Biofilm-related infections: bridging the gap between clinical management and fundamental aspects of recalcitrance toward antibiotics

Abstract

Surface-associated microbial communities, called biofilms, are present in all environments. Although biofilms play an important positive role in a variety of ecosystems, they also have many negative effects, including biofilm-related infections in medical settings. The ability of pathogenic biofilms to survive in the presence of high concentrations of antibiotics is called "recalcitrance" and is a characteristic property of the biofilm lifestyle, leading to treatment failure and infection recurrence. This review presents our current understanding of the molecular mechanisms of biofilm recalcitrance toward antibiotics and describes how recent progress has improved our capacity to design original and efficient strategies to prevent or eradicate biofilm-related infections.

FIG 1

Biofilm-related infections. (Adapted from reference with permission of the publisher and from reference .)

FIG 2

Summary of the main mechanisms involved in recalcitrance of biofilms toward antibiotics. (Adapted from reference with permission of the publisher.)

FIG 3

Main phenotypic characteristics of persister cells. (A) Persisters (red bacteria) are present under planktonic and biofilm conditions and account for only a small subset of the whole population (0.001% to 0.1%). (B) Persisters are not resistant mutants. After treatment of a bacterial population with a bactericidal antibiotic, all nonpersister cells die, giving a biphasic survival curve. After a rapid decrease, surviving cell fractions reach a plateau corresponding to persisters (red curve). After antibiotic removal and addition of rich medium, persisters resume growth. The population obtained displays a susceptible phenotype toward the antibiotic (blue curve). If a resistant mutant were present, it would be able to grow in the presence of the antibiotic (dotted line). Panel B was inspired by previous reports (13, 31, 94).

FIG 4

Main factors involved in generation of persisters. The stringent response (A) and the SOS response (B) are now considered pivotal in the generation of persisters. (C) Connection between stochasticity and persister genesis. In exponential-phase cultures, due to stochasticity, only a few bacteria reach the required threshold of a toxic molecule that is necessary to switch to the persister state (in red). Due to the factors described in panels A and B, there is an increased level of molecules inducing persistence; thus, more bacteria reach the threshold and become persisters. Note that most of these studies were conducted with planktonic bacteria. Panel C was inspired by a previous report (103).

FIG 5

Antibiofilm strategies arising from fundamental research. Approaches to preventing formation of biofilms are depicted in blue; approaches to eradicating an established biofilm are shown in red. Persister cells are shown in red. AG, aminoglycosides; c-diGMP, cyclic di-GMP; FQ, fluoroquinolones; NAC, N-acetylcysteine; QS, quorum sensing; ROS, reactive oxygen species.