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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.