Research Overview

The rapid rise in multidrug resistant organisms pose special challenges to treating bacterial infections. Therefore, therapeutic strategies that combat bacterial virulence without aggravating drug resistance are in great demand. Since antibiotics threaten the survival of microorganism, it puts selective pressure on bacteria to develop resistance. Therefore, compounds that doesn’t directly kill bacteria (antibiotics) but rather limits the microbe’s ability to harm the host (antivirulence) are attractive as novel antimicrobials in antibacterial therapy.

When and how does bacteria turn virulent?

A single cell bacterium in the planktonic mode do not have the means to impact the environment. In this state, bacteria are typically avirulent. In most instances however, bacteria seldom remain in the planktonic mode but instead communicate and cooperate with their immediate neighbors to behave like a multicellular species. In the ‘social/group mode’ bacteria makes collective decisions to fight off common threats such as a looming antibiotic attack, immune response from the host during infection, responding to resource strains in the environment etc.  Interbacterial communication helps bacteria transition from an avirulent planktonic state to a virulent social mode. This communication is facilitated by a chemical signal sensing mechanism called “Quorum Sensing”.  

How does Quorum Sensing work?

Bacteria makes specific signal molecules called autoinducers. While Gram-positive bacteria use peptide signaling, Gram-negative bacteria predominantly use Acyl Homoserine Lactones (AHLs) chemical signals to facilitate quorum sensing. A dedicated set of proteins called the I-proteins or AHL synthases make these intracellular AHL signals that are eventually released to the local environment. Since signal strength in the environment reflect local population-levels, bacteria count these signals to estimate its local population density and hence the name quorum sensing (QS). QS informs bacteria if their local population has reached quorum levels necessary to trigger social traits such as forming a biofilm, releasing virulence factors, infecting a host etc. Since a larger population gives bacteria a competitive advantage to survive an immune / antibiotic onslaught, this information is critical for them to judge the optimum timing to infect a host. Quorum sensing inhibitors would interfere with bacteria’s ability to count its population and keep them in an avirulent mode. The long-term focus in our lab is to develop quorum sensing modulators that either inhibit or activate QS in bacteria (can you think of a reason on how QS activators could also become useful tools to fight bacterial infections?). In addition to their biomedical significance, QS modulations may also serve as useful mechanistic probes to study social behavior in bacteria (sociomicrobiology).