Review Article | Published:

Understanding biofilm resistance to antibacterial agents

Nature Reviews Drug Discovery volume 2, pages 114122 (2003) | Download Citation

Subjects

Abstract

According to a public announcement by the US National Institutes of Health, “Biofilms are medically important, accounting for over 80% of microbial infections in the body”. Yet bacterial biofilms remain poorly understood and strategies for their control remain underdeveloped. Standard antimicrobial treatments typically fail to eradicate biofilms, which can result in chronic infection and the need for surgical removal of afflicted areas. The need to create effective therapies to counter biofilm infections presents one of the most pressing challenges in anti-bacterial drug development. In this article, the mechanisms that underlie biofilm resistance to antimicrobial chemotherapy will be examined, with particular attention being given to potential avenues for the effective treatment of biofilms.

Key points

  • Biofilm bacteria have been demonstrated to be significant contributors to human disease, yet our understanding of the nature of biofilm infections and their effective treatment remains underdeveloped. Recent research has begun to unlock many of the mysteries associated with biofilm infections; however, substantial research will be necessary before adequate control of biofilm infections will be generally attainable.

  • Biofilms have been shown to be generally more resistant to antimicrobial chemotherapies than free-living bacteria. No current consensus exists regarding the mechanisms of biofilm resistance to antibacterial agents. Numerous competing theories are presently under investigation, yet the phenomenon of biofilm resistance remains a subject generating many questions but few answers.

  • Multiple factors appear to contribute to the overall resistance of biofilm bacteria. These include reduced metabolic and growth rates, protection by extracellular polymeric substances and specific resistance mechanisms conferred by the altered physiology of biofilm bacteria compared with planktonic bacteria.

  • The failure of antibacterial agents to rapidly penetrate into all areas of a biofilm has been considered as a contributing factor to biofilm resistance. Reports indicate that species-composition of biofilms and the choice of antibiotic have a marked impact on antibiotic penetration.

  • Biofilm cells have been shown by a number of investigators to have reduced growth rates, and this is believed to impact the effectiveness of antibiotics that target rapidly multiplying cells. Therefore, antibiotics such as the fluoroquinolones or macrolides may be better therapeutic choices than β-lactams when treating biofilm infections.

  • Altered physiological states of biofilm cells compared with planktonic cells have been demonstrated for a number of bacteria. The activation of specific resistance genes in biofilms has been demonstrated in a few instances. Specific resistance mechanisms should, therefore, be considered when treating biofilm infections.

  • A number of alternative approaches to antibacterial treatment have been proposed for biofilms. Many of these are non-lethal treatments that are expected to enhance the activity of currently used antibiotics. For example, manipulation of electrical fields has shown some promise in enhancing the activity of certain antibiotics against biofilms. The finding that in certain bacteria autoinducers mediate the production of virulence factors, and possibly also biofilm formation, has led to developmental work on autoinducer-blocking agents. These blocking agents are expected, in certain cases, to limit disease progression at the same time as antibiotics are being administered, and, in other cases, to act to enhance the activity of an antibiotic. Biofilm-dispersion agents are currently under development and are anticipated to result in improved access of antibiotics to bacteria, and possibly to alter the physiological status of the bacteria making them more susceptible to antibiotic exposure.

  • The current state of the field indicates that enhanced antimicrobial resistance is a general trait of biofilms and is the result of numerous specific factors which depend on the species involved, the environment of the biofilm and the antimicrobial agent used. It is expected, therefore, that the effective treatment of biofilms in the future will depend on tailoring treatment strategies to specific infection conditions rather than to any general phenomenon common to all biofilms.

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  1. Department of Biological Sciences, State University of New York, Binghamton, New York 13902, USA.  dgdavies@binghamton.edu

    • David Davies

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Glossary

CONFOCAL LASER SCANNING MICROSCOPY

A microscopy technique which uses scanning laser light to excite fluorescent dyes within a thick sample, such as a biofilm. The image is collected in two dimensions and several images can be combined in an image stack to produce a cross sectional image through a sample or to create a three-dimensional rendering of the sample. CLSM is particularly useful for imaging the positioning of biological structures within a three dimensional space.

MICROCOLONY

A microscopic aggregation of cells in a biofilm.

GINGIVITIS

Infection of the gingival crevice (periodontal pocket) of the oral cavity with a variety of microorganisms, causing inflammation of the periodontal tissue and bone loss. Caused by members of the genus Capnocytophaga, Porphyromonas, Rothia and others.

PLANKTONIC

Organisms that are free-floating in a fluid environment.

MULTIDRUG EFFLUX PUMP

A molecular pump integrated into the cell envelop of certain bacteria which is able to transport antibiotics into and out of the cell.

REGULON

A set of operons that are controlled by a single regulatory protein.

NIDUS

Latin for nest, but in this context a place or point in a host where a pathogen can develop and breed.

NOSOCOMIAL

Something acquired or originating in a hospital, such as a nosocomial infection.

COMPELEMENT

A complex of blood serum proteins of the immune system that interact sequentially with antibody–antigen complexes.

HUMORAL IMMUNE SYSTEM

Extracellular branch of the immune system mediated by antibodies.

MINIMUM INHIBITORY CONCENTRATION

The minimum concentration of a substance required to prevent growth of a microoganism.

EXOPOLYMERIC MATRIX

A network of long-chain polymers produced by microorganisms of a biofilm which supports the structure of the biofilm.

AUXOTROPH

An organism that has acquired a nutritional requirement through the process of mutation.

SPORULATION

The production an endospore by bacteria of the genera Clostridia and Bacillus.

SIGMA FACTOR

Any of several bacterial DNA-binding proteins that direct the binding of DNA-directed RNA-polymerase to the promoter of an operon.

SWARMER-TO-STALK CELL TRANSITION

Upon exhaustion of nutrients, members of the group of fruiting myxobacteria swarmer cells migrate together and undergo differentiation into stalk cells, forming a vertical structure rising above a surface.

FRUITING-BODY

A structure of the fruiting myxobacteria at the end of a stalk composed of differentiated cells which are converted to myxospores (resting bodies).

TRANSPOSON

A mobile segment of DNA that has the ability to integrate into a chromosome. Transposons usually carry genes that are used in transposition as well as other genes, often selectable markers, such as for antibiotic resistance.

AUTODISPERSION

The disaggregation of a biofilm or biofilm microcolony as a result of physiological activity of the resident microorganisms.

HAEMOLYMPH

The body fluid that bathes tissues of invertebrates having an open circulatory system.

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