Background: Dental caries is the most common and one of the prevalent diseases in the world. Streptococcus mutans is one of the major oral pathogen that causes dental caries by forming biofilm on dental tissues, degrading dental enamel and consequent cavitation in the tissue. In vitro selection of drug targets is a laborious and expensive process and therefore computational methods are preferable for target identification at initial stage. Objective: The present research aims to find new drug targets in S. mutans by using subtractive proteomics analysis which implements various bioinformatics tools and databases. Methods: The proteome of S. mutans UA159 was mined for novel drug targets using computational tools and databases such as: CD-HIT, BLASTP, DEG, KAAS and CELL2GO. Results: Out of 1953 proteins of S. mutans UA159, proteins that are non-redundant, non-homologous to human and nonessential to the pathogen were eliminated. Around 178 proteins already available in drug target repositories were also eliminated. Possible functions and subcellular localization of 32 uncharacterized proteins were predicted. Substantially 13 proteins were identified as novel drug targets in S. mutans UA159 that can be targeted by various drugs against dental caries. Conclusion: This study will effectuate the development of novel therapeutic agents against dental carries and other Streptococcal infections.

Streptococcus mutans, in spite of its natural occurrence in human oral cavity, causes dental caries and rarely, in some complications, infective endocarditis. Development of vaccines or drugs to prevent or control these organisms has been under study. Histone-like protein (HLP), a nucleoid associated protein, is found essential for the survival and virulence of these pathogens. We have employed an in silico approach to specifically target the HLP of Streptococcus mutans with available approved drugs from DrugBank. Computational analysis showed conserved regions in DNA-binding domain of the S. mutans HLP and its homologues in 47-49 and 78-79 residues. The S. mutans HLP was found to be closely related within streptococcal species in phylogenetic analysis. Alanine and lysine were found to be higher in the protein which is the characteristic of histone-like proteins. The crystal structure of S. mutans HLP is similar to HLP from Mycobacterium tuberculosis despite their sequential variations and evolutionary distance. Etravirine, Abacavir, Adenosine phosphate, Flucloxacillin, Nelarabine, and Regadenoson were found to efficiently bind at the DNA binding domain of S. mutans HLP. From these results it can be concluded that these drugs can be repurposed to control streptococcal infections.

Bacteria use quorum sensing as a way of inter and intra- species communication. Quorum sensing was found to be important for bacteria for various processes including establishing an infection through virulence and biofilm formation. This is mediated autoinducers, which are usually produced by one group of bacteria and recognized by another group through a response regulator protein. LuxR is a response regulator protein first discovered in Vibreo fischeri and it recognizes autoinducers produced by the same species of bacteria. E. coli also has a response regulator called SdiA which is a homolog of LuxR, originally found to be involved in transcription and cell division. SdiA was later reported to regulate quorum sensing by binding to autoinducers called Acyl Homoserine Lactones (AHLs). SdiA is also reported to be involved in enhancing the multidrug resistance and virulence in pathogenic E. coli. Though many studies elaborate the functional aspects of SdiA, sequence and structural level analysis of this protein is missing in the literature. The current work aims at the in silico analysis and targeting of SdiA with structural analogs of AHLs. 7 compounds were found to be promising molecules to inhibit quorum sensing in E. coli.