metabolize dissolved, colloidal and solid biopolymers. Here we describe the functions, properties and constituents of the EPS matrix that make biofilms the most successful forms of life on earth.
7,041 citations
TL;DR: It is evident that biofilm formation is an ancient and integral component of the prokaryotic life cycle, and is a key factor for survival in diverse environments.
Abstract: Biofilms--matrix-enclosed microbial accretions that adhere to biological or non-biological surfaces--represent a significant and incompletely understood mode of growth for bacteria. Biofilm formation appears early in the fossil record (approximately 3.25 billion years ago) and is common throughout a diverse range of organisms in both the Archaea and Bacteria lineages, including the 'living fossils' in the most deeply dividing branches of the phylogenetic tree. It is evident that biofilm formation is an ancient and integral component of the prokaryotic life cycle, and is a key factor for survival in diverse environments. Recent advances show that biofilms are structurally complex, dynamic systems with attributes of both primordial multicellular organisms and multifaceted ecosystems. Biofilm formation represents a protected mode of growth that allows cells to survive in hostile environments and also disperse to colonize new niches. The implications of these survival and propagative mechanisms in the context of both the natural environment and infectious diseases are discussed in this review.
6,170 citations
"Approaches to Dispersing Medical Bi..." refers background in this paper
...Biofilms form when a microbe irreversibly attaches itself to a surface and commences cell division and recruitment of other microorganisms by providing more diverse adhesion sites to the substrate [2]....
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TL;DR: Bacterial biofilms are structured communities of cells enclosed in self-produced hydrated polymeric matrix adherent to an inert or living surface that have inherent resistance to antibiotics and host immune attack.
Abstract: Bacterial biofilms are structured communities of cells enclosed in self-produced hydrated polymeric matrix adherent to an inert or living surface ([1][1]). Formation of these sessile communities and their inherent resistance to antibiotics and host immune attack are at the root of many persistent
1,962 citations
"Approaches to Dispersing Medical Bi..." refers background in this paper
...aeruginosa biofilms up to 60 h with DNase I led to dispersal [41]....
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TL;DR: The extracellular matrix is a complex and extremely important component of all biofilms, providing architectural structure and mechanical stability to the attached population, and these intrinsic and extrinsic factors combine to produce a dynamic, heterogeneous microenvironment for the attached and enveloped cells.
Abstract: The extracellular matrix is a complex and extremely important component of all biofilms, providing architectural structure and mechanical stability to the attached population. The matrix is composed of cells, water and secreted/released extracellular macromolecules. In addition, a range of enzymic and regulatory activities can be found within the matrix. Together, these different components and activities are likely to interact and in so doing create a series of local environments within the matrix which co-exist as a functional consortium. The matrix architecture is also subject to a number of extrinsic factors, including fluctuations in nutrient and gaseous levels and fluid shear. Together, these intrinsic and extrinsic factors combine to produce a dynamic, heterogeneous microenvironment for the attached and enveloped cells.
1,810 citations
"Approaches to Dispersing Medical Bi..." refers background in this paper
...They provide many important functions for the establishment and persistence of biofilms including, but not limited to, structural stability, physical and chemical defense against antimicrobials and the host immune system, adhesion and aggregation of microbial cells, desiccation tolerance, sorption of organic and inorganic compounds, and can provide a carbon source in times of nutrient starvation [1,66,67]....
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...Being in a biofilm provides microbes with a host of advantages, including, but not limited to: physical protection from the host immune system and antimicrobials/antibiotics, retention of water and tolerance to desiccation, nutrient sorption and storage, high extracellular enzymatic activity, adhesion to the infection site, and cell aggregation leading to coordination of virulence factor expression via quorum sensing [1,3,4]....
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...Biofilms are communities of microorganisms protected by a self-synthesized layer of complex polysaccharides, proteins, lipids and extracellular DNA, collectively called the extracellular polymeric substance (EPS) [1]....
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...Most biofilms are highly dependent on the presence of secreted extracellular polysaccharides, or exopolysaccharides, as major EPS constituents [1,64,65]....
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TL;DR: Newly annotated are AMPs with antibiofilm, antimalarial, anti-protist, insecticidal, spermicidal, chemotactic, wound healing, antioxidant and protease inhibiting properties and various database applications in research and education are summarized.
Abstract: The antimicrobial peptide database (APD, http://aps.unmc.edu/AP/) is an original database initially online in 2003. The APD2 (2009 version) has been regularly updated and further expanded into the APD3. This database currently focuses on natural antimicrobial peptides (AMPs) with defined sequence and activity. It includes a total of 2619 AMPs with 261 bacteriocins from bacteria, 4 AMPs from archaea, 7 from protists, 13 from fungi, 321 from plants and 1972 animal host defense peptides. The APD3 contains 2169 antibacterial, 172 antiviral, 105 anti-HIV, 959 antifungal, 80 antiparasitic and 185 anticancer peptides. Newly annotated are AMPs with antibiofilm, antimalarial, anti-protist, insecticidal, spermicidal, chemotactic, wound healing, antioxidant and protease inhibiting properties. We also describe other searchable annotations, including target pathogens, molecule-binding partners, post-translational modifications and animal models. Amino acid profiles or signatures of natural AMPs are important for peptide classification, prediction and design. Finally, we summarize various database applications in research and education.
1,391 citations
"Approaches to Dispersing Medical Bi..." refers background in this paper
...To date, more than 2600 peptides with antimicrobial properties have been discovered, with 2169 of those being antibacterial [68]....
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