Microbial sessile communities attached to a substratum or interphases or to each other, known as biofilms embedded in self-secreted extracellular matrices containing protein, polysaccharide, nucleic acid, and lipid substances, display an altered phenotype in comparison with planktonic microbial cells (Muras et al., 2021; Wang et al., 2022). Extracellular polymeric substances (EPS) is greatly involved in the stability of the structure and the function of biofilm (Ashrafudoulla et al., 2020). Over 80% of microbial infections are associated with biofilm formation, while it has been characterized as one of the crucial medical hurdles over the century (Brackman and Coenye, 2015; Wang et al., 2022). Moreover, bacteria cells within biofilms have shown 1,000 times more resistance to various stresses rather than the planktonic form (Ashrafudoulla et al., 2019). In addition to their impact on human health, biocorrosion and biofouling based on biofilm formation of microorganisms cause enormous financial problems in the shipping and medical industries (Muras et al., 2021; Wang et al., 2022). Therefore, due to the importance of this issue, some researchers present multiple challenges of biofilm formation and their impact on food safety, particularly poultry and seafood products (Ashrafudoulla et al., 2023; Chowdhury et al., 2023), and fully discuss the new insights to combat biofilms in the food industry (Mevo et al., 2021; Rahman et al., 2023; Uddin Mahamud et al., 2024). In recent years, numerous natural products have been identified as antibacterial and anti-biofilm agents (Song et al., 2018; Lu et al., 2019; Mulat et al., 2022) which can inhibit cellular adhesion, abolish the quorum sensing signaling, prevent biofilm formation, disrupt extracellular matrix (ECM) structure, and decrease the production of quorum sensing-regulated virulence factors in pathogenic bacteria (Lu et al., 2019). Therefore, several research studies have been focused on natural anti-biofilm agents obtained from plants, microorganisms, and marine extracts or metabolites to control human infections (Mishra et al., 2020; Danquah et al., 2022; Ashrafudoulla et al., 2023). Among various natural products, it is well known that marine and algal bioactive compounds are utilized for prevention and treatment of bacterial biofilm (Melander et al., 2020).

Algae are known as renewable sources of bioactive compounds, in particular, carotenoids and polysaccharides, with a wide range of biological activities, such as antioxidant, antimicrobial, anti-inflammatory, anti-obesity, antidiabetic, anticancer, and anti-Alzheimer activities (Oliyaei et al., 2023). Macroalgae or seaweeds are classified into Chlorophyceae (green algae), Phaeophyceae (brown algae), and Rhodophyceae (red algae) (Oliyaei et al., 2022). Some research studies revealed that their extracts or metabolites have the potential to inhibit biofilm formation (Zammuto et al., 2022). Similarly, microalgae, microscopic and photosynthetic organisms, are rich in various metabolites (polyphenols, lipids, and carotenoids) with various bioactivities. Microalgal derivatives are promising candidates in novel, biocontrol agents against pathogens (Sampathkumar et al., 2019).

Based on the importance of biofilm, and concern about its serious problems, natural substances became attractive. Moreover, considering the potential of the use of algae as a novel source of biological agents, determining the antibiofilm activities of their derivatives is crucial. To the best of our knowledge, there is no review article about the anti-biofilm inhibitory potential of different algal-based bioactive compounds. Therefore, this review summarizes an overview of biofilm formation, quorum sensing pathway, and new identified marine algae natural products, as anti-biofilm agents will be discussed. These natural substances are interesting candidates that suggest novel strategies for controlling biofilm-related infections.

Biofilm is a sessile complex of microorganisms produced on food surfaces. Biofilms create serious concerns in the healthcare and food industries. The structure complexity of biofilms causes intrinsic resistance against antibiotics and also promotes the colonization of microorganisms by providing nutrients which protect microbial cells from antimicrobial agents (Ashrafudoulla et al., 2021). Biofilm occurrence forms in multiple steps as shown in Figure 1: (i) conditioning the surfaces with organic and inorganic molecules influencing initial adherence of the microbial cells and (ii) producing extracellular matrices causing attachment of cells to the substratum more firmly. This allows the cells to grow and mature from microcolonies to three-dimension communities. The physiological responses of the microbial cells in the biofilm community will change based on the existing conditions in the biofilm, (iii) detaching the cells from the biofilm, disperse and form a biofilm on other surfaces or release as a planktonic state (Brackman and Coenye, 2015; López and Soto, 2019).

A biofilm association is evaluated as one of the most impressive sites of genome expression of bacterial cells, in which the microbial cells are well preserved and metabolically act more efficiently. However, a biofilm arrangement with attributes, such as survival, adaptive, and protective values, behaves differently from the planktonic cells that are not very efficient and are only used for propagating and colonizing new surfaces. The population of microbial cells embedded in the biofilm matrix is between 10⁴ and 10⁸ cells/cm², by which the differences between invisibility and visibility of biofilms are being considered (Costerton et al., 1995; Lazar, 2011; Lamin et al., 2022).

Moreover, a biofilm community resists microbial cells inside the matrices to antibiotics by numerous mechanisms. The small dissemination of antibiotics across the extracellular matrices of biofilm communities, altered physiological traits of microbial cells by the low growth rate in response to restrict oxygen and nutrient quantity or environmental stress, changed phenotypic properties of cells, quorum sensing. Then, it results in exchanging the resistance of genes between microbial cells inside the biofilm and resisting the cells exposed to antimicrobial agents due to the remaining cells and cell debris. In addition, the structure of the biofilm would be effective in its mechanism of antimicrobial resistance which avoids the immune system function and phagocytosis (López and Soto, 2019). A large number of microbial species tend to communicate with other cells, make an interaction with their surrounding environment, and display multicellularity, resulting in biofilm formation (Kalia et al., 2015; Muras et al., 2021; Majdura et al., 2023). It is mostly related to the ability of microbial cells to communicate with themselves at high and uncommonly low cell densities through the signaling phenomenon called quorum sensing. Quorum sensing system was utilized to synchronize gene expression to biofilm formation, indicating cell density and facilitating collective behaviors. Cell-to-cell communication known as quorum sensing has been found to be crucial in biofilm formation of both gram-negative and gram-positive with the surrounding extracellular matrix. By detecting and quantifying the accumulation of specific self-produced signal molecules released by the community, quorum sensing allows bacteria to determine the population density. The quorum sensing system mediates changes in the production of biofilm matrix components, such as exopolysaccharides, lipids, nucleic acids, and proteins. In addition, this system is also coordinated with other environmental factors such as pH, salinity, temperature, oxidative stress, and availability of nutrients progressing the cellular adaptation to the environment and enhancing their survival likelihood. However, interfering with the quorum sensing system is known as a promising approach to avoid bacterial biofilm proliferation (Machado et al., 2020; Muras et al., 2021).

As mentioned above, there is a cell-to-cell communication among the microbial cells involved in the biofilm matrix. Quorum sensing is mediated by the production and secretion of low molecular weight chemicals, also known as auto-inducers (AIs) (Menaa et al., 2021), using bacterial cells depending on their cell density (Lazar, 2011; Machado et al., 2020). These diffusible signaling molecules are responsible to regulate gene expression depending on cell density and to adjust some prokaryotic phenotypes such as bioluminescence, production of secondary metabolites (toxins and antibiotics), secretion of intercellular enzymes, production of virulence factor, and biofilm formation (Borges and Simões, 2019; Lamin et al., 2022). Over the last years, the function of the quorum sensing system has been investigated in several important biological processes. It has been shown that quorum sensing mechanism regulates food spoilage. In addition to regulating gene expression, it has also an impressive effect on the survival and growth of food pathogens (Bai and Vittal, 2014; Machado et al., 2020). Studies have demonstrated the crucial role of the quorum sensing process in different stages of biofilm formation (Machado et al., 2020). The most identified microorganisms involved in biofilm formation mediated by quorum sensing signaling network include Pseudomonas aeruginosa, P. fluorescens, Chromobacterium violaceum, Campylobacter jejuni, Aliivibro ficheri, Vibrio harveyi, V. parahaemolyticus, Escherichia coli, Acinetobacter spp., Salmonella enterica, and Salmonella Thompson. They are known as human opportunistic pathogens causing infections such as pneumonia, chronic otitis, chronic wounds, and catheter infection (Ashrafudoulla et al., 2019, 2023; Ćirić et al., 2019).

However, quorum sensing signaling systems can be used in expanding quorum sensing inhibitors to control the biofilm propagation, specifically unwanted bacterial embedding in the biofilm matrix (Machado et al., 2020). The auto-inducers (AIs) are synthesized steadily and diffused into the environment with the cell density increment gaining a threshold value called quorum level of signaling molecules (Borges and Simões, 2019; Machado et al., 2020). Different types of quorum sensing signaling systems (Figure 2) distinguished between gram-negative bacteria cytoplasm and gram-positive bacteria cell membrane, exploiting the gene regulation-mediated quorum sensing (Borges and Simões, 2019). Hormone-like AIs diffusible from gram-negative bacteria, such as acyl-homoserine-lactones (AHL), non-diffusible autoinducing peptides (AIP) at gram-positive bacteria, and autoinducer-2 (AI-2) in both gram-positive and gram-negative bacteria are major quorum sensing systems which are recognized as precursor peptides releasing outside by protein transport machinery (Lazar, 2011; Brackman and Coenye, 2015; Borges and Simões, 2019). Moreover, the other typical signaling molecules such as Pseudomonas quinolone signal (2-heptyl-3-hydroxy-4-quinolone), fatty acids (cis-2-dodecenoic acid), and autoinducer-3 (from E. coli O157:H7) have been identified, while the LuxI/R-type system, the Agr system, and the LuxS/AI-2 system are known as the main quorum sensing systems (Bai and Vittal, 2014; Borges and Simões, 2019). The LuxI/R-type system consists of the proteins called LuxI (AHL synthase) and LuxR (AHL receptor), utilized by gram-negative bacteria. The regulation of the luminescence production in gram-negative marine bacterium V. fischeri, which is known as the cell density-dependent mechanism, is mediated by the AHL quorum sensing system (Papenfort and Bassler, 2016; Borges and Simões, 2019). The Agr system consists of RNA II and RNA III regulating signals. It is a signaling peptide presenting in gram-positive bacteria such as Staphylococcus aureus as activating/inhibiting peptides that contain a membrane-bound sensor and an intracellular response regulator (Brackman and Coenye, 2015; Vadakkan et al., 2018; Borges and Simões, 2019). The third signaling system is the LuxS/AI-2 system which is associated with the AI-2 production mediating the interaction between gram-negative and gram-positive bacteria (Brackman and Coenye, 2015). The LuxS protein is key a metallo-enzyme with two tetrahedral metal-binding sites being in some bacterial species, i.e., Streptococcus spp., Lactococcus lactis, Clostridium perfringens, Neisseria meningitidis, E. coli, and Haemophilus influenza (Brackman and Coenye, 2015; Wang et al., 2018).

However, it has been demonstrated that biofilm spoilage related to the quorum sensing network is highly responsible for contaminating various food products such as milk and dairy, meat, fisheries, and vegetables products (Machado et al., 2020; Lamin et al., 2022). For instance, Salmonella spp., Campylobacter spp., Listeria monocytogenes, E. coli, S. aureus, and Bacillus cereus as foodborne pathogens are capable to connect different surfaces in various industries causing biofilm distribution, which would be a severe health and hygiene problem and an economic problem (Giaouris et al., 2015). Therefore, since there are still more to learn about the key role of quorum sensing in biofilm formation, antagonist molecules, known as quorum sensing inhibitors/quorum quenching agents by binding to different sites on the receptors (LuxR-type receptor), block the signal activations. The blocking agents compete or interfere with AHL signal molecules, target production of cell signaling molecules, deteriorate signal systems, and inhibit the attachment of signals to the receptors or signal transportation to prevent the biofilm formation (Bai and Vittal, 2014; Brackman and Coenye, 2015). However, quorum sensing inhibition as an alternative strategy might result in the inhibition of particular phenotype expression blocking cell-to-cell communication that would be more acceptable rather than conventional sanitizers (Muras et al., 2021).

Several strategies have been expanded to eradicate quorum sensing network and biofilm-related infections. Applying liposomes, bacterial interference, bacteriophages, hydrogels, iontophoresis, and nanoparticles are some approaches combatting biofilm propagation, although new approaches are also required (López and Soto, 2019). Therefore, the inhibition of the quorum sensing network using new materials and strategies is a promising tool for interfering bacterial biofilms, while they resist to a variety of regular antimicrobial agents (Lazar, 2011; Kalia et al., 2015). The polymeric matrix on the surface of the substratum, which is mostly made up of exopolysaccharides, extracellular proteins, nucleic acids, and other components, facilitates the irreversible adhesion of bacteria. Cell adhesive properties also depend heavily on extracellular elements, such as surface-exposed proteins, extracellular glucan-binding proteins, and glycosyltransferases. Hence, the anti-biofilm function of natural compounds is related to the blockage of polymer matrix synthesis, elimination of cell-to-cell and cell-to-surface attachment, extracellular matrix disruption, lowering of the formation of virulence factors, and, subsequently, hampering quorum sensing system and biofilm formation (Lu et al., 2019). Quorum sensing inhibition or quorum quenching mechanism is referred to the enzymatical inactivation of quorum sensing signals. It describes the disruption of microbial cell communication by quorum sensing inhibitory chemicals using targeted to AI signaling molecules, receptors, and downstream signaling cascades (Figure 3) (Lazar, 2011; Kalia et al., 2015; Muras et al., 2021).

It has been reported that blocking the microbial quorum sensing signals as a prevalent strategy has already been applied by a variety of organisms to protect themselves from pathogenicity and virulence (Lazar, 2011; Sampathkumar et al., 2019). This strategy inhibits intercellular signaling by (i) hindering diffusion of homoserine-lactone (HSL) signal and lowering the concentration of extracellular HSL. Signal molecules are degraded by enzymes such as AHL-lactonases and AHL-acylases, which hydrolyze the lactone ring and release free HSL and fatty acid, respectively; (ii) inhibiting the signal receptors by competitive synthetic or naturally synthesized molecules using some bacteria strains including V. fischeri, Agrobacterium tumefaciens, Chromobacterium violaceum, and Aeromonas salmonicida, producing inhibitor proteins which express new functions to cells or by some uncompetitive molecules cause disruption of HSL binding to proteins; (iii) interfering intercellular signaling systems using quorum sensing inhibitors produced by algae, microorganisms, herbs, fruits, spices, and animals (Lazar, 2011; Bai and Vittal, 2014; Machado et al., 2020). Quorum sensing inhibitors as intrinsic ammunition are considered to preserve from treatment to surviving the host cells or hindering the ecological balance (Sampathkumar et al., 2019). Generally, quorum sensing inhibitors are divided into three main classes, namely, AHL analogs, 2 (5H)-furanones, and compositions that are not structurally related to AHLs (Lazar, 2011). However, there are four enzymatic ways to degrade AHL, including AHL acylases (amidohydrolysis) and AHL lactonases (lactone hydrolysis), which hydrolyze the amide bonds of the AHL molecules irreversibly and the HSL rings reversibly; AHL oxidases and AHL reductases (oxidoreduction) alter the activity of AHL but are not able to degrade the AHL molecules (Dong et al., 2000; Uroz et al., 2009; Borges and Simões, 2019). It has repeatedly been shown in several studies that AHL analogs modified the acyl side or lactone ring, or amide moiety by which the lactone moiety is replaced by cyclopentyl or cyclohexanone rings or triazolyldihydrofuranone moiety, interfering biofilm development and indicating biofilm inhibitory action against Serratia marcescens, P. aeruginosa, and Burkholderia spp. (Ishida et al., 2007; Morohoshi et al., 2007; Brackman et al., 2012). Nevertheless, exploring new and natural sources for inhibiting biofilm-related infections would be crucial to be used in clinical and industrial practices. Meanwhile, biological molecules from algal sources are promising agents due to their vast species diversity, habitat they live in, and great biological defense activity compared with their counterparts from other resources (López and Soto, 2019).

Recently, some investigations have been focused on natural products with anti-biofilm attributes. Therefore, various bioactive compounds have been identified from marine sponges, including the diterpene alkaloid (−)-ageloxime D 121, derived from Agelas nakamurai with prevention of S. epidermidis biofilm formation (Hertiani et al., 2010), diterpene, darwinolide 122 from Dendrilla membranosa with inhibition of the attachment and biofilm formation of MRSA (von Salm et al., 2016), tryptamine derivative bufotenine 123, from the Mediterranean gorgonian Paramuricea clavate with anti-adhesion activity against Pseudoalteromonas sp. D41 (Pénez et al., 2011). Sometimes, these natural compounds, such as bufotenine (5) and 1,3,7-trimethylisoguanine (10), two bromoindole derivatives, are more effective than commercial compounds and have more strong anti-adhesion properties against bacteria (Pénez et al., 2011). The marine-based natural anti-biofilm agents are well reviewed by Melander, Basak (Melander et al., 2020). However, some algae species producing inhibitors such as red marine algae, Delisea pulchra, synthesizes halogenated furanones as the first quorum sensing inhibitor group which competitively inhibits AHL binding to intracellular receptors and then bacterial colonization and biofilm development. It has happened by preventing the key quorum sensing pathway through bacterial cells as the AHSL regulatory system in Gram-negative bacteria and also AI-2 signaling network in both Gram-negative and Gram-positive species (Manefield et al., 1999; Dong et al., 2000; Borges and Simões, 2019). Moreover, it has been observed that extracts from red seaweeds Sarcodiotheca gaudichaudii and Chondrus crispus interfere with biofilm formation by S. enteritidis (Kulshreshtha et al., 2016). The great anti-bacterial and anti-biofilm activities of methanolic extract of Padina pavonica were obtained against S. aureus, Enterococcus faecalis, P. aeruginosa, Klebsiella pneumonia, and B. subtilis (Makhlof et al., 2023). Attenuation of AHL function of several marine actinomycetes extracts has been discovered against biofilm formation of Vibrio spp., hindering quorum sensing signaling by blocking the AHL receptor site of the LuxR homologs (You et al., 2007).

Several microbial infections are associated with the biofilm formation. A large number of microbial species tend to communicate with others, interact with their surrounding environment, and display multicellularity, resulting in biofilm formation. Communication of microbial cells is dependent on their cell density through quorum sensing signaling phenomenon mediated by the production and secretion of AIs. The involvement of quorum sensing signaling molecules in biofilm formation has been frequently reported, which is responsible for a variety of infections, food spoilage, biofouling, and biocorrosion. However, quorum sensing systems can be applied in expanding quorum sensing inhibitors as an alternative strategy in the inhibition of particular phenotypes expression blocking cell-to-cell communication causing to control the biofilm propagation and can be of great value in the future treatment of bacterial infections. Meanwhile, natural products are an interesting substance to combat with bacterial biofilm and related infections. The results obtained by numerous investigations performed over the last decade promoted the use of marine and algae extracts and their metabolites as anti-biofilm agents. Various algae extracts inhibited the bacterial adhesion, biofilm formation, and biosynthesis of quorum sensing key enzymes. All the above studies demonstrated that marine natural products possess anti-microbial and anti-biofilm activity toward a large number of pathogens.

Experimenting with a combination of extracts or biopolymers in silver nanoparticles or dental composites also provides anti-bacterial and anti-biofilm activities and is promising for the development of anti-biofilm novel formulations. However, some studies are needed to identify the role of algae substances in anti-biofilm attributes of silver nanoparticles and composites. Moreover, the effect of various microalgae and macroalgae extracts and their other metabolites, such as pigments, are recommended. In addition, in vivo studies and clinical trials are necessary for treating human infections.

AB and NO established this concept, searched the literature, and wrote the first draft of this manuscript. MM-N improved and revised the manuscript. All authors contributed to the article and approved the submitted version.