Research
The main interest of our lab is in bacterial stress response pathways (SRPs), mediated by either second messengers (e.g., the universal stringent response alrmones (p)ppGpp, cyclic AMP etc) or two component systems. These SRPs are vital for bacterial survival of various stresses including antibiotic challenges and phage attacks in natural environments. Therefore, SRPs are intimately linked with bacterial antibiotic tolerance, persistence and resistance, and phage-bacteria arms-race. To this, interdisciplinary tools such as systems biology, crystallography, omics, biophysical and molecular tools, infection models are used in combination via collaborating with international leading researchers, to study the fundamental molecular mechanisms of bacterial virulence, stress/antibiotic tolerance and resistance. Current focus is described below.
ppGpp homeostasis
Bacteria rapidly synthesize ppGpp from ATP and GT/DP in response to various stresses (including starvation of nutrients, physicochemical challenges), and degrade ppGpp once stress is alleviated. We aim to unravel the molecular mechanisms how the enzyme activities of RelA (ppGpp synthetase I) and SpoT (ppGpp synthetase II & hydrolase) are regulated in response to these environmental changes.
ppGpp target proteins
Once produced, ppGpp targets a variety of proteins involved in the central dogma information flow chain. Recently, we systematically identified many novel ppGpp target proteins, most of which are highly conserved. The molecular effect of ppGpp on the target proteins is a major focus in the lab.
ppGpp physiology
The production of the universal ppGpp and its binding on the many target proteins have profound effects on bacterial physiologies, including virulence, tolerance and resistance to antibiotics, and persistent infections. We aim to uncover the underlying molecular linkages, so that novel strategies and drug targets could be developed to combat multidrug resistant superbugs.
Key words: stringent response, ppGpp, antibiotic tolerance, persistence, antibiotic resistance, second messenger
Fundings
