A druggable target protein from S. mutans. A highly reliable structural model for uracil-diphosphate acetyl-glucosamine epimerase, shown by hydropathy plot (red as hydrophobic, blue as hydrophilic) and featuring a long, narrow pocket for drug binding. Figure courtesy of Jeremy Horst.
Genomic sequences of many bacterial species are now available, and having the entire derived proteome at hand offers many opportunities for drug development. However, one still needs to find the appropriate targets among the proteome. Horst and colleagues (PSI NYSGRC) have developed a strategy to identify potential drug targets in the bacterium Streptococcus mutans in the context of other dental plaque bacteria.
Dental caries cause irreversible damage to teeth and represent a heavy burden on global public health. Many factors contribute to the etiology of dental caries, including dietary sugars and the presence of certain bacterial species in dental plaque. While some species such as S. mutans are cariogenic, others can have a protective effect. Thus, a potential way to prevent and combat dental caries is to specifically target the cariogenic bacteria while preserving those that are non-cariogenic.
The authors followed three analytical steps to find useful drug targets among the 2,391 predicted proteins in S. mutans. First, they used MODELLER-v9.10, a restraint-based comparative modeling program, to produce models of 1,631 proteins, of which 616 were considered highly reliable (available at ModBase). Next, they assessed those 616 models along with 81 structures available in the PDB for “druggability,” i.e., the presence of favorable drug-binding sites, whittling the list to 110 proteins. Those included 15 virulence factors, 16 proteins with available crystal structures and 84 previously unidentified proteins.
Finally, the authors examined the specificity of these targets, by generating phylogenetic profiles for each of those proteins, among other cariogenic (target) and non-cariogenic (antitarget) bacteria. Unfortunately, none of the druggable proteins identified were differentially abundant among cariogenic bacteria, indicating that drugs designed against those proteins would affect the non-cariogenic species as well. This arose due to a lack of sufficient structural templates for the etiologic proteins and their control mechanisms.
It is likely that there are druggable and specific target proteins among S. mutans and other cariogenic bacteria that could not be modeled in this work. This limitation should be overcome as more protein structures become available. Nevertheless, the work provides a valuable map to streamline target selection for rational drug discovery against chronic multibacterial diseases.