Targeting the Quorum sensing in ‘ESKAPE’ organisms through Sortase A and Biofilm Inhibition: Design, Synthesis, Sortase A and Biofilm Inhibitory Potential of some New Antibacterials
Implementing Organization
Y. B. Chavan College Of Pharmacy
Principal Investigator
Dr. Jaiprakash Navnath Sangshetti
Y. B. Chavan College Of Pharmacy, Maharashtra
jnsangshetti@rediffmail.com
CO-Principal Investigator
Nil
Project Overview
The resistance of the drugs is a major hurdle in discovery of effective antibacterial agents . To address the issue in past number of new targets have been explored. Quorum sensing (QS) is considered as important phenomenon of cell-to-cell communication which is mediated by chemicals expressed in many microbial species. QS play an essential role in intensifying disease condition through dominating microbial life events. The critical life events include the formation of biofilm, articulation of virulence determinant etc Generally, low molecular weight chemical signals steer microbial cell communication to carry out indispensable life events. The genesis of biofilm which is a multistep process is thus one of the essential processes that help microbial cells withstand unfavorable environments and sustain their survival. In last few decades inhibiting the biofilm formation has been considered as an important target in antibacterial drug discovery. The enzyme sortase A, present on the bacterial cell surface plays a key role in bacterial virulence without affecting the bacterial viability. In past few years Inhibition of sortase A activity has also been considered as powerful stratergy to discover new antibacterial agents. The enzyme sortase A, present on the bacterial cell surface plays a key role in bacterial virulence without affecting the bacterial viability. Designing the compounds which inhibits or targets at multiple sites in bacteria is one of the significant aspect in antibacterial research. Utilizing this approach will be in future a significant and successful approach in the search for new antibacterial agents.This approach helps in reducing the frequency of mutations in bacteria. This approach interrupt the immediate commencement of resistance in bacteria and this is the key significant aspect of this approach which have been proved in number of literature reports in last ten years.Considering this targeting the different steps involved Quorum sensing by inhibiting Biofilm formation and enzyme Sortase A can be proved fruitful in discovery of new antibacterial agents and there by addressing the resistance issue. With this view we have decided to focus on the Sortase A enzyme and biofilm inhibition from “ESKAPE” pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanni, Pseudomonas aeruginosa, and Enterobacter ). We have designed some important novel cores which will be inhibit enzyme Sortase A and biofilm formation in bacteria . This is the first attempt from India to work on this approach. Targeting sortase A enzyme, bacterial adhesion, EPS synthesis for designing the molecules is most novel aspect of the project. The library of more than 80 compounds which are completely novel using different synthetic protocol is another important aspect of the project. RTPCR analysis performed which helps additionally to identify the key protein involvement in biofilm inhibition processes.