Bacterial biofilm formation and associated phenotypes are causative for chronic infection
in humans. The major regulators of biofilm formation in Gram-negative and Gram-positive bacteria
are nucleotide-based second messenger signaling pathways. Nucleotide-based signaling is a ubiquitous
signal transduction mechanism in all domains of life that relay changes in the extracellular or intracellular
milieu to protein or RNA effectors, leading to adaptive physiological responses. To date,
six bona fide nucleotide signaling pathways, (p)ppGpp, cAMP, cGMP, c-di-AMP, c-di-GMP and
cGAMP, have been characterized with respect to basic pathway modules and phenotypic and physiological
output. Thereby, c-di-GMP is by far the most complex signaling network with up to over 100
turnover proteins in some bacteria. While c-di-GMP is a ubiquitous regulator of the motility/sessility
switch which translates into the transition from acute to chronic infection, and (p)ppGpp has been
shown to be required for persistence, the role of other nucleotide signaling pathways is comparatively
poorly characterized. Due to their importance in chronic infections, interference with these signal
transduction systems has emerged as a strategy for the control of recurrent bacterial infections. Substantial
efforts are being placed in finding small molecules for antibiofilm chemotherapy. The purpose
of this review is to provide an overview of our current knowledge on bacterial nucleotide signaling
and to provide an up-to-date perspective on small molecules thwarting these transduction pathways.
Furthermore, we summarize the high-throughput approaches developed for the discovery of
small-molecule inhibitors of nucleotide turnover proteins or effectors from large chemical libraries.
Implications and future prospects for the control of biofilm-related infections are discussed. We also
highlight the current needs and future directions that could lead to a better understanding of these important
Keywords: Biofilm, Nucleotide signaling, c-di-GMP, c-di-AMP, cAMP, cGMP, cGAMP, (p)ppGpp, Small-molecule inhibitors.
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