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A Review of Biofilm Formation of Staphylococcus aureus and Its Regulation Mechanism
Open accessAbstract
Bacteria can form biofilms in natural and clinical environments on both biotic and abiotic surfaces. The bacterial aggregates embedded in biofilms are formed by their own produced extracellular matrix. Staphylococcus aureus (S. aureus) is one of the most common pathogens of biofilm infections. The formation of biofilm can protect bacteria from being attacked by the host immune system and antibiotics and thus bacteria can be persistent against external challenges. Therefore, clinical treatments for biofilm infections are currently encountering difficulty. To address this critical challenge, a new and effective treatment method needs to be developed. A comprehensive understanding of bacterial biofilm formation and regulation mechanisms may provide meaningful insights against antibiotic resistance due to bacterial biofilms. In this review, we discuss an overview of S. aureus biofilms including the formation process, structural and functional properties of biofilm matrix, and the mechanism regulating biofilm formation.
Overview
CoChat Summary
TL;DR
This narrative review summarizes the formation process, matrix components, and regulatory mechanisms of *Staphylococcus aureus* biofilms. It emphasizes that biofilms protect *S. aureus* from host immunity and antibiotics and that understanding their regulation may inform anti-biofilm strategies.
Key findings
- *S. aureus* biofilm development is described in four stages—adhesion, aggregation, maturation, and dispersion—and the review states that more than 80% of chronic infections are mediated by bacterial biofilms.
- Biofilm matrix formation involves PIA/PNAG via the *icaADBC* operon, protein-dependent adhesins such as Bap, FnBPs, ClfA/B, SasG, SasC, SdrC/D/E, and CAN, and eDNA regulated by *cidA* and *lrgAB*; Bap contains 2276 amino acids, and PIA oligomers produced by *icaAD* reach a maximum length of 20 residues unless *icaC* is co-expressed.
- Regulation is multi-layered: the Agr quorum-sensing system upregulates RNAIII and PSMs and promotes biofilm dispersion, while LuxS/AI-2 reduces PIA; SarA, σB, CodY, ica repressors (IcaR, TcaR, Rob), two-component systems (SrrAB, SaeRS, LytSR, ArlRS), c-di-AMP, and sRNAs also modulate biofilm formation.
- Clinically, biofilms protect bacteria from the immune system and antibiotics, often requiring long-term high-dose antibiotic therapy and increasing risks of antibiotic resistance and drug toxicity.
Methods
- Design: narrative review of *S. aureus* biofilm formation and regulation; no primary experimental data are presented.
- Data or sample: not stated in the paper; the review synthesizes previously published literature rather than analyzing a new sample.
- Main analysis: thematic synthesis of the biofilm life cycle, matrix components, and regulatory systems, including quorum sensing, global regulators, two-component systems, second messengers, and sRNAs.
Limitations
- The paper states that researchers have not yet understood the synergy between different regulatory networks, that biofilm regulation is dynamic across growth times and environments, and that little is known about whether in vivo regulation matches in vitro regulation.
- The paper states that results from reference strains may differ from clinical isolates and that mixed-species biofilms with other bacteria and/or fungi are important but not included in the review’s scope.
- Evident from the text: no systematic search strategy, inclusion criteria, or quantitative synthesis is described; as a narrative review, it does not provide primary experimental validation.
Model-written summary. Check it against the paper before relying on it.
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Figures
![Figure 1 A model of the growth cycle of biofilm. In the first step of biofilm formation, planktonic cells attach to the surface via surface-associated proteins. After attachment, the cells gradually aggregate and begin to produce ECM, thus forming microcolonies. With cell division, a mature biofilm is gradually formed. Finally, in the separation stage, enzymes such as protease, nuclease, and a quorum sensing system promote the dispersion of biofilm, allowing the bacterial cells to detach from the biofilm and return to a planktonic state to colonize new ecological niches [40].](/paper-figures/73c2c4b88e8c4ba088c3258358f740ec/a-review-of-biofilm-formation-of-staphylococcus-aureus-and-its-regulation-figure-1.jpg)
![Figure 2 The structure of polysaccharide intercellular adhesin (PIA). PIA is a beta-linear homoglycan composed of 1,6-linked N-acetylglucosamine residues, 15–20% of which are deacetylated and therefore positively charged [41].](/paper-figures/0bd4ba0f0ce8475689ff35bad46fd447/a-review-of-biofilm-formation-of-staphylococcus-aureus-and-its-regulation-figure-2.jpg)
![Figure 3 Genetic encoding and biosynthesis of PIA. PIA is synthesized from the product of icaADBC operon. IcaA and IcaD are two membrane proteins that polymerize N-acetylglucosamine from the activated precursor UDP-N-acetylglucosamine monomers. This chain may be exported by the membrane protein IcaC. IcaB is an acetylase attached to the outer surface of bacteria. By deacetylation of residues, IcaB introduces a positive charge into the originally neutral PIA molecule [41].](/paper-figures/d0abde206b714f70b4e3535833151dc3/a-review-of-biofilm-formation-of-staphylococcus-aureus-and-its-regulation-figure-3.jpg)
![Figure 4 The role of the Agr quorum sensing system in biofilm formation in S. aureus. The Agr system is controlled by agr operon. AgrD is the precursor of self-induced peptides (AIPS), which is modified by AgrB and secreted into the extracellular matrix. AIPs are intracellular signal molecules that respond to cell density. When the bacterial density increases, AIP activates the transmembrane protein AgrC. Phosphorylated AgrC further activates AgrA and finally promotes the expression of target genes. AgrA acts on P2, which regulates the Agr protein, and P3, which can activate RNAIII expression. RNAIII is the effector molecule of agr locus. RNAIII induces the expression of virulence factors, such as protease and toxin. On the other hand, RNAIII also inhibits the expression of surface adhesion proteins [83].](/paper-figures/8a2d1a90042f4db9b0d1d362b3e9bab0/a-review-of-biofilm-formation-of-staphylococcus-aureus-and-its-regulation-figure-4.jpg)
![Figure 5 The interaction between Agr quorum sensing system and some important biofilms regulators (LytSR TCS, SigB, CodY and SarA) [20].](/paper-figures/0bbd2d3dc2df472ea928825f2d19fd22/a-review-of-biofilm-formation-of-staphylococcus-aureus-and-its-regulation-figure-5.jpg)
Verification
Claims the paper makes
0 Valid · 1 Not valid · 183 Not checked · 5 Own results and interpretations
In the paper
“The product of the icaC gene is a transmembrane protein that mediates the transfer of the newly synthesized PIA to the cell surface [46].”
§ A Review of Biofilm Formation of Staphylococcus aureus and Its Regulation Mechanism > 3. Biofilm Formation Mechanism > 3.1. Polysaccharide Intercellular Adhesion(PIA)-Dependent Mechanism
What the sources say
- Not checked yetcites [46] Atkin, 2014, A different path: Revealing the function of staphylococcal proteins in biofilm formation, FEBS Lett. source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Among the polymeric molecules involved in ECM, polysaccharide intercellular adhesion (PIA) (also known as poly-N-acetylglucosamine; PNAG) is an important factor in S. aureus biofilm formation [41].”
§ A Review of Biofilm Formation of Staphylococcus aureus and Its Regulation Mechanism > 3. Biofilm Formation Mechanism > 3.1. Polysaccharide Intercellular Adhesion(PIA)-Dependent Mechanism
What the sources say
- Not checked yetcites [41] Nguyen, 2020, The staphylococcal exopolysaccharide PIA—Biosynthesis and role in biofilm formation, colonization, and infection, Comput. Struct. Biotechnol. J. source
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“During the aggregation stage, bacteria regulate biofilm formation by sensing environmental signals that trigger regulatory networks and intracellular signal molecules.”
§ A Review of Biofilm Formation of Staphylococcus aureus and Its Regulation Mechanism > 2. Biofilm Formation Process
What the sources say
- Not checked yetcites [25] Mayes, 2016, Bacterial biofilms and quorum sensing: Fidelity in bioremediation technology, Biotechnology and Genetic Engineering Reviews source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“During the growth and development of biofilm, surfactant phenol-soluble modulins (PSMs) are a key effector molecule for the dispersion and transmission of S. aureus biofilms [35].”
§ A Review of Biofilm Formation of Staphylococcus aureus and Its Regulation Mechanism > 2. Biofilm Formation Process
What the sources say
- Not checked yetcites [35] Periasamy, 2012, How Staphylococcus aureus biofilms develop their characteristic structure, Proc. Natl. Acad. Sci. USA source
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In S. aureus, α-PSM1 and α-PSM4 peptides are the main amyloid proteins involved in the α-PSMs fibril production [39].”
§ A Review of Biofilm Formation of Staphylococcus aureus and Its Regulation Mechanism > 2. Biofilm Formation Process
What the sources say
- Not checked yetcites [39] Marinelli, 2016, Dissecting the contribution of Staphylococcus aureus α-phenol-soluble modulins to biofilm amyloid structure, Sci. Rep. source
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Furthermore, its ability to form robust biofilms on medical devices and prosthetic implants enhances persistence by shielding bacteria from antimicrobial agents and host defenses, driving chronic and recurrent infections [6].”
From Staphylococcus aureus: A Review of the Pathogenesis and Virulence Mechanisms (2025) · cites this paper as [6]
In the citing paper
“Biofilm-forming strains are 3–5 times more likely to persist in the throat, complicating eradication efforts [6].”
From Staphylococcus aureus: A Review of the Pathogenesis and Virulence Mechanisms (2025) · cites this paper as [6]
In the citing paper
“Regarding pathogenesis, the attachment of S. aureus to the tissues of the host through MSCRAMMs facilitates the formation of biofilms, a critical factor in chronic infections [6,85].”
From Staphylococcus aureus: A Review of the Pathogenesis and Virulence Mechanisms (2025) · cites this paper as [6]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ A Review of Biofilm Formation of Staphylococcus aureus and Its Regulation Mechanism > 4. Regulation Mechanism of Biofilm Formation > 4.2. The Global Response Regulator
“in the icaR deletion mutant, the transcript level of icaA gene was extremely low and the amount of biofilm formation was low”
§ A Review of Biofilm Formation of Staphylococcus aureus and Its Regulation Mechanism > 4. Regulation Mechanism of Biofilm Formation > 4.3. ica Operon
“IcaR is a DNA-binding protein that negatively regulates icaADBC expression by binding to the upstream region of the icaA start codon [127].”
Citations
Cites
Bacterial biofilms: from the Natural environment to infectious diseases
Hall-Stoodley, L., Costerton, J. W., & Stoodley, P. (2004) · Nature Reviews Microbiology · doi:10.1038/nrmicro821 · Cited by 7,143
Staphylococcus aureus Infections
Lowy, F. D. (1998) · New England Journal of Medicine · doi:10.1056/nejm199808203390806 · Cited by 6,005
Biofilm formation as microbial development
O'Toole, G., Kaplan, H. B., & Kolter, R. (2000) · Annual Review of Microbiology · doi:10.1146/annurev.micro.54.1.49 · Cited by 3,571
Molecular mechanisms of biofilm-based antibiotic resistance and tolerance in pathogenic bacteria
Hall, C. W., & Mah, T.-F. (2017) · FEMS Microbiology Reviews · doi:10.1093/femsre/fux010 · Cited by 1,696
Bacterial biofilm and associated infections
Jamal, M., Ahmad, W., Andleeb, S., Jalil, F., Imran, M., Nawaz, M. A., Hussain, T., Ali, M., Rafiq, M., & Kamil, M. A. (2018) · Journal of the Chinese Medical Association · doi:10.1016/j.jcma.2017.07.012 · Cited by 1,642
Principles of c-di-GMP signalling in bacteria
Hengge, R. (2009) · Nature Reviews Microbiology · doi:10.1038/nrmicro2109 · Cited by 1,578
Biofilm Matrixome: Extracellular Components in Structured Microbial Communities
Karygianni, L., Ren, Z., Koo, H., & Thurnheer, T. (2020) · Trends in Microbiology · doi:10.1016/j.tim.2020.03.016 · Cited by 1,487
Mechanisms of antibiotic resistance in bacterial biofilms
Stewart, P. S. (2002) · International Journal of Medical Microbiology · doi:10.1078/1438-4221-00196 · Cited by 1,385
Bacterial biofilm formation on implantable devices and approaches to its treatment and prevention
Khatoon, Z., McTiernan, C. D., Suuronen, E. J., Mah, T.-F., & Alarcon, E. I. (2018) · Heliyon · doi:10.1016/j.heliyon.2018.e01067 · Cited by 1,187
Regulation by Small RNAs in Bacteria: Expanding Frontiers
Storz, G., Vogel, J., & Wassarman, K. M. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.08.022 · Cited by 1,177
Cited by
Staphylococcus aureus: A Review of the Pathogenesis and Virulence Mechanisms
Touaitia, R., Mairi, A., Ibrahim, N. A., Basher, N. S., Idres, T., & Touati, A. (2025) · Antibiotics · doi:10.3390/antibiotics14050470 · Cited by 273
Kaushik, A., Kest, H., Sood, M., Steussy, B., Thieman, C., & Gupta, S. (2024) · Pathogens · doi:10.3390/pathogens13010076 · Cited by 199
Biofilm Resilience: Molecular Mechanisms Driving Antibiotic Resistance in Clinical Contexts
Almatroudi, A. (2025) · Biology · doi:10.3390/biology14020165 · Cited by 187
Wu, X., Wang, H., Xiong, J., Yang, G., Hu, J., Zhu, Q., & Chen, Z. (2024) · Biofilm · doi:10.1016/j.bioflm.2023.100175 · Cited by 173
Biofilm formation in food industries: Challenges and control strategies for food safety
Elafify, M., Liao, X., Feng, J., Ahn, J., & Ding, T. (2024) · Food Research International · doi:10.1016/j.foodres.2024.114650 · Cited by 92
Metadata
- Authors
- Peng, Q., Tang, X., Dong, W., Sun, N., & Yuan, W.
- Affiliations
- Guangzhou Medical University (CN)
- Guangzhou First People's Hospital (CN)
- Corresponding author
- Sun, Ning
- Yuan, Wenchang
- Venue
- Antibiotics
- Publisher
- MDPI AG
- Published
- 2022-12-22
- Volume
- 12
- Issue
- 1
- Pages
- 12
- ISSN
- 2079-6382 (ISSN-L)
- PMC
- PMC9854888
- OpenAlex
- W4312186359
- Semantic Scholar
- 22fe4e210b0310d487397e69a459bed97b74ee07
- Cited by
- 440
- References
- 186
- Citations by year
- 2026: 157 · 2025: 161 · 2024: 95 · 2023: 27
- FWCI
- 7.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Antibiotics (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81703333, 2020A1515011326, 2021A1515011360, 202102080469, 2020A010015, C2021077)
- Natural Science Foundation of Guangdong Province (81703333, 2020A1515011326, 2021A1515011360, 202102080469, 2020A010015, C2021077)
- Guangzhou Science and Technology Project (81703333, 2020A1515011326, 2021A1515011360, 202102080469, 2020A010015, C2021077)
- Guangzhou Health Science and Technology Project (81703333, 2020A1515011326, 2021A1515011360, 202102080469, 2020A010015, C2021077)
- Medical Scientific Research Foundation of Guangdong Province (81703333, 2020A1515011326, 2021A1515011360, 202102080469, 2020A010015, C2021077)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
- Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- Staphylococcus aureus, biofilm formation, biofilm regulation, extracellular matrix, antibiotic resistance, biofilm-associated infections, host immune evasion, biofilm treatment
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