Research Overview

The rise of multidrug-resistant bacteria creates an urgent need for new approaches to treating infections. Alongside conventional antibiotics, strategies that interfere with bacterial communication, nutrient acquisition, and interactions with the host offer promising opportunities for therapeutic development. In the Nagarajan laboratory, we combine mechanistic enzymology, chemical biology, and small-molecule discovery to investigate these processes. Our research encompasses three interconnected areas: quorum sensing, sialic acid scavenging, and substrate recognition by acyl-CoA- and acyl-ACP-utilizing enzymes.

How do bacteria communicate and coordinate their behavior?

Bacteria respond to their surroundings both as individual cells and as communities. One mechanism that helps coordinate community behavior is quorum sensing (QS), a form of chemical communication mediated by signals called autoinducers. Many Gram-negative bacteria use acyl homoserine lactones (AHLs), while peptide signals are common in Gram-positive bacteria. As these signals accumulate, they bind to receptors and alter gene expression, helping bacteria coordinate activities such as biofilm development, nutrient acquisition, and the production of virulence factors.

Our laboratory investigates AHL synthases, also called I-proteins, which produce AHL signals. We seek to understand how these enzymes recognize their substrates and catalyze signal synthesis, and to develop small molecules that interfere with this process. We also investigate quorum sensing modulators as mechanistic probes of bacterial communication and social behavior. Targeting QS may provide opportunities to reduce pathogenic behavior.

How do bacteria exploit host-derived sialic acids?

Sialic acids are sugars found on host cell surfaces and in mucus. Some bacteria acquire these sugars through scavenging pathways that involve their release from host glycoconjugates, transport into bacterial cells, and enzymatic breakdown. Sialic acid utilization can provide nutrients that support bacterial growth and colonization. Certain bacteria also incorporate sialic acids into their surface structures, helping them evade immune recognition.

Our laboratory is investigating the enzyme mechanisms underlying sialic acid scavenging and developing small-molecule inhibitors to probe their functions. By combining biochemical assays, enzyme kinetics, and computational screening, we aim to identify opportunities to disrupt bacterial access to host-derived nutrients and evaluate this pathway as a potential target for anti-infective strategies.

How can cyclic acyl-chain scaffolds reveal enzyme function and guide inhibitor design?

Many enzymes use substrates carried by coenzyme A (CoA) or acyl carrier protein (ACP). These enzymes must recognize both the carrier and its attached acyl group. Understanding this recognition is essential for explaining substrate preferences and designing inhibitors that distinguish among enzymes utilizing similar substrates.

We investigate cyclic acyl-chain scaffolds as tools for probing these interactions. Replacing flexible acyl chains with ring-containing structures allows us to examine how substrate shape and rigidity influence binding, catalysis, and substrate inhibition. These studies connect our work on AHL synthases with broader questions about acyl-CoA- and acyl-ACP-utilizing enzymes. Our goal is to establish principles of substrate recognition that can guide the development of potent and selective enzyme inhibitors.