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Cushioned lipid bilayers are structures consisting of a lipid bilayer supported on a solid substrate with an intervening layer of soft material. They offer possibilities for studying the behavior and interactions of biological membranes more accurately under physiological conditions. In this work, we continue our studies of cushion formation induced by histatin 5 (24Hst5), focusing on the effect of the length of the peptide chain. 24Hst5 is a short, positively charged, intrinsically disordered saliva peptide, and here, both a shorter (14Hst5) and a longer (48Hst5) peptide variant were evaluated. Experimental surface active techniques were combined with coarse-grained Monte Carlo simulations to obtain information about these peptides. Results show that at 10 mM NaCl, both the shorter and the longer peptide variants behave like 24Hst5 and a cushion below the bilayer is formed. At 150 mM NaCl, however, no interaction is observed for 24Hst5. On the contrary, a cushion is formed both in the case of 14Hst5 and 48Hst5, and in the latter, an additional thick, diffuse, and highly hydrated layer of peptide and lipid molecules is formed, on top of the bilayer. Similar trends were observed from the simulations, which allowed us to hypothesize that positively charged patches of the amino acids lysine and arginine in all three peptides are essential for them to interact with and translocate over the bilayer. We therefore hypothesize that electrostatic interactions are important for the interaction between the solid-supported lipid bilayers and the peptide depending on the linear charge density through the primary sequence and the positively charged patches in the sequence. The understanding of how, why, and when the cushion is formed opens up the possibility for this system to be used in the research and development of new drugs and pharmaceuticals.

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Peptide dhvar4, derived from the active domain of our salivary peptide histatin 5, bears a Phe residue in the middle of its hydrophilic face when folded into an α-helix. We then synthesized an analog with this Phe replaced by Lys and two analogs preserving Phe but bearing two and three α-aminoisobutyric acid (Aib) residues to stabilize the helical structure. The aim of this design was to verify which of the two features is more favorable to the biological activity. We performed a conformational study by means of circular dichroism and nuclear magnetic resonance, made antibacterial tests, and assessed the stability of the peptides in human serum. We observed that amphiphilicity is more important than helix stability, provided a peptide can adopt a helical conformation in a membrane-mimetic environment.

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Histatin-5 (Hist-5) is an antimicrobial peptide found in human saliva that functions to defend the oral cavity from microbial infections, such as those caused by the fungal pathogen Candida albicans (C. albicans). Hist-5 can bind Cu in multiple oxidation states, Cu2+ and Cu+in vitro, and supplemental Cu2+ has been shown to improve the fungicidal activity of the peptide against C. albicans in culture. However, the exact role of Cu on the antifungal activity of Hist-5 and whether direct peptide-Cu interactions occur intracellularly has yet to be fully determined. Here, we used a combination of fluorescence spectroscopy and confocal microscopy experiments to show reversible Cu-dependent quenching of a fluorescent Hist-5 analogue, Hist-5*, indicating a direct interaction between Hist-5 and intracellular Cu. X-ray fluorescence microscopy images revealed peptide-induced changes to cellular Cu distribution and cell-associated Cu content. These data support a model in which Hist-5 can facilitate the hyperaccumulation of Cu in C. albicans and directly interact with Cu intracellularly to increase the fungicidal activity of Hist-5.

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Antimicrobial peptides have appeared to be promising candidates for therapeutic purposes due to their broad antimicrobial activity and non-toxicity. Histatin-5 (Hst-5) is a notable salivary antimicrobial peptide that exhibited therapeutic properties in the oral cavity. Oral mucositis is an acute inflammation of the oral cavity, following cancer therapy. The current treatment methods of oral mucositis have low effectiveness. The aim of this study was to design, formulate and characterize a mucoadhesive gel delivery system for Hst-5 usage in the treatment of oral mucositis. Carbopol 934 and hydroxypropyl methylcellulose (HPMC) have been used in the development of a Hst-5 mucoadhesive gel that was optimized by using Box-Behnken design. The optimized formulation was evaluated in-vitro, based on mucoadhesive strength, viscoelasticity, spreadability, release rate, peptide secondary structure analysis, antimicrobial activity, and storage stability. The efficacy of Hst-5 gel was assessed in vivo in a chemotherapy-induced mucositis model. The results showed a sustained release of Hst-5 from the new formulation. Hst-5 gel exerted antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Candida albicans. The histopathological, immunohistochemical and statistical analysis showed that the Hst-5 gel had wound healing activity in vivo. The findings of this study indicate that the mentioned compound possesses promising potential as a novel and efficient therapeutic agent in managing oral mucositis. Moreover, the results suggest that the compound is commercially feasible for further development and utilization.

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This study aimed to investigate the effects of salivary histatin 5 (Hst5) on Porphyromonas gingivalis (P. gingivalis) biofilms in vitro and in vivo and the possible mechanisms. In in vitro experiments, P. gingivalis biomass was determined by crystal violet staining. Polymerase chain reaction, scanning electron microscopy, and confocal laser scanning microscopy were used to determine the Hst5 concentration. A search for potential targets was performed using transcriptomic and proteomic analyses. In vivo experimental periodontitis was established in rats to evaluate the effects of Hst5 on periodontal tissues. Experimental results showed that 25 µg/mL Hst5 effectively inhibited biofilm formation, and increased concentrations of Hst5 increased the inhibitive effect. Hst5 might bind to the outer membrane protein RagAB. A combination of transcriptomic and proteomic analyses revealed that Hst5 could regulate membrane function and metabolic processes in P. gingivalis, in which RpoD and FeoB proteins were involved. In the rat periodontitis model, alveolar bone resorption and inflammation levels in periodontal tissues were reduced by 100 µg/mL Hst5. This study showed that 25 µg/mL Hst5 inhibited P. gingivalis biofilm formation in vitro by changing membrane function and metabolic process, and RpoD and FeoB proteins might play important roles in this process. Moreover, 100 µg/mL Hst5 inhibited periodontal inflammation and alveolar bone loss in rat periodontitis via its antibacterial and anti-inflammatory effects. KEY POINTS: • Anti-biofilm activity of histatin 5 on Porphyromonas gingivalis was investigated. • Histatin 5 inhibited Porphyromonas gingivalis biofilm formation. • Histatin 5 showed inhibitory effects on the occurrence of rat periodontitis.

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Mesenchymal stem cell and 3D printing-based bone tissue engineering present a promising technique to repair large-volume bone defects. Its success is highly dependent on cell attachment, spreading, osteogenic differentiation, and in vivo survival of stem cells on 3D-printed scaffolds. In this study, we applied human salivary histatin-1 (Hst1) to enhance the interactions of human adipose-derived stem cells (hASCs) on 3D-printed ß-tricalcium phosphate (ß-TCP) bioceramic scaffolds. Fluorescent images showed that Hst1 significantly enhanced the adhesion of hASCs to both bioinert glass and 3D-printed ß-TCP scaffold. In addition, Hst1 was associated with significantly higher proliferation and osteogenic differentiation of hASCs on 3D-printed ß-TCP scaffolds. Moreover, coating 3D-printed ß-TCP scaffolds with histatin significantly promotes the survival of hASCs in vivo. The ERK and p38 but not JNK signaling was found to be involved in the superior adhesion of hASCs to ß-TCP scaffolds with the aid of Hst1. In conclusion, Hst1 could significantly promote the adhesion, spreading, osteogenic differentiation, and in vivo survival of hASCs on 3D-printed ß-TCP scaffolds, bearing a promising application in stem cell/3D printing-based constructs for bone tissue engineering.

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Osteoarthritis (OA) is an inflammation-driven degenerative joint disease. Human salivary peptide histatin-1 (Hst1) shows pro-healing and immunomodulatory properties. but its role in OA treatment is not fully understood. In this study, we investigated the efficacy of Hst1 in the inflammation modulation-mediated attenuation of bone and cartilage damage in OA. Hst1 was intra-articularly injected into a rat knee joint in a monosodium iodoacetate (MIA)-induced OA model. Micro-CT, histological, and immunohistochemical analyses showed that Hst1 significantly attenuates cartilage and bone deconstruction as well as macrophage infiltration. In the lipopolysaccharide-induced air pouch model, Hst1 significantly reduced inflammatory cell infiltration and inflammation. Enzyme-linked immunosorbent assay (ELISA), RT-qPCR, Western blot, immunofluorescence staining, flow cytometry (FCM), metabolic energy analysis, and high-throughput gene sequencing showed that Hst1 significantly triggers M1-to-M2 macrophage phenotype switching, during which it significantly downregulated nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinases (MAPK) signaling pathways. Furthermore, cell migration assay, Alcian blue, Safranin O staining, RT-qPCR, Western blot, and FCM showed that Hst1 not only attenuates M1-macrophage-CM-induced apoptosis and matrix metalloproteinase expression in chondrogenic cells, but it also restores their metabolic activity, migration, and chondrogenic differentiation. These findings show the promising potential of Hst1 in treating OA.

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Histatin-5 (Hst5) is a member of the histatin superfamily of cationic, His-rich, Zn(II)-binding peptides in human saliva. Hst5 displays antimicrobial activity against fungal and bacterial pathogens, often in a Zn(II)-dependent manner. In contrast, here we showed that under in vitro conditions that are characteristic of human saliva, Hst5 does not kill seven streptococcal species that normally colonize the human oral cavity and oropharynx. We further showed that Zn(II) does not influence this outcome. We then hypothesized that Hst5 exerts more subtle effects on streptococci by modulating Zn(II) availability. We initially proposed that Hst5 contributes to nutritional immunity by limiting nutrient Zn(II) availability and promoting bacterial Zn(II) starvation. By examining the interactions between Hst5 and Streptococcus pyogenes as a model Streptococcus species, we showed that Hst5 does not influence the expression of Zn(II) uptake genes. In addition, Hst5 did not suppress growth of a ΔadcAI mutant strain that is impaired in Zn(II) uptake. These observations establish that Hst5 does not promote Zn(II) starvation. Biochemical examination of purified peptides further confirmed that Hst5 binds Zn(II) with high micromolar affinities and does not compete with the AdcAI high-affinity Zn(II) uptake protein for binding nutrient Zn(II). Instead, we showed that Hst5 weakly limits the availability of excess Zn(II) and suppresses Zn(II) toxicity to a ΔczcD mutant strain that is impaired in Zn(II) efflux. Altogether, our findings led us to reconsider the function of Hst5 as a salivary antimicrobial agent and the role of Zn(II) in Hst5 function.

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PURPOSE: To determine the efficacy of Histatin-5 (Hst5) peptide treatment in ameliorating dry eye disease (DED) phenotype in an in-vivo mouse model of scopolamine and desiccating stress (SDS) dry eye. METHODS: SDS was induced in female C57BL/6 mice by subcutaneous injections of scopolamine hydrobromide and exposure to low relative humidity and forced air draft for five days. Mouse eyes were topically treated with synthetic Hst5 peptide or balanced salt solution (BSS) twice a day for four days. Control mice were not exposed to SDS induction and did not receive any treatments. Oregon green dextran (OGD) staining was used to evaluate corneal permeability. Histologically, staining with periodic acid schiff (PAS), immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), were used to quantify the number of goblet cells (GC), CD45+ immune cells and apoptotic cells respectively in formalin fixed paraffin embedded (FFPE) mouse whole eye sections. RESULTS: Compared to treatment with BSS, Hst5 treatment significantly lowered corneal epithelial permeability, prevented conjunctival epithelial GC loss, decreased conjunctival CD45+ immune cell infiltration and reduced conjunctival epithelial cell apoptosis. CONCLUSIONS: Hst5 peptide topical treatment significantly improves the clinical parameters observed in SDS experimental model of DED. This is the first report of the efficacy of Hst5 treatment of dry eye phenotype, and potential novel treatment for DED in the clinic. Hst5 represents a new class of efficacious therapeutic agents, demonstrating pro-epithelial and anti-inflammatory activities at the ocular surface.

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Aging is a gradual and progressive deterioration of integrity across multiple organ systems that negatively affects gingival wound healing. The cellular responses associated with wound healing, such as collagen synthesis, cell migration, proliferation, and collagen contraction, have been shown to be lower in gingival fibroblasts (the most abundant cells from the connective gingival tissue) in aged donors than young donors. Cellular senescence is one of the hallmarks of aging, which is characterized by the acquisition of a senescence-associated secretory phenotype that is characterized by the release of pro-inflammatory cytokines, chemokines, growth factors, and proteases which have been implicated in the recruitment of immune cells such as neutrophils, T cells and monocytes. Moreover, during aging, macrophages show altered acquisition of functional phenotypes in response to the tissue microenvironment. Thus, inflammatory and resolution macrophage-mediated processes are impaired, impacting the progression of periodontal disease. Interestingly, salivary antimicrobial peptides, such as histatins, which are involved in various functions, such as antifungal, bactericidal, enamel-protecting, angiogenesis, and re-epithelization, have been shown to fluctuate with aging. Several studies have associated the presence of Porphyromonas gingivalis, a key pathogen related to periodontitis and apical periodontitis, with the progression of Alzheimer's disease, as well as gut, esophageal, and gastric cancers. Moreover, herpes simplex virus types 1 and 2 have been associated with the severity of periodontal disease, cardiovascular complications, and nervous system-related pathologies. This review encompasses the effects of aging on periodontal tissues, how P. gingivalis and HSV infections could favor periodontitis and their relationship with other pathologies.

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Artificial oil bodies covered by a recombinant surface protein, caleosin fused with histatin 3 (a major human salivary peptide), were employed to explore the relative astringency of eight tea catechins. The results showed that gallate-type catechins were more astringent than non-gallate-type catechins, with an astringency order of epicatechin gallate > epigallocatechin gallate > gallocatechin gallate > catechin gallate > epigallocatechin > epicatechin > gallocatechin > catechin. As expected, the extension of brewing time led to an increase in catechin content in the tea infusion, thus elevating tea astringency. Detailed analysis showed that the enhanced proportion of gallate-type catechins was significantly higher than that of non-gallate-type catechins, indicating that tea astringency was elevated exponentially, rather than proportionally, when brewing time was extended. Rough surfaces were observed on artificial oil bodies when they were complexed with epigallocatechin gallate (a catechin), while a smooth surface was observed on those complexed with rutin (a flavonol glycoside) under an atomic force microscope and a scanning electron microscope. The results indicate that catechins and flavonol glycosides induce the sensation of rough (puckering) and smooth (velvety) astringency in tea, respectively.

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Histatin-5 (Hist-5) is a polycationic, histidine-rich antimicrobial peptide with potent antifungal activity against the opportunistic fungal pathogen Candida albicans. Hist-5 can bind metals in vitro, and metals have been shown to alter the fungicidal activity of the peptide. Previous reports on the effect of Zn2+ on Hist-5 activity have been varied and seemingly contradictory. Here, we present data elucidating the dynamic role Zn2+ plays as an inhibitory switch to regulate Hist-5 fungicidal activity. A novel fluorescently labeled Hist-5 peptide (Hist-5*) was developed to visualize changes in internalization and localization of the peptide as a function of metal availability in the growth medium. Hist-5* was verified for use as a model peptide and retained antifungal activity and mode of action similar to native Hist-5. Cellular growth assays showed that Zn2+ had a concentration-dependent inhibitory effect on Hist-5 antifungal activity. Imaging by confocal microscopy revealed that equimolar concentrations of Zn2+ kept the peptide localized along the cell periphery rather than internalizing, thus preventing cytotoxicity and membrane disruption. However, the Zn-induced decrease in Hist-5 activity and uptake was rescued by decreasing the Zn2+ availability upon addition of a metal chelator EDTA or S100A12, a Zn-binding protein involved in the innate immune response. These results lead us to suggest a model wherein commensal C. albicans may exist in harmony with Hist-5 at concentrations of Zn2+ that inhibit peptide internalization and antifungal activity. Activation of host immune processes that initiate Zn-sequestering mechanisms of nutritional immunity could trigger Hist-5 internalization and cell killing.

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Treating diabetic ulcers is a major challenge in clinical practice, persecuting millions of patients with diabetes and increasing the medical burden. Recombinant growth factor application can accelerate diabetic wound healing via angiogenesis. The local administration of recombinant growth factors has no robust clinical efficiency because of the degradation of append short duration of the molecules in the hostile inflammatoryenvironment.The present study focused on the pathophysiology of impaired neovascularization and growth factor short duration in the diabetic wound. We prepared a collagen-binding domain (CBD)-fused recombinant peptide (C-Histatin-1) that had both pro-angiogenesis capacity and collagen-affinity properties. Next, we created a biocompatible acellular dermal matrix (ADM) as a drug delivery carrier that featured collagen-richness, high porosity, and non-cytotoxicity. C-Histatin-1 was then tethered on ADM to obtain a sustained-release effect. Finally, a functional scaffold (C-Hst1/ADM) was developed. C-Hst1/ADM can sustain-release Histatin-1 to promote the adhesion, migration, and angiogenesisof vascular endothelial cells in vitro. Using a diabetic wound model, we showed that C-Hst1/ADM could significantly promote angiogenesis, reduce scar widths, and improve extracellular collagen accumulation. Therefore, the results of this study provide a foundation for the clinical application of C-Hst1/ADM covering scaffold in the treatment of diabetic wounds.

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OBJECTIVES: The aims of this study were to investigate the efficacy of Histatin-1 in wound closure as well as effects on gene expression of nicotine-treated human Periodontal Ligament Fibroblast cells (HPDL) in vitro. DESIGN: HPDL grown in 2.5% culture medium treated with 10 ng/ml Histatin - 1 in the presence/absence of 0.5 µM nicotine were subjected to wound assay and migration was studied at 0 h, 6 h, 12 h and 24 h. Cells grown in 2.5% medium served as control. Cell migration was studied by wound gap and transwell migration assays. The effect of Histatin-1 on expression of matrix metalloproteinase 8 (MMP-8), insulin-like growth factor 1 (IGF-1), transforming growth factor beta (TGF-ß), collagen type I (COL1) and plasminogen activator inhibitor 1 (PAI-1) were studied. RESULTS: Histatin-1 treatment significantly decreased percentage wound gap at 12 h (62.96 ± 3.22 vs 79.23 ± 1.73; p < 0.05) and at 24 h (38.78 ± 7.59 vs 75.21 ± 4.94; p < 0.001) compared with controls. In nicotine+Histatin-1 treated cells, wound gap decreased to 70.2 ± 2.9% (p < 0.01) at 24 h compared to nicotine alone in which 82 ± 1.64% of wound gap was retained. Transwell migration assays showed significant migration of HPDL with Histatin-1 (p < 0.05). Gene expression demonstrated significant upregulation for IGF-1, TGF ß, COL1 and PAI-1 with Histatin-1. CONCLUSION: Histatin-1 significantly mitigated the effect of nicotine in wound healing assay involving HPDL fibroblast cells at 24 h. Histatin-1 aided wound closure is attributed to the upregulation of IGF-1, TGF ß, COL1, and PAI-1 genes.

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Alzheimer's disease (AD) represents the most frequent type of dementia in elderly people. There are two major forms of the disease: sporadic (SAD)-whose causes are not completely understood-and familial (FAD)-with clear autosomal dominant inheritance. The two main hallmarks of AD are extracellular deposits of amyloid-beta (Aß) peptide and intracellular deposits of the hyperphosphorylated form of the tau protein (P-tau). An ever-growing body of research supports the infectious hypothesis of sporadic forms of AD. Indeed, it has been documented that some pathogens, such as herpesviruses and certain bacterial species, are commonly present in AD patients, prompting recent clinical research to focus on the characterization of antimicrobial peptides (AMPs) in this pathology. The literature also demonstrates that Aß can be considered itself as an AMP; thus, representing a type of innate immune defense peptide that protects the host against a variety of pathogens. Beyond Aß, other proteins with antimicrobial activity, such as lactoferrin, defensins, cystatins, thymosin ß4, LL37, histatin 1, and statherin have been shown to be involved in AD. Here, we summarized and discussed these findings and explored the diagnostic and therapeutic potential of AMPs in AD.

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BACKGROUND/AIM: The prognosis of advanced stage head and neck squamous cell carcinoma (HNSCC) has remained unimproved for the past decades. Therefore, novel diagnostic markers and treatment options are required. Recently, an inhibitor for immune checkpoint program death ligand-1 (PD-L1), was approved by the FDA, and used in HNSCC patients. Histatins (HTNs), one of the common antimicrobial peptides in saliva, have demonstrated wound healing and antifungal capabilities and other functions on the oral epithelium. Dysregulation of HTN1 and HTN3 has also been reported in HNSCC through genomic and proteomic studies. This study aimed to investigate the association between histatins (HTN1 and HTN3) and PD-L1 in advanced HNSCC. PATIENTS AND METHODS: Data of gene expression in HNSCC were collected from TCGA and analyzed using a data-mining platform website (https://ualcan.path.uab.edu/). Tissue microarrays containing 98 samples of HNSCC patients and non-neoplastic controls were immunolabeled against PD-L1, HTN1, and HTN3. The immunohistochemistry results were quantified using ImageJ. RESULTS: The expression of PD-L1 and HTN1 was significantly higher in tumors than normal tissues (p<0.001), but no significant difference was found regarding HTN3. Metastatic HNSCC samples exhibited significantly higher expression of PD-L1 (p<0.018), compared to the non-metastatic group. Association between HTN1 and HTN3 was found using Pearson correlation coefficient (r=0.603, p<0.001). No overall survival difference was evident among our samples. CONCLUSION: PD-L1 and HTN1 are associated with the progression of HNSCC. PD-L1 expression correlated with that of HTN3.

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Engineering of the acquired enamel pellicle using salivary peptides has been shown to be a promising anticaries strategy. However, the mechanisms by which these peptides protect teeth against tooth decay are not fully understood. In this study, we evaluated the effect of the engineered salivary peptides DR9-DR9 and DR9-RR14 on enamel demineralization in two experimental conditions: (1) adsorbed onto the enamel surface forming the AEP, and (2) forming the AEP combined with their use to treat the biofilms 2×/day, using a validated cariogenic Streptococcus mutans in vitro biofilm model. Biofilms were grown for 144 h on enamel slabs and then collected to determine the bacterial viability (CFU/biofilm) and biofilm mass (mg protein/biofilm), and to extract cellular/extracellular proteins, which were characterized by mass spectrometry. The culture medium was changed 2×/day to fresh medium, and pH (indicator of biofilm acidogenicity) and calcium concentration (indicator of demineralization) was determined in used medium. DR9-RR14 peptide significantly reduced enamel demineralization (p < 0.0001) in both experimental conditions. However, this peptide did not have a significant effect on biofilm biomass (p > 0.05) nor did it modulate the expression of cellular and extracellular bacterial proteins involved in biofilm cariogenicity. These findings suggest that DR9-RR14 may control caries development mainly by a physicochemical mechanism.

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Micro-/macroangiopathy, neuropathy and prolonged inflammation are common in diabetic wound, however, traditional wound dressing cannot treat these problems in the same time. Herein, we developed a multifunctional hydrogel with promoted angiogenesis, cell proliferation and anti-inflammation ability to treat diabetic wound. The hydrogel was composed of natural polymers, including gelatin and chitosan, which have excellent biocompatibility. Histatin-1 (His-1) was added into the hydrogel to improve the cell adhesion, proliferation and angiogenesis. Besides, polypyrrole based conductive nanoparticles (G-Ppy) were introduced in the hydrogel to enhance the electrical signal conduction between skin and promote the mechanical strength of the hydrogel. The polypyrrole nanoparticles were growth in the chain of methacryloyl grafted gelatin (Gel-MA), leading to a better biocompatibility and water dispersibility. In vivo wound healing experiment proved that the hydrogel accelerated the wound healing rate, down regulation the expression of pro-inflammation factor TNF-α and upregulation the expression of CD31 and α-SMA, indicating the prospects in the application of diabetic wound healing.

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Since the modification of the proteinaceous components of the Acquired Enamel Pellicle (AEP) could influence the adhesion of Streptococcus mutans, the most cariogenic bacteria, to dental surfaces, we assessed if engineered salivary peptides would affect the adherence and modulate the bacterial proteome upon adherence. Single-component AEPs were formed onto hydroxyapatite (HAp) discs by incubating them with statherin, histatin-3, DR9, DR9-DR9, DR9-RR14, RR14, and parotid saliva. Then, the discs were inoculated with S. mutans UA159 and the bacteria were allowed to adhere for 2 h, 4 h, and 8 h (n = 12/treatment/time point). The number of bacteria adhered to the HAp discs was determined at each time point and analyzed by two-way ANOVA and Bonferroni tests. Cell-wall proteins were extracted from adhered, planktonic, and inoculum (baseline) bacteria and proteome profiles were obtained after a bottom-up proteomics approach. The number of adhered bacteria significantly increased over time, being the mean values obtained at 8 h, from highest to lowest, as follows: DR9-RR14 > statherin > RR14 = DR9-DR9 > DR9 = histatin3 > saliva (p < 0.05). Treatments modulated the bacterial proteome upon adherence. The findings suggested a potential use of our engineered peptide DR9-DR9 to control S. mutans biofilm development by reducing bacterial colonization.