Research
Doctoral Research: Design and synthesis of hydrogel encapsulated dental biofilm inhibitors
Dental caries represents a pervasive oral health concern characterized by the degradation of tooth enamel due to the acidic milieu generated by acidogenic bacteria thriving within intricate biofilm communities. Among these pathogens, Streptococcus mutans (S. mutans) stands out as a primary culprit. This bacterium secretes glucosyltransferase (Gtf) enzymes, which act as chain producing machines pivotal in catalyzing the synthesis of adhesive glucans, which form a scaffold for bacterial aggregation, culminating in robust biofilm formation. Within this biofilm, S. mutans and its acidogenic cohorts metabolize dietary sugars to produce lactic acid, instigating tooth demineralization. While conventional preventive measures like oral hygiene practices offer some reprieve, biofilm recalcitrance persists, necessitating novel intervention strategies. Mouthwashes are powerful in killing oral bacteria, but they also eliminate beneficial microbiota indiscriminately.
During my doctoral studies, I undertook a targeted approach, aiming to disrupt biofilm formation by inhibiting Gtf activity, thereby impeding glucan synthesis. This strategy, distinct from bactericidal approaches, seeks to render the bacteria disarmed rather than eliminating them outright. Leveraging high-throughput computational screening of extensive compound libraries, we identified small molecule inhibitors of Gtf enzymes, subsequently subjecting them to structure-activity relationship (SAR) studies to optimize efficacy. The efficacy of these lead compounds was evaluated through rigorous in vitro assays involving S. mutans and select commensal species such as S. gordonii, S. sanguinis, and S. parasanguinis, shedding light on their specificity and potential impact on oral microbiota equilibrium. Most promising candidates underwent encapsulation within polymeric nanomaterials to afford pH-responsive delivery, ensuring targeted action within the acidic microenvironment of dental biofilms.
Encouragingly, our encapsulated biofilm inhibitors demonstrated significant efficacy in vivo, as validated through rat models, offering promising prospects for clinical translation. These findings have been disseminated through peer-reviewed publications in esteemed journals such as the ACS Medicinal Chemistry Letters4 and Journal of Medicinal Chemistry, with another manuscript ready to be published to extend our investigations using alternative polymeric matrices for encapsulation.
In essence, my research endeavors epitomize a concerted effort to unravel the intricate dynamics of dental biofilm formation and devise innovative strategies for targeted intervention, poised to alleviate the burden of dental caries while preserving the delicate balance of the oral microbiome.
Watch the video
The story about discovery of G43, an antibiofilm agent for prevention of dental caries made news in 2017 (News Medical and Medical Express). Since then it has been one of the most important projects for Dr. Velu. Parmanand Ahirwar picked up this project when he joined Dr. Velu's lab in 2018. Since then they published 90 modifications to G43 (ACS Medicinal Chemistry Letters) while looking for a better biofilm inhibitor and to understand effects of change in inhibitor structure on its antibiofilm activity. University of Alabama at Birmingham covered G43 in their video in 2020.
Master's thesis: Structure-based study, design, and synthesis of inhibitors against histidine kinase protein from Streptococcus pneumoniae
During my master’s studies at the esteemed Indian Institute of Technology Bombay, I focused on designing and synthesizing histidine kinase inhibitors to disrupt the two-component signaling system in Streptococcus pneumoniae. This research aimed to counteract bacterial drug resistance mechanisms. Specifically, I developed small molecules based on sulfonyl pyrazole scaffolds and evaluated their efficacy through in vitro assays, calculating minimum inhibitory concentrations using functional bioassays.
Industrial research – Cerflux Inc.
In my current part-time position as a medicinal chemist at Cerflux Inc, I am tasked with screening potential cancer drugs for their efficacy against colorectal cancer cell lines and bioprinted organoid tumors (BOTs). Utilizing an epMotion robot, I conduct dose-dependent drug treatments on various colorectal cell lines. Subsequently, I employ fluorescent microscopy to image the resulting plates, enabling the estimation of cell viability at different drug doses by distinguishing between live and dead cells. Additionally, I perform a CellTiterGlo luminescence assay to confirm IC50 values, ensuring accurate assessment of drug potency.