Bacterial biofilms are detected in almost 80% of human bacterial infections. Certain D-amino acids have been recently determined to serve as biofilm disruptors by their misincorporation into the bacterial cell wall by a promiscuous enzyme, transpeptidase. The introduction of the amino acid then interferes with protein synthesis, leading to proteotoxicity. Even with the novelty of this discovery, the number of functionalized D-amino acids that have been screened is minimal. To begin to address this void, undergraduate scientists in my laboratory have synthesized unnatural D-amino acids. Upon optimization of coupling conditions, the amino acid was deprotected and purified. A small library of D-glutamic acid variants was generated and will be screened for biofilm inhibition in virulent gram-positive bacteria such as Staphlococcus epidermidis. Quorum sensing is a process of chemical communication in bacteria that leads to biofilm formation and virulence. Thus, impeding this mechanism could lead to new avenues for the development of antivirulence strategies. In gram-negative bacteria, a family of molecules known as the N-acyl homoserine lactones (AHLs) is the agents of communication. Recently, hydrolysis of the critical lactone moiety that leads to signal inactivation has been hypothesized to be attenuated by a key n to pi* orbital interaction between the N-acyl functionality and corresponding lactone carbonyl. The goal of my laboratory is to investigate how rates of hydrolysis are impacted by disrupting that interaction through the synthesis of N-benzoyl homoserine lactone (BHL) derivatives. Through the introduction of electron withdrawing and electron donating groups onto the BHL scaffold, a linear free energy relationship for lactone hydrolysis is being established so that the impact of the interaction on lactone hydrolysis rate can be quantitatively assessed. This could give insight into new strategies for inhibiting quorum sensing (or quorum quenching).

Synthetic strategies to control bacterial virulence

249th National Meeting (2015)

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