Dissecting Molecular Recognition in Key Events of Bacterial Quorum Quenching and Acid Resistance via Mechanistic Crystallography

In an effort to target bacterial stress response for antimicrobial discovery, Liu studied lactonases related to quorum quenching and a PLP-dependent transcription activator GabR related to acid resistance. Both types of proteins possess potentials for developing new treatments for persistent lung infections. Lactonases are bimetallo hydrolases that degrade various quorum-sensing signals and could be used as therapeutic reagents subverting virulence expression. With a regulation domain homologous to type I aminotransferases, GabR requires simultaneous binding of both PLP and y-aminobutyric acid (GABA) to activate a pathway regenerating glutamate from GABA under acidic stress. Unique in bacteria, GabR could be an anti-virulence target. Assisted by biochemical and biological assays, Liu obtained a series of high-resolution crystallographic snapshots to dissect their mechanisms of molecular recognition, revealing both ligand intermediates and protein dynamics critical for their respective biological functions. Their mechanisms of molecular recognition showed that lactonases possess broad substrate specificity while GabR triggers a specific response to the increase in GABA concentration. Revealed mechanisms provide foundations for further efforts in developing anti-virulence methods.