Bacterial biofilm development as a multicellular adaptation: antibiotic resistance and new therapeutic strategies

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Highlights

  • Biofilms may have evolved as an adaptive response to environmental stresses.

  • Biofilm formation is a complex process involving sophisticated regulatory networks.

  • Biofilms are highly resistant to diverse antibiotics.

  • Resistance is adaptive and mediated through a plethora of molecular mechanisms.

  • Potential new therapeutics that specifically target biofilms are under development.

Bacteria have evolved the ability to form multicellular, surface-adherent communities called biofilms that allow survival in hostile environments. In clinical settings, bacteria are exposed to various sources of stress, including antibiotics, nutrient limitation, anaerobiosis, heat shock, etc., which in turn trigger adaptive responses in bacterial cells. The combination of this and other defense mechanisms results in the formation of highly (adaptively) resistant multicellular structures that are recalcitrant to host immune clearance mechanisms and very difficult to eradicate with the currently available antimicrobial agents, which are generally developed for the eradication of free-swimming (planktonic) bacteria. However, novel strategies that specifically target the biofilm mode of growth have been recently described, thus providing the basis for future anti-biofilm therapy.

Introduction

Biofilms are structured aggregations of microorganisms associated with surfaces that have been widely studied over the past few decades in part because they cause 65% or more of all infections, being particularly prevalent in device-related infections, infections on body surfaces (skin and soft tissue, lung, bladder, endocarditis, etc.) and chronic infections [1, 2, 3]. They are particularly problematic due to their resistance to host defence mechanisms and to conventional antimicrobial therapy, which substantially hinders their treatment in the clinic [1, 2, 3, 4]. From a broader perspective, biofilms are ancient phenotypic adaptations to the environment and are ubiquitous in Nature [1].

In this review, we will summarize the most recent advances in the field of biofilm research and analyze these findings from the perspective that biofilms have developed as a survival strategy of adaptation to environmental stress. In this context, we explain the most recent findings about the adaptive antibiotic resistance mechanisms displayed by biofilms, as well as the new therapeutic strategies aimed at effectively inhibiting and/or eradicating biofilms.

Section snippets

Biofilm formation: an adaptive response to hostile environments

Biofilms appear early in the fossil record (∼3.25 billion years ago), and are common in a broad range of organisms, including not only bacteria but also archaea and eukaryotic microbes such as fungi [1]. The emergence of these primitive biofilms appears to have coincided with the first evidence of an evolutionary transition from unicellular to multicellular organization, which was provided by fossils of prokaryotic filamentous and mat-forming cyanobacteria-like organisms [1]. This suggests that

Biofilm formation in Nature and in the clinic

Biofilms are formed in diverse environmental niches, including hydrothermal hot springs and deep-sea vents, freshwater rivers, rocks, etc. [1, 2]. Additionally, these multicellular structures have been observed in various industrial and clinical settings [1, 2, 11, 12, 13•]. This suggests that the presence of stress signals in most natural and human ecosystems drives bacteria to exist predominantly within the protective milieu of a biofilm structure. Cells within biofilms have been shown to be

Mechanisms of antibiotic resistance in biofilms

While many explanations have been advanced to explain the high antibiotic resistance displayed by bacterial biofilms, it constitutes a clear example of adaptive resistance, a phenomenon that is increasingly attracting the attention of clinical microbiologists [17]. The adaptive nature of biofilm resistance is evidenced by the fact that cells taken from a biofilm and brought back to the planktonic state generally recover their original susceptibility [18]. It is worth noting, however, that

New concepts in biofilm prevention and eradication

The traditional focus on discovering compounds that target the planktonic mode of growth, both in vitro and in vivo, and the insufficient level of understanding of the biofilm phenotype have resulted in a lack of available drugs that specifically target bacterial biofilms. In the clinic, biofilm infections are usually treated with combinations of antibiotics [11, 12, 13•, 14]. Conversely, in the case of device-related biofilm infections, the device often has to be removed and replaced, a

Conclusions and future directions

Throughout their evolution, bacteria have gradually adapted to endure situations of environmental stress. One such adaptation entails the formation of biofilms, multicellular specialized structures that have become very efficient at tolerating external insults. On the basis of our current knowledge about the biology of biofilms, we can speculate that the evolutionary adaptation to the biofilm mode of growth may have been driven by stress signals present in the natural environment. One

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors would like to apologize for the numerous studies on biofilms that could not be included here given the concise nature of this review article. This work was supported by grants from the National Institutes of Health, Canadian Institutes for Health Research, Cystic Fibrosis Canada. REWH holds a Canada Research Chair in Health and Genomics. CDLF-N received a scholarship from the Fundación ‘la Caixa’ and Fundación Canadá (Spain).

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