Abstract
Bacterial resistance is a rapidly escalating threat to public health as our arsenal of effective antibiotics dwindles. Therefore, there is an urgent need for new antibiotics. Drug discovery has historically focused on bacteria growing in planktonic cultures. Many antibiotics were originally developed to target individual bacterial cells, being assessed in vitro against microorganisms in a planktonic mode of life. However, towards the end of the 20th century it became clear that many bacteria live as complex communities called biofilms in their natural habitat, and this includes habitats within a human host. The biofilm mode of life provides advantages to microorganisms, such as enhanced resistance towards environmental stresses, including antibiotic challenge. The community level resistance provided by biofilms is distinct from resistance mechanisms that operate at a cellular level, and cannot be overlooked in the development of novel strategies to combat infectious diseases. The review compares mechanisms of antibiotic resistance at cellular and community levels in the light of past and present antibiotic discovery efforts. Future perspectives on novel strategies for treatment of biofilm-related infectious diseases are explored.
Highlights
Bacterial resistance is a rapidly escalating threat to public health as our arsenal of effective antibiotics dwindles
Microorganisms predominantly live in communities: biofilms composed of tightly packed cell aggregates encased within a secreted matrix that includes exopolysaccharides, amyloid fibers and extracellular DNA [8,24,25]
The starvation-induced stringent (SOS) response has been implicated in enhanced biofilm-specific resistance towards various classes of antibiotics in organisms such as P. aeruginosa and Escherichia coli [33,35]
Summary
The discovery of penicillin opened a new era in the treatment of infectious diseases, described as the “golden age” of antibiotic research (1940–1962) [1]. As a result of the initial success of antibiotics, bacterial diseases were naively considered to be permanently defeated. With increasing use of antibiotics, more and more pathogenic bacteria developed resistance to their inhibitory effects [3]. Despite their initial effectiveness, most antibiotics have a limited life, and from their first introduction they select for pathogen variants that have intrinsic or acquired resistance mechanisms [4]. Antimicrobial resistance threatens the effective prevention and treatment of an ever-expanding range of infections. Combatting bacterial infections requires both an understanding of intracellular genetics and biochemistry, and an understanding of how the biofilm mode of life affects antibiotic uptake and resistance (Figure 1)
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