Abstract
In most ecosystems, bacteria exist primarily as structured surface-associated biofilms that can be highly tolerant to antibiotics and thus represent an important health issue. Here, we explored drug repurposing as a strategy to identify new antibiofilm compounds, screening over 1,000 compounds from the Prestwick Chemical Library of approved drugs for specific activities that prevent biofilm formation by Escherichia coli Most growth-inhibiting compounds, which include known antibacterial but also antiviral and other drugs, also reduced biofilm formation. However, we also identified several drugs that were biofilm inhibitory at doses where only a weak effect or no effect on planktonic growth could be observed. The activities of the most specific antibiofilm compounds were further characterized using gene expression analysis, proteomics, and microscopy. We observed that most of these drugs acted by repressing genes responsible for the production of curli, a major component of the E. coli biofilm matrix. This repression apparently occurred through the induction of several different stress responses, including DNA and cell wall damage, and homeostasis of divalent cations, demonstrating that biofilm formation can be inhibited through a variety of molecular mechanisms. One tested drug, tyloxapol, did not affect curli expression or cell growth but instead inhibited biofilm formation by suppressing bacterial attachment to the surface.IMPORTANCE The prevention of bacterial biofilm formation is one of the major current challenges in microbiology. Here, by systematically screening a large number of approved drugs for their ability to suppress biofilm formation by Escherichia coli, we identified a number of prospective antibiofilm compounds. We further demonstrated different mechanisms of action for individual compounds, from induction of replicative stress to disbalance of cation homeostasis to inhibition of bacterial attachment to the surface. Our work demonstrates the potential of drug repurposing for the prevention of bacterial biofilm formation and suggests that also for other bacteria, the activity spectrum of antibiofilm compounds is likely to be broad.
Highlights
In most ecosystems, bacteria exist primarily as structured surface-associated biofilms that can be highly tolerant to antibiotics and represent an important health issue
In order to identify new antibiofilm compounds, we screened 1,280 off-patent drugs approved for human use by the Food and Drug Administration (FDA) from the Prestwick Chemical Library for their ability to suppress the growth as well as the formation of submerged biofilms of E. coli K-12 strain W3110, a common biofilm model [19, 23]
This group of compounds included mostly established antibacterial drugs but, more surprisingly, antiviral and other drugs. These novel antibacterial compounds might be promising as potential drugs, their activity spectra and mechanisms of action require future investigation. Most of these growthinhibitory compounds proportionally reduced the biomass of surface-attached cells in a crystal violet (CV) assay (Fig. 1), suggesting that their effect on biofilm formation is the consequence of growth inhibition
Summary
Bacteria exist primarily as structured surface-associated biofilms that can be highly tolerant to antibiotics and represent an important health issue. We observed that most of these drugs acted by repressing genes responsible for the production of curli, a major component of the E. coli biofilm matrix This repression apparently occurred through the induction of several different stress responses, including DNA and cell wall damage, and homeostasis of divalent cations, demonstrating that biofilm formation can be inhibited through a variety of molecular mechanisms. CsgD, which regulates the inverse coordination between planktonic motile and biofilm sessile lifestyles, is mediated by mutual inhibition between the S/CsgD curli and flagellar gene expression control cascades [23, 24] The latter consists of three classes of flagellar genes, where the master regulator FlhDC (class I) induces the expression of class II (middle) genes, including the flagellum-specific sigma factor FliA, which in turn activates the expression of class III (late) flagellar genes [25]
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