The human oral cavity has over 700 bacterial species, harboring the second most diverse microbiome in the body (Pathak et al., 2021). Dental caries is one of the prominent chronic diseases worldwide. S. mutans is considered as the most significant contributor to dental caries due to its cariogenic ability of acid production, acid tolerance and biofilm formation (Pitts et al., 2017; Cui et al., 2019). The biofilm is a structured community that consists of a wide range of microbial species embedded in a self-organized matrix of extracellular polymeric substances (EPSs) (Flemming et al., 2016; Jakubovics et al., 2021). The EPSs not only provide a scaffold for biofilm maturation but also enhance the biofilm tolerance to antimicrobial agents (Jakubovics et al., 2021). The traditional antimicrobial agents, such as the broad-spectrum antimicrobials, pose the challenges for maintaining commensal bacteria (Huang et al., 2021). Though chlorhexidine has a strong bactericidal ability (Coelho et al., 2017), the side effects such as tooth staining, unpleasant taste, mouth irritation, and disturbing the homeostasis of the oral microbiome have limited its usage (Brookes et al., 2020). A larger number of evidence showed that natural products and their derivatives exhibited inhibitory activities against S. mutans growth (Sparks et al., 2017). However, the identification and isolation of active compounds from plants are complex and time-consuming. Moreover, the emergence of antibiotic resistance has necessitated the search for novel antibacterial agents target specific oral bacterial pathogens and inhibit EPSs formation (Coelho et al., 2017; Xia et al., 2019).

The ideal anti-biofilm approach is to facilitate the biofilm dispersion, inhibit the reproduction and metabolism of pathogens, as well as avoid the emergence of antibiotic-resistant bacteria and not disturb the homeostasis of the oral microbiome (Kanwar et al., 2017; Simon et al., 2019). Based on FDA-approved drugs database and small molecule database screening, the drug repurposing has advantages of lower toxicity and faster clinical transition (Wishart et al., 2006; Cui et al., 2019). And the rapid advance of computer technology makes it possible to investigate the biomolecular interactions and design/redesign chemical molecules, which enhance a better understanding the mechanism of inhibition and reveal essential structural properties at the molecular level. The antimicrobial peptides (AMPs) have been considered as potential drug candidates (Bin Hafeez et al., 2021), but it is challenging to improve the specificity of AMPs against S. mutans (Mai et al., 2011). Computational tools enable exploration of previously unexplored regions of AMP sequence space which may yield synthetic peptides with enhanced biological function (Torres et al., 2021). This review introduced emerging computer approaches including drugs repurposing of small-molecule compounds, computer-aided drug design (CADD), and new synthetic antimicrobial peptides ( Figure 1 ).

Drug repurposing is a method for discovering new uses of the original drugs beyond the scope of the medical indications. Compared to new drug discovery and development, it offers the advantages of lowering drug development cost and risk as existing drugs have already gone through clinical development stages (Ashburn and Thor, 2004). Small molecule compounds, with a molecular weight <1000 Da, have shown good antimicrobial activity, good stability and low toxicity (Xie et al., 2017; Roman, 2021). Recently, a number of comprehensive small molecule databases have emerged including DrugBank (Wishart et al., 2006), ChEMBL (Bento et al., 2014), PharmGKB (Hewett et al., 2002), Zinc (Williams, 2008), and PubChem (Wang et al., 2012), which have improved the chances of success by enabling the pre-selection of active compounds to test in vitro. In silico prediction of interactions between drugs and target proteins provides a convenient method to predict the new drug–target interactions (DTIs) (Wang and Zeng, 2013). Molecular docking, ligand-based and network-based approaches have been commonly used in virtually screening for a large number of compounds against a target protein (Ekins et al., 2007; Wang and Zeng, 2013). Moreover, Li (Li et al., 2011) have obtained a high enrichment of true positives predictions by using known interaction docking, consensus scoring, and specificity criteria.

Nitro group is critical for the anti–infective activity of nitro-based antimicrobial drugs, including nitroimidazoles, nitrothiazoles, and nitrofurans (Stover et al., 2000; Torreele et al., 2010). Based on the antimicrobial activity of nitrofurans against S.mutans, Zhang (Zhang et al., 2019) synthesized a novel water–soluble hybrid of indolin-2-one and nitrofuran ZY354, which exhibited low cytotoxicity and remarkable antimicrobial activity against S.mutans in multi-species biofilms. Toremifene, an FDA-approved drug for treating breast cancer, has also shown good inhibitory effect on the growth of S. mutans (Gerits et al., 2017a). Kuang (Kuang et al., 2020) identified a natural anticancer compound napabucasin (NAP) showed antimicrobial activity against oral streptococci. Using NAP as a lead compound, Xiao (Lyu et al., 2021) redesigned and synthesized a novel molecule LCG-N25. LCG-N25 exhibited stronger antimicrobial activity toward S.mutans with lower cytotoxicity.

Vitamin C and vitamin D are essential nutrients to human health. Interestingly, increased evidence showed that salivary vitamin C and serum vitamin D levels were associated with the occurrence of dental caries (Syed et al., 2019). Vitamin C has been reported to inhibit the synthesis of EPSs via inhibition of the quorum sensing and other stationary phase regulatory mechanisms (Pandit et al., 2017). Moreover, there was a concentration-dependent inhibitory effect of vitamin C on S. mutans growth and biofilm formation (Eydou et al., 2020). Vitamin D plays a key role in tooth mineralization, and it can lead to the “rachitic tooth” if the levels are unregulated (Foster et al., 2014). Saputo (Saputo et al., 2018) had screened FDA-approved drugs to identify old drugs with new therapeutic effects against S. mutans, and identified the vitamin D derivative doxercalciferol could interfere with S. mutans wall synthesis. Doxercalciferol exhibited synergistic activity in combination with bacitracin and possessed lytic activity against S. mutans through a bacitracin resistance mechanism of MbrABCD. Ferumoxytol was an FDA approved nanoparticle to treat iron deficiency (Schwenk, 2010). Liu (Liu et al., 2018) proved that ferumoxytol could disrupt intractable oral biofilms and prevent dental caries via intrinsic peroxidase-like activity.

Other drugs, such as dihydrofolate reductase inhibitor, trimetrexate analogues (Zhang et al., 2015), antiasthmatic drug zafirlukast (Gerits et al., 2017b), antifungal azoles lotrimazole and econazole (Qiu et al., 2017), efflux inhibitors reserpine (Zeng et al., 2017) have also been shown as potential inhibitors against S. mutans growth (Cui et al., 2019). Dipeptidyl peptidase (DPP IV) is a well-known therapeutic target in Type II diabetes. Anti-human DPP IV drugs saxagliptin can affect S. mutans growth (De et al., 2016; De et al., 2018).

Although drug repositioning has advantages such as lower cost, shorter development timelines and higher safety, the side effects and adverse reactions are yet to be solved (Yang et al., 2021). Firstly, the cytotoxicity of the novel molecules, particularly for the synthetic molecules should be comprehensively evaluated before clinical translation. In addition, drug resistance by oral bacteria still requires long-term evaluation both in vitro and in vivo models (Saputo et al., 2018). And the indications of reused drugs are narrow compared to antibiotics due to their original effects.

Rapid developments in computer technology makes it possible to investigate biomolecular interactions at the molecular level and design/redesign new chemical molecules through computer-aided drug design (CADD) (Dixon et al., 2006). High research costs and significant decrease in the number of new drug approvals have made commercial pharmaceutical companies hesitant to spend on drug discovery research to some extent (Kitchen et al., 2004). CADD provides information about the bioactive parts of compounds virtually and allow rapid examination of the synthesis processes in a resource-efficient, more reliable, and cost-effective way without actually manufacturing them (Kitchen et al., 2004; Thomford et al., 2018; Xu et al., 2022a). Structure-based virtual screening (SBVS) and ligand-based virtual screening (LBVS) are two main strategies commonly applied in computer-aided drug discovery (Khan et al., 2019). SBVS depends on the structure of the target and interactions with the ligands, while LBVS relies on the central similarity-property principle which indicates that similar molecules should exhibit similar properties (Ekins et al., 2007). The chemical similarity calculations are the core of LBVS (Willett, 2003). The methods of LBVS include similarity and substructure searching, quantitative structure-activity relationships (QSAR), and pharmacophore and 3D shape matching (Lavecchia and Di Giovanni, 2013). On the other hand, SBVS employs the 3D structure of the biological target to dock the candidate molecules and ranks them based on their predicted binding affinity or complementarity to the binding site (Lavecchia and Di Giovanni, 2013). SBVS and LBVS significantly minimize the complexity of finding potential therapeutic compounds against the pathogenic bacterial (Tan et al., 2008). Carmen identified ALS-31 as a small molecule inhibitor of S. mutans superoxide dismutase (SOD) by LBVS and SBVS, which inhibited planktonic growth and biofilm formation of S. mutans (Cerchia et al., 2022). Pushkaran and his colleagues (Pushkaran et al., 2019) computationally evaluated repurposing of an FDA approved drug Diosmin (DIO) using structure-based drug design method. They identified Diosmin (DIO) targeting the active site residues of L, D-transpeptidase (Ldt) enzymes which involved in Mycobacterium tuberculosis (M. bt) cell wall biosynthesis.

The process of CADD usually includes the following steps. First, various compounds aimed at the target enzyme undergo high-throughput screening. Then an absorption, distribution, metabolism and excretion (ADME) analysis is performed to determine the pharmacokinetic properties of these screened compounds. Next, molecular docking is applied to investigate the mechanism of interaction between these compounds and the target enzyme structure at the molecular level. Finally, molecular dynamic (MD) simulations and binding free energy calculations are performed to analyze the structure stability (Kitchen et al., 2004; Thomford et al., 2018). Key virulence factors such as antigens I/II, Gtfs and SrtA are usually exploited as the targets for computer-aided drug design against S. mutans ( Table 1 ).

Antimicrobial peptides (AMPs) are small bioactive proteins that comprise a part of the body’s first line to inactivate pathogens (Magana et al., 2020). AMPs can inhibit the growth of bacteria, disrupt bacterial cell membrane structure and compete with bacteria for adhesion (Jenssen et al., 2006; Guaní-Guerra et al., 2010; Magana et al., 2020). However, natural antimicrobial peptides generally have limitations, such as a short half-life, unstable in the variable oral environment, and might lead to bacterial resistance (Torres et al., 2019; Niyonsaba et al., 2020). The synthetic AMPs has the advantages including slower emergence of resistance, increased selectivity, and decreased cytotoxicity toward healthy cells (Sullivan et al., 2011; Dalzini et al., 2016; Pletzer et al., 2016). The artificial antimicrobial peptides also have favorable pharmacokinetics and desirable stability (Niu et al., 2021a; Niu et al., 2021b). The synthesized antimicrobial peptide SET-M33D, an isomeric form with D amino acids, can kill multi-resistant pathogens, including Gram-positive S. aureus, S. saprophyticus, and various Gram-negative Enterobacteriaceae with high efficacy and low toxicity (Brunetti et al., 2020). The synthesized antimicrobial peptide GH12 induced low toxicity in human gingival fibroblasts and significantly reduce the cariogenic properties of S. mutans by decreasing the lactic acid production and water-insoluble EPS synthesis (Wang et al., 2018). GH12 could make S. sanguinis and S. gordonii expand their ecological advantages by promoting hydrogen peroxide production, shifting the microbial composition to a more balanced one (Jiang et al., 2018; Jiang et al., 2020).

The methods of AMPs synthesis or discovery can be grouped into three approaches: rational design, computational design and high-throughput screening (Torres et al., 2019; Lei et al., 2021).

Traditional anti-caries agents, such as fluoride, chlorhexidine, and antibiotics, are characterized by side-effects and low selectivity, which may destroy the homeostasis of oral microbiome. More attention is being directed to find alternative agents to control biofilm-related diseases. Drug repurposing of small molecule compounds lower drug development cost and risk. However, it has come to a consensus that preventing or treating dental biofilms are particularly challenging with small-molecule drugs due to low solubility, brief topical-exposure regimens, salivary clearance, and limited drug diffusion into EPS biofilm matrix (Sims et al., 2020; Osman et al., 2022). Nanoparticle carriers have shown good ability to increase small- molecule drug penetration to biofilms, improve drug stability, and enhance drug bioavailability (Sims et al., 2020; Zhang et al., 2021), which may be potential candidates for clinical translation (Xu et al., 2022b). CADD provides information about the bioactive parts of compounds virtually and allow rapid examination of the synthesis processes. Using friendly and publicly accessible web-servers may be the future direction of prediction methods and computational tools development (Porto et al., 2018). And one of the limitations of computer-guided methods is the need for standardized and reliable biological data as input for designing process. The new synthesized antimicrobial peptide showed increased selectivity and decreased cytotoxicity, but AMPs perform poorly in the oral cavity due to low target specificity in solution, anionic protein adsorption and the diluting effects of saliva (Ramburrun et al., 2021). Designing hydroxyapatite-binding antimicrobial peptide (HBAMP), or incorporation into liquid crystalline systems (LCS) may be effective in the delivery of peptides, more strategies are still required to improve AMPs physiological in vitro and in vivo stability.

Moreover, it is noteworthy that current studies have mainly focused on in vitro or animal studies using single-species biofilms, which would limit the clinical translation of these approaches. The mechanism of small-molecule compounds’ inhibitory effect on the biofilm is still unclear. The multi-species microbial, saliva, and enzyme make the oral cavity environment complex, affecting the efficacy of the novel agents in vivo. Combining these new methods, such as computational tools and algorithms, may be an effective way to synthesize novel antimicrobial agents. Further studies are also necessary to evaluate the antimicrobial activities, bioactivity, and biocompatibility of the novel drug more comprehensively and find effective drug delivery systems.

BZ contributed to original draft preparation and writing. MZ and JT contributed to review and editing. LL and RH contributed to revise the manuscript. All authors contributed to writing and reviewing the manuscript.

This work was funded by the Health Research Fund of Shaanxi Province (NO. 2021E020) and Interdisciplinary Innovation Projects of West China Hospital of Stomatology (RD-03-202103).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.