Mimicking AMPs as an Approach to Improve Oral Health Maintenance: Ceragenins--Lipid Analogs of AMPs  
As stated above, the primary way to modulate the biological activity of natural AMPs, both in terms of biological activity and their selectivity to bacterial cells or toxicity to host cells, is to alter the amino acid sequence to change its basic physicochemical characteristics, such as charge or hydrophobicity. Ultimately, such changes lead to the modulation of the peptide's internalization into the biological membranes of the pathogen, allowing for the exertion of a direct antimicrobial effect. On the other hand, mimicking the specific characteristics of AMPs that determine their membrane-interacting abilities, in particular, positive charge and facial amphipachicity, is an innovative way to obtain new biologically active molecules. Using such an approach, ceragenins were developed as non-peptide mimics of AMPs [120]. Ceragenins are derived from cholic acid, a common bile acid that inherently displays facial amphipachicity and is secreted into the gastrointestinal tract to aid in the solubilization of lipids. Because they are based on cholic acid, ceragenins were originally referred to as cationic steroid antibiotics, but to eliminate any implication that these compounds could have steroid-like characteristics, they were renamed as ceragenins. Importantly, since ceragenins are based on the structure of cholic acid, they are not substrates for proteases [121], which are ubiquitous physiologically and are commonly produced by pathogenic microorganisms [122]. Ceragenins are well tolerated by local administration [123]. A key characteristic of ceragenins is that their preparation is simpler and less expensive than the peptides they mimic [124; 125] (Table 2). Collectively, ceragenins are highly efficient against Gram-positive and Gram-negative bacteria [126], both aerobic [127] and anaerobic [124], as well as against yeast and filamentous fungi [128], and viral pathogens [129]. Such broad-spectrum activity of ceragenins is proposed to be due to their ability to associate with microbial and viral membrane components and induce membrane disruption, likely by the carpet model mechanism. Studies performed by [PERSON] et al. demonstrated that the target of ceragenins with Gram-negative bacteria is the lipid A portion of lipopolysaccharide-NDR, which assures a considerable selectivity of these compounds toward bacterial cells over the host cells [130]. Interestingly, in Gram-positive bacteria, which do not produce LPS, the bactericidal activity of ceragenins was correlated with a content of phosphatidylinositolamine in the bacterial membrane [131]. With either type of target, the ability of ceragenins to depolarize and permeabilize microbial membranes is recognized as crucial for their killing activities [132]. Some studies also describe the ceragenin-mediated induction of oxidative stress due to the overproduction of reactive oxygen species in treated microbial cells [133]. In addition to this membrane-based-established mechanism of activity, most recent research carried out using a combination of whole-genome sequencing (WGS) and transcriptome sequencing (RNA-seq) revealed that ceragenin CSA-13 promotes the downregulation of acid stress-associated genes and a distinct dysregulation of genes involved in carbon metabolism, resulting in a switch from pyruvate fermentation to the glyoxylate pathway [134]. As such, ceragenins as metabolism-regulating molecules should also be recognized apart from their membrane-permeabilizing features. Moreover, in addition to the potent activities of ceragenins against planktonic microorganisms, they also display considerable antibiofilm activities, which are associated