MINI-REVIEW Molecular mechanisms of compounds affecting bacterial biofilm formation and dispersal Paolo Landini & Davide Antoniani & J. Grant Burgess & Reindert Nijland Received: 20 November 2009 / Revised: 22 January 2010 / Accepted: 22 January 2010 / Published online: 18 February 2010 # Springer-Verlag 2010 Abstract Bacteria can switch between planktonic forms (single cells) and biofilms, i.e., bacterial communities growing on solid surfaces and embedded in a matrix of extracellular polymeric substance. Biofilm formation by pathogenic bacteria often results in lower susceptibility to antibiotic treatments and in the development of chronic infections; thus, biofilm formation can be considered an important virulence factor. In recent years, much attention has been directed towards understanding the biology of biofilms and towards searching for inhibitors of biofilm development and of biofilm-related cellular processes. In this report, we review selected examples of target-based screening for anti-biofilm agents: We focus on inhibitors of quorum sensing, possibly the most characterized target for molecules with anti-biofilm activity, and on compounds interfering with the metabolism of the signal molecule cyclic di-GMP metabolism and on inhibitors of DNA and nucleotide biosynthesis, which represent a novel and promising class of biofilm inhibitors. Finally, we discuss the activation of biofilm dispersal as a novel mode of action for anti-biofilm compounds. Keywords Biofilm formation and dispersal . Quorum sensing . c-di-GMP . Target-directed screening . Structure-directed screening . Antimicrobial drugs Introduction Bacteria are able to switch between two different “life- styles”: single cells (planktonic mode) and biofilms. A biofilm is defined as a sessile microbial community characterized by adhesion to a solid surface and by production of a matrix, which surrounds the bacterial cells and includes extracellular polysaccharides (EPS), proteins, and DNA. Transition from planktonic cells to biofilm is regulated by a variety of environmental and physiological cues, such as bacterial cell density, nutrient availability, and cellular stress. A detailed discussion of biofilm-related cellular processes and of their molecular mechanisms goes beyond the aim of this mini-review: extensive descriptions of the biology of biofilm development can be found in excellent reviews devoted to this subject (Miller and Bassler 2001; Tamayo et al. 2007; Karatan and Watnick 2009). Biofilm and planktonic cells differ significantly in their physiology, gene expression pattern, and even morphology. Bacteria growing in biofilms are less sensitive to treatments with antimicrobial agents compared to planktonic cells (Costerton et al. 1995; Anderl et al. 2000; Ceri et al. 2001). Although the molecular mechanisms of tolerance to anti- biotics are not yet fully understood, it has been proposed that the extracellular matrix can affect penetration of antibiotics into bacterial cells. In addition, a dormant metabolic state of a fraction of biofilm cells would also contribute to their decreased antibiotic sensitivity (reviewed in Lewis 2008). Interestingly, exposure to subinhibitory concentrations of antibiotics can itself act as an environ- mental signal triggering biofilm formation (Hoffman et al. 2005; Anderson and O'Toole 2008; Nucleo et al. 2009). Since pathogenic bacteria are normally exposed to subin- hibitory concentrations of antibiotics during antimicrobial P. Landini (*) : D. Antoniani Department of Biomolecular Sciences and Biotechnology, Università degli Studi di Milano, Via Celoria 26, 20133 Milan, Italy e-mail: paolo.landini@unimi.it J. G. Burgess : R. Nijland The Dove Marine Laboratory, School of Marine Science and Technology, Newcastle University, NE30 4PZ Newcastle, UK Appl Microbiol Biotechnol (2010) 86:813–823 DOI 10.1007/s00253-010-2468-8