albicans_ growth in models imitating clinical cariogenic conditions and demonstrated that _L. plantarum_ 14917 and the AMP produced by this organism--plantaricid--had an inhibitory effect on the expression of _S. mutans_ and _C. albicans_ virulence genes, as well as on the formation of _C. albicans_ hyphae [72]. As an agent to improve oral health, microcapsules containing the probiotic _Streptococcus salivarius_ LAB813 strain were developed by [PERSON] et al. [73]. A similar approach was tested most recently by [PERSON] and co-workers who developed a chewing gum containing _Lactobacillus_ spp. and _Bifidobacterium_ spp. in both lyophilized and microencapsulated form. In an in vitro investigation, they found that both microorganisms had a strong capability to limit the growth of cariogenic _Streptococcus mutans_ UA 159, and this was attributed to the generation of AMPs, which caused the cariogenic bacteria to be inhibited. Significantly, the inhibitory effects of this method were similar to those of the oral antiseptic chloroxididine 0.2% under laboratory conditions, indicating its strong potential for clinical use [74]. Natural AMPs, Their Synthetic Analogs, and Their Potential Utility in the Treatment of Oral Diseases--Recent Insights  
Due to the spectrum of beneficial features of AMPs, including antimicrobial [43], immunomododulatory [45], and regenerative [46] activities, AMPs have been evaluated as therapeutic agents for the treatment of oral diseases such as halitosis [75], caries [76], mucositis [77], and periodontitis [78]. Several recent reviews [43; 52; 79] describe the therapeutic potential of defensins against bacterial, fungal, and viral pathogens. Moreover, a compelling amount of data suggest their utility in the diagnosis and treatment of head and neck cancers [80]. Attention has also turned to milk AMPs. Through the utilization of an integrated approach that incorporates in vitro proteolysis optimization, antimicrobial activity assays, proteomics profiling, and MBPDB database matching, researchers have successfully isolated and proven the efficacy of casein-derived peptides against oral pathogens, specifically _S. mutans_ and _P. gingialis_, in both planktonic and biofilm states [81]. Although the activity of the milk-derived peptides themselves did not differ significantly from other peptides of natural origin, the authors' high-throughput approach itself directed further research on other peptides for oral disease therapy. In addition to highly promising results obtained using naturally occurring AMPs, recent studies have also involved synthetic AMPs, developed based on both human and non-human sources. Such an approach is highly understandable and justified considering some crucial limitations for naturally occurring antimicrobials, including hampered extraction and problems with large-scale preparation, short half-life, susceptibility to pro -tease degradation, inactivation by physiological salt concentration, and the presence of saliva [82]. For these reasons, a spectrum of modifications to AMPs has been made, namely polymerization of \(\alpha\)-amino acid N-carboxyanhydride, PEGylation, usage of D-amino acids, or unnatural amino acids, cyclization, lipidation, and backbone modifications [83]. One such modified peptide is [W\({}^{7}\)]KR12-KAEK, which was developed by the substitution of isoleucine to tryptophan at the seventh position and the addition of KAEK to the sequence of KR-12 peptide (i.e., 18-29 amino residues of LL-37). As [PERSON] et al. demonstrated, [W\({}^{7}\)]KR12-KAEK exhibited potent anti-_E. faecalis_ activity in contrast to the inefficient KR-12 peptide, and they concluded that this difference in peptide activity resulted in interactions of specific amino acids within the sequence. Specifically, the substitution for tryptophan, which is prevalent in many AMPs due to its hydrophobicity and charge, as well as the insertion of the KAEK sequence at the C-terminal position of KR-12, caused an increase in the peptide chain size and altered its charge and amphipability [84].