Strategies for combating bacterial biofilms: A focus on anti-biofilm agents and their mechanisms of action

Figures & data

Table 1. Different methods used for biofilm quantification.

S. No.	Methods of biofilm detection	Principle	References
1	Tissue culture plate method	TCP method is a standard method for biofilm detection. It simply involves the staining of cells with crystal violet dye.	^84
2	Tube method	Crystal violet staining → A visible lining appears on the bottom and wall of tube → confirms biofilm formation	^84
3	Congo red agar method	Congo red staining → black colonies in crystalline form appears → confirms biofilm production	^85
4	Bioluminescent assay	This assay is based on the signaling based detection of metabolically active cells. It involves the catalysis of ATP and luciferin by luciferase.	^86
5	Crystal violet assay (CV assay)	The CV assay quantifies the dye bound to biofilm. It actually quantifies all biomass (live, dead and also matrix of biofilm)	^83
6	XTT reduction assay	It is mainly used for the quantification of Candida biofilms. The reagent XTT: (2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide is involved here. XTT is an age dependent assay hence mature biofilms gives low intensity of color with XTT due to less viability of cells.	^88,100
7	Scanning Electron Microscopy	This is used to study the morphology of bacteria attached on the surface and for enumeration of adhered bacteria.	^253
8	Fluorescent In-situ Hybridization (FISH)	This is used to visualize the patterns of microbial colonization and the composition of microbial communities.	^108
9	Confocal scanning laser microscopy	This gives the 3-dimensional view of the microbial community. It can show the focused part as well as the part out of focus.	^90-92
10	Infrared spectroscopy	This technique is used to study molecules such as proteins, polysaccharides, metabolites essential for biofilms. It also gives the information about different hydrogen bonding states of water. Using Attenuated Total Reflectance Infrared (ATR-IR spectroscopy, the early biofilm development stages including bacterial attachment and growth can be studied.	^94,95
11	Piezoelectric sensors	These monitors the shift in the frequency due to accumulation of mass on the surface of sensor	^87

Table 2. Different anti-biofilm molecules and their target bacteria.

S.N.	Anti-biofilm molecules	Source	Target bacteria	MIC/MBC/MBIC/IC50 values	Reference
1.	Epigallocatechin gallate (EGCG)	Camellia sinesis (Green tea)	Acinetobacter baumannii,	MIC = 64–512 µg/ml	^254
			Pseudomonas aeruginosa,
			Staphylococcus aureus,	MBC = 64–1024 µg/ml
			Escherichia coli,
			Stenotrophomonas maltophilia
2.	Ellagic acid	Camellia sinensis	Streptococcus dysgalactiae	MIC=4µg/ml	^245
3.	Esculetin	Santolina oblongifolia, Alchemilla speciose, Tagetes lucida	S. aureus	MIC >512 µg/ml	^245
4.	Fisetin	Fragaria ananassa, Malus domestica, Vitis vinifera, Allium cepa, Solanum lycopersicum, Cucumis sativus	S. aureus	MIC =64 µg/ml	^245
			Streptococcus dysgalactiae	MIC = 64 µg/ml
5.	Reserpine	Rauwolfia vomitoria, Rauwolfia serpentine	Klebsiella pneumoniae	MIC= 1000 µg/ml MBIC = 15.6 µg/mL	^255
6.	Quercetin	Usnea longissima	P. aeruginosa,	MIC= 80 µg/ml	^256
			K. pneumoniae
7.	Linoleic acid	Hydrastis canadensis,	K. pneumoniae	MIC = 250 µg/ml MBIC = 31.2 µg/ml	^255
		Coptis chinensis, Berberis aquifolium, B. vulgaris, B. aristata
8.	Berberine	Berberis aquifolium, B. vulgaris, B. aristata	K. pneumoniae	MIC = 2000 µg/ml MBIC = 62.5 µg/ml	^255
9.	Chitosan	Chitin	K. pneumoniae	MIC = 500 µg/ml MBIC= 62.5 µg/ml	^255
10.	Eugenol	Ocimum plants,	K. pneumoniae	MIC = 250 µg/ml MBIC = 62.5 µg/ml	^255,257
		Syzigium aromaticum
			S. mutans	MIC = 0.3125 µg/ml
11.	Curcumin	Curcuma longa	K. pneumoniae	MIC = 12500 µg/ml MBC = 250 µg/ml	^255
			Helicobacter pylori	MBC = 8 µg/ml
12.	Synthetic halogenated furanone (F-56)	Derived from natural furanone	P. aeruginosa,	—	^123
			Serratia liquifaciens
13.	Peptide 1018	-	P. aeruginosa	MIC = 64 µg/ml	^134
				MBIC50 = 5 µg/ml
				MBIC100 = 10 µg/ml
			E. coli	MIC = 32 µg/ml
				MBIC50 = 8 µg/ml
				MBIC100 = 10 µg/ml
			A. baumannii	MIC = 128 µg/ml
				MBIC50 = 2 µg/ml
				MBIC100 = 10 µg/ml
			K. pneumoniae,	—
			S. aureus,
			S. typhimurium,
			Burkholderia cenocepacia	MIC>256 µg/ml
				MBIC50 = 2 µg/ml
				MBIC100 = 10 µg/ml
14.	CFT073 group-II capsular polysaccharide (Serotype K2)	Produced by extra intestinal E.coli of phylogenetic group B2 or D	E. coli,	—	^225
			P. aeruginosa,
			K. pneumoniae,
			S. aureus
15.	Pel polysaccharide	P. aeruginosa	S. aureus	—	^225,229,258
16.	Psl polysaccharide	P. aeruginosa	S. aureus	—	^225,229,258
17.	Sophorolipid (Biosurfactant)	Produced on microbial cells or excreted extracellular hydrophobic and hydrophilic moeities	Cupriavidus	5%(v/v)	^191
			necator,
			Bacillus subtilis, S. aureus
18.	Colistin (PolymixinE)	Paenibacillus polymyxa	S. maltophilia	MIC = 158 µg/ml	^254
				MBC = 256 µg/ml
	Polymyxin B	—	P. aeruginosa,	MIC = 158 µg/ml	^259
			S. aureus,
			E. coli	MBC = 256 µg/ml
19.	Lantibiotics: Nisin	Lactococcus lactis	S. aureus,	—	^189,190
			Staphylococcus epidermis
	Subtilin	B. subtilis strain ATCC6633	Lactococcus lactis	MIC=1µg/ml
	Epidermin	Staphylococcus epidermidis Tu3298	Lactococcus lactis	MIC = 4–8 µg/ml
	Gallidermin	Staphylococcus gallinarum Tu3928	S. aureus	MIC = 0.5µg/ml
			S. epidermidis	MIC = 2.0µg/ml
20.	Antimicrobial peptide (AMP): LL-37	Human cationic host defense peptide	P. aeruginosa,	MIC = 0.5 µg/ml	^259,260,171,179,201-203
			S. aureus,
			E. coli
	Lytic peptide (PTP-7)	Synthetic analog from Gaegurin 5	P. aeruginosa,	MIC = 2–16 µM
			S. aureus,
			E. coli
	Sushi peptides	Derived from sushi-3 domain of Factor C, which is a LPS-sensitive serine protease of horseshoe crab coagulation cascade	P. aeruginosa,	—
			S. aureus,
			E. coli
	PMAP-23	Cathelicidin-derived peptide identified from porcine leukocytes	P. aeruginosa,	—
			S. aureus,
			E. coli
	PR-39	Isolated from the pig's small intestine	P. aeruginosa,	MIC = 0.94 µM
			S. aureus,
			E. coli
	Buforin-II	Derived from Buforin-I (stomach tissue of Bufobufo gargarizans)	P. aeruginosa,	MIC = 0.25–4.0 µg/ml
			S. aureus,
			E. coli
	Indolicidin	From cytoplasmic granules of bovine neutrophils	P. aeruginosa,	MIC = 50 µg/ml
			S. aureus,
			E. coli
	Pyrrhocoricin		P. aeruginosa,	IC50<0.3 µM
			S. aureus,
			E. coli
	Microcin B17	Post-translationally modified peptide that is produced by E. coli containing the plasmid-borne MccB17 operon	E. coli	IC50 = 0.9 µM	^261
21.	Chelating agents: (a)Sodium citrate (b)Tetrasodium EDTA (c) Disodium-EDTA		Staphylococcus species,	MIC ≥ 0.5%	^260
			P. aeruginosa
22.	Tannic acid	Caesalpinia spinosa, Rhus semialata, Quercus infectoria, Rhus coriaria	S. aureus	—	^146
23.	Enzymes: Deoxyribonuclease I, glycoside hydrolase (dispersin B)		Staphylococcus and Enterococcus	—	^121,260
24.	Bacteriophage-encoded endolysin (PlyC)		Streptococcus pyogenes	MIC = 0.04–0.08 µg/ml	^150
				MBC = 0.02–0.08 µg/ml
				MBIC = 1.25–5 µg/ml
25.	Silver		P. aeruginosa, S. proteamaculans	MBIC = 100000– 150000 µg/ml	^193
26	Octenidine hydrochloride		P. aeruginosa,	—	^193
			S. aureus
27	Chlorhexidine		P. aeruginosa,	—	^193
			S. aureus
28	Cadexomer iodine		S. aureus	—	^193
			P. aeruginosa
29	Polyhexamethylene biguanide		P. aeruginosa	—	^193
30	Usnic acid	A secondary lichen metabolite	S. aureus, C. albicans	—	^132,175

Table 3. Mechanisms followed by different Anti-biofilm molecules.

S. N.	Mechanism of action	Molecules associated	Reference
1.	Inhibition of AHL-mediated quorum sensing pathway	Halogenated furanone compounds, Quercetin	^123,256
2.	Inhibition of (p)ppGpp regulated stringent response	Peptide-1018, Peptide-1038	^134,140
3.	Dispersion of Extracellular Polymeric Substance (EPS) of biofilm	Deoxyribonuclease I and glycoside hydrolase dispersin B	^259
4.	Cleavage of peptidoglycan	Tannic acid, Endolysins (PlyC), Epigallocatechin gallate (EGCG)	^146,150,159
5.	Biofilm disassembly	A cyclic autoinducing peptide (AIP), Nuclease, extracellular proteases (eg. sarA, sigB, Esp), antiamyloid molecules (AA-861, parthenolides), D- Tyrosine, Ethyl-pyruvate	^77,160,168,172
6.	Neutralization/disaggregation of LPS	Polymyxin (B and E), Gramicidin S, Sushi peptides, PMAP-23	^177,180,262
7.	Alteration of membrane permeabilization	Lantibiotics (nisin, gallidermin), Lytic peptides (PTP-7), Sophorolipids, Polyhexamethylene biguanide, Chlorhexidine, Pentasilver hexaoxoiodate	^179,186,191,192
8.	Inhibition of cell division or cell survival	Pyrrhocoricin, Microcin B17	^194,198
9.	Inhibition of macromolecule synthesis and adhesion of cells	Buforin II, PR-39, Indolicidin, LL-37, Bacteriocins, Cadexomer iodine, Mannosides, Pilicides	^39,193,201,202,204,209,221,222
10.	Inhibition of biofilm by polysaccharides	EPS273, Psl and Pel, K2, PAM galactan, A101, PslG, Polysaccharides of algae, plants and animals	^224,225,227,228,230,235
11.	Inhibition of c-di-GMP signaling system	LP 3134, LP 3145, LP 4010, LP 1062, ebselen, ebselen oxide Desformylflustra bromine	^6,238,239
12.	Inhibition of curli biosynthesis	Analogs of FN075 and BibC6 of ring-fused 2-pyridones	^169

Figure 1. Schematic representation of overview of the targets of anti-biofilm molecules.

Figure 2. Structures of the anti-biofilm molecules that inhibit AHL-mediated quorum sensing. (a) EGCG²⁶³, (b) Quercetin²⁶⁴, (c) Synthetic halogenated furanone²⁶⁵, (d) Reserpine²⁶⁶, (e) Curcumin²⁶⁷, (f) Ellagic acid²⁶⁸, (g) Tannic acid²⁶⁹.

Figure 3. Structures of the anti-biofilm molecules that inhibit the stringent response. (a) Eugenol²⁷⁰.

Figure 4. Structure of anti biofilm molecules that disassemble the biofilm. (a) Berberine²⁷¹, (b) Usnic acid²⁷².

Figure 5. Structures of the anti-biofilm molecules that inhibit lipopolysachharides. (a) Colistin (Polymixin E)²⁷³, (b) Polymixin B^274,275, (c) Gramicidin S²⁷⁶, (d) Sushi peptide (S1 domain)¹⁸¹.

Figure 6. Structures of the anti-biofilm molecules that alter the membrane potential or membrane permeabilization. (a) Nisin^277,278, (b) Subtilin²⁷⁹, (c) Epidermin²⁸⁰, (d) Gallidermin²⁸¹, (e) Chlorhexidine²⁸², (f) Sophorolipid²⁸³, (g) Polyhexamethylene biguanide²⁸⁴.

Figure 7. Structures of the anti-biofilm molecules that inhibit cell division and survival. (a) Microcin B17^285,286, (b) Chitosan²⁰⁰, (c) Pyrrhocoricin²⁸⁷, (d) Sodium Citrate²⁸⁸, (e) Tetrasodium EDTA²⁸⁹.

Figure 8. Structures of the anti-biofilm molecules that Inhibit adhesion molecule synthesis and function (a) Cadexomer iodine²⁹⁰, (b) LL-37²⁹¹.

Figure 9. Structures of the anti-biofilm molecules that inhibit polysaccharides. (a) Psl polysaccharide^292,293, (b) Pel polysaccharide²⁹⁴, (c) CFT073 group-II capsular polysaccharide (Serotype K2)²⁹⁵.

Figure 10. Structures of the antibiofilm molecules with unknown mechanism of action. (a) Esculetin²⁹⁶, b) Fisetin²⁹⁷, c) Octenidine hydrochloride²⁹⁸.

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