Target-based screening for natural products against Staphylococcus aureus biofilms

Figures & data

Figure 1. Potential S. aureus biofilm formation contact surfaces along the whole food supply chain.

Figure 2. Scheme of the network pathways governing biofilm formation and disruption in S. aureus. PIA, Polysaccharide intercellular adhesin; eDNA, Extracellular DNA; QS, Quorum sensing; LuxS, S-ribosylhomocysteine lyase; AI-2, Interspecies autoinducer; Agr, Accessory gene regulator protein locus; Spx, Global transcriptional regulator Spx; IcaR, Biofilm operon icaADBC HTH-type negative transcriptional regulator; SarA, Transcriptional regulator; SarR, HTH-type transcriptional regulator; σB, RNA polymerase sigma factor; PSMs, phenol-soluble modulins; CidA, Holin-like protein.

Table 1. Natural Products screening for inhibiting biofilm formation or removing pre-formed biofilm targeted adhesion proteins.

Class	Source	Compounds	Structure	MIC	Concentration, contact time (Biofilm formation inhibition rate)	Concentration, contact time (Pre-formed biofilm removal activity)	Mechanisms of action (Targets)	References
	Essential oils from Alaska yellow cedar trees, some herbs, and grapefruit	(+)-nootkatone		200 μg/mL	100 μg/mL, 24 h (99.8%); 50 μg/mL, 24 h (>90%) 25 μg/mL, 24 h (47%)	200 μg/mL, 24 h (50%)	spa	(Farha et al. 2020)
Flavanol	Tea, broccoli	Kaempferol		>1024 µg/mL	64 µg/mL, 512 µg/mL, 12 h (80%, 90%)	NS	Srt A, fnbpA, fnbpB, clfA, clfB, sarA	(Ming et al. 2017)
Flavonoid	Licorice	Licochalcone A		4 μg/ mL	NS	64 μg/ mL, 24 h, 48 h 5000–6000 mm thickness reduction	fnbB, clfA	(Shen et al. 2015)
	Tea, berries and red wine	Myricetin		>200 μM >1024 μg/ml	100 μM, 24 h (≈75%) 64 µg/mL, 18–24 h (≈60–70%)	NS	Srt A, Bap	(Silva et al. 2017)(Lopes et al. 2017)
	Geranium phaeum, Fagopyrum esculentum	Isovitexin		>1024 μg/mL	256 μg/mL, 24 h (≥ 61% inhibition)	NS	Srt A	(Mu et al. 2018)
	Ashitaba	Chalcone		>76 μM	76 μM, 18 h (≈60%)	NS	Srt A	(B. Zhang et al. 2017)
Essential oil	Melaleuca alternifolia	Tea tree oil	NS	1–2 mg/mL	NS	2 mg/mL, 48 h (75%)	fnbB	(Zhao et al. 2018)
Phenolic	Pine needles of Cedrus deodara	3-p-trans-coumaroyl-2-hydroxyquinic acid		5 mg/mL	0.3125–2.5 mg/mL, 24 h (53–88%)	No disruption effect	Srt A, ClfB, FnbpB, etc.	(Wu et al. 2019b) (X. Liu et al. 2021)
Phenolic acid	Salvia miltiorrhiza Bunge	Salvianolic acid A		>1024 μg/ml	256 μg/mL, 18 h (33.14%)	NS	Srt A	(Mu et al. 2020)
Phenolic	Oak	Tannic acid		40–160 µg/mL	20–80 µg/mL, 24 h (34%–100%)	NS	Peptidoglycan	(Dong et al. 2018)
Phenols	Loquat leaves	Resveratrol		350 μg/mL	100 μg/mL, 18 h (39.85%±0.18)	150 μg/mL, 18 h (23.42%±0.15 removal	Surface proteins and capsular polysaccharides. (cap)	(Qin et al. 2014)
Anthraquinone	P. cuspidatum and R. palmatum	Emodin		4–8 μg/ mL	4 μg/ mL, 24 h (≈60% inhibition)	NS	Srt A	(Yan et al. 2017)
Bibenzyl	Dendrobium chrysotoxum	Erianin		512 μg/mL	64 μg/mL, 24 h (≈50%)	NS	Srt A	(Ouyang et al. 2018)
Terpenoid	Loquat leaves	Ursolic acid		37 μg/mL	30 μg/mL, 18 h (66.30%±0.18)	NS	Reduce adhesins (isdB, srtB, ebh, and sdrC), amino acids metabolism (arcA, aur)	(Qin et al. 2014)

NS = Not specified

Figure 3. Mechanism of surface protein anchoring to the cell wall mediated by sortase A. Surface proteins precursors P1 with a C-terminal LPXTG motif are produced in the cytoplasm. SrtA is responsible for cleaving the amide bond between the threonine and glycine of the motif and catalyzing the formation of amide bond to form a Gly5 cross-bridge between the surface protein fragment and the peptidoglycan biosynthesis intermediate lipid II (Gao et al. 2016). Key molecule can be seen as antibiofilm and antibacterial targets, encircled in red. P1, P2, P3 represent Surface proteins precursors in different stages. MSCRAMMs: microbial surface components recognizing adhesive matrix molecule.

Table 2. Natural Products screening for inhibiting biofilm formation or removing pre-formed biofilm targeted EPS.

Class	Source	Compounds	Structure	MIC	Concentration, contact time (Biofilm formation inhibition rate)	Concentration, contact time (Pre-formed biofilm removal activity)	Mechanisms of action (Targets)	References
Terpenoid	Essential oils from Alaska yellow cedar trees, some herbs, and grapefruit	(+)-nootkatone		200 μg/mL	100 μg/mL, 24h (99.8%); 50 μg/mL, 24h (>90%) 25 μg/mL, 24h (47%)	200 μg/mL, 24h (50%)	IcaA, sarA,	(Farha et al. 2020)
	B. monnieri	Bacoside A		400 μg/mL	NS	200 μg/mL, 24h (≈90%)	EPS	(Parai et al. 2017)
	Litsea cubeba	Citral		500 μL/mL	NS	2000 μL/L, 45 °C, 60 min (> 5 log CFU reduction)	EPS	(Espina et al. 2017)
	Cabreuva oil	Farnesol		≈2 mg/mL	44 μg/mL, 24h (reduce significantly)	1–2 mg/mL, 20 min, (18–78%)	PIA	(Jabra-Rizk et al. 2006) (Unlu et al. 2018)
Carbohydrate	Marine biowaste	Chitosan		200–600 μg/mL	100 μg/mL, 24 h, (95.44%–56%)	100 μg/mL, overnight (60.69%)	EPS, slime synthesis	(Rubini et al. 2018a)
	Geranium	1,2,3,4,6-Penta-O-Galloyl-D-Glucopyranose		>50 μM	6.25, 12.5, 25 and 50 μM ,6 h (75%–99%)	NS	EPS	(Lin et al. 2011)
Essential oil	Melaleuca alternifolia	Tea tree oil	NS	0.25 mg/mL	0.25 mg/mL, 24 h, 51.23%	2 mg/mL, 24 h, 100%	EPS	(Zhao et al. 2018) (T. Liu et al. 2020)
	Peppermint	Menthol, menthone, (+)-isomenthone, and (+)-isomenthol	NS	5 mg/mL 3.1 μL/mL	0.25 mg/mL-2 mg/mL, 24 h, (≈1–6 log CFU/mL inhibition) 3.1 μL/mL, 24 h, 74.7%	3.1 μL/mL, 24 h, 67.5%	EPS	(Kang et al. 2019) (Bazargani and Rohloff 2016)
	Pogostemon heyneanus	(E)-nerolidol, acetophenone, Linalool and (E)-cinnamaldehyde	NS	2–6%v/v	0.5–3%v/v, 24 h (60–80%)	1–3% v/v, 24 h (70–80%)	Reduce EPS and slime synthesis	(Rubini et al. 2018b)
	Cinnamomum tamala		NS	2–6%v/v	1–3%v/v, 24 h (55–65%)	1–3% v/v, 24 h (60–65%)	Reduce EPS and slime synthesis	(Rubini et al. 2018b)
Acyclic sesquiterpene	Pogostemon heyneanus	Nerolidol		0.025%v/v	0.0125%v/v, 24 h (88%)	0.0125%v/v, 24 h (85%)	Reduce EPS and slime synthesis	(Rubini et al. 2018b)
Flavonoids	Licorice	Licochalcone A		1–8 μg/mL	MIBC: 8–64 μg/ mL 16–128 μg/ mL, thinner	NS	sarA, cidA, icaA	(Shen et al. 2015)
	Ruta leaves, Tobacco leaves, et al.	Rutin		800–1600 μg/ mL	1/16MIC-1/2MIC, 48 h (19–88%)	NS	Exopolysaccharide, PIA	(Al-Shabib et al. 2017b)
	Tea, berries and red wine	Myricetin		>200 μM >1024 μg/mL	100 μM, 24 h (≈75%) 64 µg, 18–24 h (≈60–70%)	NS	EPS	(Silva et al. 2017)(Lopes et al. 2017)
	Scutellaria spp.	Baicalein		256 μg/mL	32 μg/mL, 3 days (≈60%–80% inhibition)	64 μg/mL, 3 days, 7 days (≈1.5log CFU/mL reduction)	icaA, sarA	(Chen et al. 2016)
Pyranonaphthoquinone	Mitracarpus frigidus	Psychorubrin		5–80 μg/mL	2.5–80 μg/mL, 24 h (12%–52%)	2.5–80 μg/mL, 24 h (46%–85%)	EPS	(Lemos et al. 2018)
Polyhydroxylphenolic	Gall, tea, et al.	Gallic acid		2–8 mg/mL	2 mg/mL,24 h (31.7%)	4 mg/mL, 24 h (5.55 log CFU/ mL reduction)	Ica operon	(M. Liu et al. 2017)
Trihydroxyanthraquinone	P. cuspidatum and R. palmatum	Emodin		4–8 μg/ mL	4 μg/ mL, 24 h (≈60%)	NS	eDNA, cidA, icaA, dltB, and sarA	(Yan et al. 2017)
Phenols	Magnolia Bark	Honokiol		4–16 μg/ mL	NS	MBIC: 32–128 μg/ mL	eDNA, PIA, icaA, sarA, cidA	(Li et al. 2016)
	Caesalpinia sappan L	Brazilin		32 µg/mL	8–32 µg/mL, 24 h, 48 h (≈26–52%, 41%–60%)	64 µg/mL, 48 h (0.35 log CFU/mL reduction)	icaA	(Peng et al. 2018)
	Oregano oil	Carvacrol		>1 mM	0.5–1 mM, 24 h (≈25%–80%)	500μL /L, 45 °C, 60 min (> 5 log CFU reduction)	EPS	(Burt et al. 2014) (Espina et al. 2017)
Lipopeptides	Bacillus subtilis	Surfactin		32 μg/mL	8–16 μg/mL, 24 h (40–70%);	500 μg/mL, 1000 μg/mL, 2000 μg/mL,1–4 h (50%–90%)	icaA, icaD	(J. Liu et al. 2019)
Diterpene alkaloid	Totarol tree, Coptidis rhizoma	Totarol, Berberine chloride		0.5–2 μg/mL, 32–128 μg/mL	NS	4 μg/mL ≈ 37% 128 μg/mL (≈45%) Two compounds Combination, 24 h (84.5%)	icaA sarA, cidA	(Guo et al. 2015)
Aldehydes	Camphor leaves	Cinnamaldehyde		0.06–2 mg/mL	0.24 mg/mL, 6 h (57.1% ± 2.0% reduction in metabolic activity)	1–2 mg/mL, 20 min, (22–78%)	eno, ebps, fib, icaA, icaD SarA	(Kot et al. 2020) (Unlu et al. 2018)

NS = Not specified

Figure 4. Mechanism of quorum sensing system (QS) Agr/AIP for biofilm regulation in S. aureus. The precursor of autoinducer peptide (AIP) is produced in the cytoplasm mediated by AgrD, Subsequently, AgrB is involved in the externalization of mature AIP. AgrC-AgrA two component system is activated at an AIP threshold concentration. Phosphorylated AgrA activates transcription of RNAII and RNAIII. The RNAIII inhibits biofilm by down- regulating adhesion surface proteins. AgrA increases transcription of the psmα and psmβ operons, encoding PSM peptides which improve biofilm dispersion. Key molecule can be seen as antibiofilm and antibacterial targets, encircled in red (Xie et al. 2019; Srivastava et al. 2014; Nicod et al. 2014).

Table 3. Natural products screening for inhibiting biofilm formation or removing pre-formed biofilm targeted QS system.

Class	Source	Compounds	Structure	MIC	Concentration, contact time (Biofilm Inhibition rate)	Concentration, contact time (Pre-formed biofilm removal activity)	Mechanisms of action (Targets)	References
Essential oils	Thymus daenensis	Carvacol, γ-terpinene, p-cymene, etc.	NS	0.0625 μL/ mL;	0.0312 μL/mL), 24 h (≈80%–90%)	0.0625 μL/mL, 24 h (≈30%–40%)	QS/Agr	(Sharifi et al. 2018)
	Satureja hortensis	Thymol, γ-terpinene and p-cymene, etc.	NS	0.125 μl/ mL	0.0625 μl/mL, 24 h (≈60%)	0.0625 μL/mL, 24 h (≈40%–45%)	QS/Agr	(Sharifi et al. 2018)
Monoterpenoid	Essential oils of Eucalyptus globulus	1,8-cineole		0.048–3.125 mg/mL	0.095-0.003 mg/mL, 24 h (≈70%–97% );	MIC-4MIC, 24 h (77.46 ± 1.91–90.81 ± 4.05%)	QS/Agr	(Merghni et al. 2018)
Lipopeptides	Bacillus subtilis	Surfactin		32 μg/mL	8–16 μg/mL, 24 h (40–70%);	500 μg/mL, 1000 μg/mL, 2000 μg/mL, 1–4 h (50%–90%)	QS (LuxS/AI-2)	(J. Liu et al. 2019)
Extracellular protease	Actinomycetes culture supernatants	Proteinase K	NS	<0.1 μg /mL	0.1 μg /mL, > 80%	NS	Detach biofilm and enhance biofilm dispersal	(Park et al. 2012)
Polyphenols	Caesalpinia sappan L	Brazilin		32 µg/mL	8–32 µg/mL, 24 h, 48 h (≈26–52%, 41%–60%)	64 µg/mL, 48 h (0.35 log CFU/mL)	QS (agrA)	(Peng et al. 2018)
Phenols	Oregano oil	Carvacrol		>1mM	0.5–1 mM, 24 h (≈25%–80% inhibition)	500 μL/L, 45 °C, 60 min (> 5 log CFU reduction)	QS	(Burt et al. 2014) (Espina et al. 2017)
	Loquat leaves	Resveratrol		350 μg/mL	100 μg/mL, 18 h (39.85%±0.18);	150 μg/mL, 18 h (23.42%±0.15)	Disturb Agr-QS	(Qin et al. 2014)
	Tea	Tea polyphenols	NS	300 μg/mL	300 μg/mL, 5 days, (≈40%)	NS	QS/AI-2	(H. Zhang et al. 2014)
Aldehydes	Black garlic	5-hydroxymethylfurfural		>125 μg/mL	125 μg/mL, 24 h (82% )	NS	QS	(Vijayakumar and Ramanathan 2018)
Flavonoids	Scutellaria spp.	Baicalein		256 μg/mL	32 μg/mL, 3 days (≈60%–80%)	64 μg/mL, 3 days, 7 days (≈1.5log CFU/ml reduction)	QS	(Chen et al. 2016)

NS = Not specified

Figure 5. Mechanism of quorum sensing system (QS) LuxS/AI-2 for biofilm regulation in S. aureus. Biosynthesis of Autoinducer 2 (AI-2) is catalyzed by LuxS and repressed the expression of rbf. Rbf could bind to the SarX and rbf promoters to upregulate their expression. Rbf can improves PIA-dependent biofilm formation via the repression of icaR expression. Polysaccharide intercellular adhesin (PIA) is synthesized regulated via proteins IcaA, IcaD, IcaB, and IcaC, encoded within the intercellular adhesin (ica) operon. IcaA and IcaD synergistically synthesize UDP-N-acetylglucosamine and exported via IcaC. Subsequently, IcaB regulates the partial deacetylation of PIA, improving adhesion via increased positive charge. Key molecule can be seen as antibiofilm and antibacterial targets, encircled in red.

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