title: Identification of small molecules inhibiting diguanylate cyclases to control bacterial biofilm development.
abstract: Biofilm formation by pathogenic bacteria is an important virulence factor in the development of numerous chronic infections, thereby causing a severe health burden. Many of these infections cannot be resolved, as bacteria in biofilms are resistant to the host's immune defenses and antibiotic therapy. An urgent need for new strategies to treat biofilm-based infections is critically needed. Cyclic di-GMP (c-di-GMP) is a widely conserved second-messenger signal essential for biofilm formation. The absence of this signalling system in higher eukaryotes makes it an attractive target for the development of new anti-biofilm agents. In this study, the results of an in silico pharmacophore-based screen to identify small-molecule inhibitors of diguanylate cyclase (DGC) enzymes that synthesize c-di-GMP are described. Four small molecules, LP 3134, LP 3145, LP 4010 and LP 1062 that antagonize these enzymes and inhibit biofilm formation by Pseudomonas aeruginosa and Acinetobacter baumannii in a continuous-flow system are reported. All four molecules dispersed P. aeruginosa biofilms and inhibited biofilm development on urinary catheters. One molecule dispersed A. baumannii biofilms. Two molecules displayed no toxic effects on eukaryotic cells. These molecules represent the first compounds identified from an in silico screen that are able to inhibit DGC activity to prevent biofilm formation.
authors.affiliation: a Wound Infections , Walter Reed Army Institute of Research , Silver Spring , MD , USA ;
authors.forename: Karthik
authors.initials: K
authors.lastname: Sambanthamoorthy
authors.forename: Chunyuan
authors.initials: C
authors.lastname: Luo
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Pattabiraman
authors.forename: Xiarong
authors.initials: X
authors.lastname: Feng
authors.forename: Benjamin
authors.initials: B
authors.lastname: Koestler
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waters
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Palys
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000502:physiology; D018441:Biofilms / Q000187:drug effects*; D003198:Computer Simulation; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D019761:Phosphorus-Oxygen Lyases / Q000037:antagonists & inhibitors*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries
chemical_list: D029968:Escherichia coli Proteins; D054852:Small Molecule Libraries; D019761:Phosphorus-Oxygen Lyases; C060720:diguanylate cyclase; D006152:Cyclic GMP