Table 6.

Biofilm-dispersing molecules. Supplemented and modified based on information provided in [6].

Dispersal Signals
Name	Summary	References
YhjH	E. coli phosphodiesterase that can be induced in vivo, led to the reduction of c-di-GMP and dispersal of biofilms on silicone implants in a mouse foreign body infection model.	[139]
PA2133	A functional protein gene containing an EAL domain to degrade c-di-GMP, and can inhibit biofilms formation of P. aeruginosa, resulting in much sparser and thinner biofilms.	[140]
Nitrate	Nitrate shows the effect of reducing intracellular levels of the second messenger c-di-GMP and inhibiting biofilm formation of P. aeruginosa, S. aureus and Burkholderia pseudomallei.	[141,188,189]
NO	An endogenously produced dispersal signal which can be generated and recognized by both prokaryotes and eukaryotes and are highly conserved. It has been shown to be involved in the dispersal of biofilms formed by P. aeruginosa, E. coli, Fusobacterium nucleatum, Serratia marcescens, V. cholerae, B. licheniformis, Shewanella woodyi, Neisseria gonorrhoeae, Pseudoalteromonas, Vibrio fischeri, S. aureus, B. subtilis, Legionella pneumophila, Nitrosomonas europaea, P. putida, C. albicans, Candida tropicalis, and Ulva linza.	[142]
Glutamate	The second molecule known to induce the release of cells from P. aeruginosa biofilms, and does so in nutrient-induced dispersion process, and may share the same mechanism with NO-induced biofilm dispersions.	[144,145,146]
C3Ds	A NO-donor prodrug that selectively release NO from the prodrug through contacting with biofilm β-lactamases, and allows targeted enhancement of bacterial killing by conventional antimicrobials at sites of biofilm infections, while also minimizing NO- mediated toxicity. It has been proved to effectively disperse P. aeruginosa biofilms in vitro.	[147]
Nitroxides	Sterically hindered NO analogues, which exert biological responses via NO-mimetic properties, and has been proved to induce biofilm dispersal in P. aeruginosa and E. coli, including carboxy-TEMPO, CTMIO and DCTEIO.	[148,149]
Cis-2-decenoic acid (CDA)	A kind of fatty acid cross-kingdom signaling molecule, also known as a diffusible signal factor (DSF), which was originally found to be produced by P. aeruginosa. This particular DSF has been shown to trigger the dispersal of biofilms formed by P. aeruginosa, E. coli, K. pneumoniae, Proteus. mirabilis, S. pyogenes, B. subtilis, S. aureus, C. albicans, Salmonella enterica, and S. mutans. It should be noted that other DSFs, such as Burkholderia diffusible signal factor (BDSF) [190] and Xanthomonas diffusible signal factor (XDSF), have been isolated and exhibited similar inductions of dispersal events [191].	[192,193,194,195]
Anti-Matrix Molecules
Rhamnolipids	A microbial-produced surfactant that, at normal levels, is important for the maintenance of mature biofilms, particularly for fluid channel maintenance and cellular migration. At elevated levels, however, these rhamnolipids have been shown to trigger the dispersal of P. aeruginosa, E. coli, S. aureus, B. subtilis, M. luteus, and Yarrowia lipolytica biofilms.	[150,151,152,153]
PSM	Surfactant-like peptides that promote biofilm disassembly in their monomeric form, by reducing the surface tension, but form amyloid-like fibers when they undergo orderly aggregations.	[154,155]
Polyamines	Polyamines such as spermidine and norspermidine have been proved to effectively inhibit the biofilm formation of B. subtilis and S. aureus. However, in some cases both spermidine and norspermidine serve as signaling molecules that induce biofilm formation.	[156,157,158,159]
D-amino acids	D-isoforms of certain amino acids, including D-Leu, D-Met, D-Trp, D-Tyr, and D-Phe, have been shown to cause the disassembly of biofilms through multiple hypothesized mechanisms, including (1) inhibition of genes involved in EPS production; (2) incorporation of D-amino acids into the bacterial cell wall, resulting in the loss of cell-surface fibers which are vital to biofilm formation. D-amino acids have been demonstrated to exhibit efficacy against S. aureus, P. aeruginosa, and B. subtilis biofilms.	[161,163,164,165]
Urea	An amide that is theorized to break down biofilms by disrupting the hydrogen bonds that are vital for EPS mechanical stability, and has exhibited dispersal ability against S. epidermidis, P. aeruginosa and K. pneumoniae biofilms.	[196,197]
Chitosan	A polycationic macromolecule derived from the polysaccharide chitin, and has been shown to penetrate and possibly disrupt biofilms formed by Cryptococcus neoformans, L. monocytogenes, P. fluorescens, Bacillus cereus, S. enterica, C. albicans, and P. aeruginosa. It is important to note that it has not been proved that chitosan has any direct effect on the biofilm matrix, and it is possible that the molecule achieves biofilm disruption by penetrating the matrix and acting on the microbes themselves.	[198,199,200,201,202]
Sequestration Molecules
BdcA	A protein that reduces unbound c-di-GMP concentrations by binding to, but not degrading, the molecules, hindering the activation of biofilm-related cellular processes, and has been shown to disperse biofilms formed by E. coli, P. aeruginosa, P. fluorescens, and Rhizobium meliloti.	[168,169,170]
EDTA	Ethylenediaminetetraacetic acid (EDTA) is a metal-ion chelator that can sequester EPS-matrix-stabilizing ions, triggering biofilms dispersal of P. aeruginosa, H. influenzae, S. epidermidis, C. tropicalis, and Enterococcus faecalis.	[203,204,205,206,207,208]
Lactoferrin	An iron-binding protein from the innate immune system which triggers active dispersal through chelating irons, an essential bacterial nutrient and global regulator of a variety of processes, including biofilm development and growth. It has been shown to be effective against P. aeruginosa, E. coli, S. aureus, E. faecalis and S. epidermidis biofilms.	[209,210]
Metabolic Interference Molecules
Deferoxamine, Deferasirox	FDA-approved iron chelators that have been proved to interfere with bacterial iron metabolism, preventing the formation of P. aeruginosa biofilms and reducing established biofilm biomass.	[175]
L-Arg	Exogenous amino acids can affect both biofilm metabolism and development, and it has been proved that L-Arg can effectively disrupt biofilm of Streptococcus gordonii and S. mutans.	[176,178]
D-Arg	D-Arg can inhibit and dissociate EPS production from biofilm and can alter the Porphyromonas gingivalis biofilm structure in relatively high concentrations.	[181]
L-Met	L-Met can up-regulate DNase gene expression and target eDNA components in biofilms. It has been proved to be effective on biofilm formed by P. aeruginosa.	[182]
Ga	A transition metal that is chemically similar to Fe, thus it can substitute for Fe in many biologic systems and inhibit Fe-dependent processes. It was shown that Ga can inhibit P. aeruginosa growth and biofilm formation and kill planktonic and biofilm bacteria.	[187]