Tu-Anh Huynh

The role of c-di-AMP in bacterial adaptation and pathogenesis

In order to adapt, bacteria need to survey environmental conditions and reprogram themselves accordingly. There are many signaling mechanisms that enable bacteria to sense the environment, relay the signals, and regulate relevant molecular targets. Nucleotide second messengers are important components of all these events that ultimately facilitate bacterial growth and adaptation.

C-di-AMP is a ubiquitous nucleotide second messenger produced by thousands of bacterial species representing important human pathogens, gut symbionts, and environmental bacteria. C-di-AMP is essential to the growth of many bacteria, and its depletion results in loss of virulence, increased antibiotic susceptibility, among other defects. However, bacteria that produce c-di-AMP also need to maintain a balanced level of this nucleotide, since c-di-AMP accumulation also attenuates virulence and diminishes stress response.

A major focus of our lab is to understand how c-di-AMP mediates bacterial stress response, adaptation, and pathogenesis. Our models for c-di-AMP work are the human pathogen Listeria monocytogenes, the first bacterium found to make c-di-AMP; and the Gram-positive model Bacillus subtilis. Active projects address the following themes:

• How do bacteria regulate c-di-AMP levels to achieve homeostasis?

• How does c-di-AMP regulate its molecular targets?

• How does c-di-AMP regulate bacterial adaptation in mammalian hosts?

Mechanisms of antibiotic resistance

Antibiotic resistance is an urgent public health threat, with estimated 2.8 million antibiotic-resistant infections a year in the US. A long-term goal of our lab is to develop novel antibiotics or adjuvants that potentiate the efficacy of current antibiotics. We currently focus on understanding resistance mechanisms to cell wall-targeting antibiotics, including beta-lactams and D-cycloserine. Active projects address the following themes:

• How does c-di-AMP regulate bacterial cell wall synthesis and cell envelope stress response?

• What are the resistance mechanisms to cell wall-targeting antibiotics in Gram-positive bacteria?

Discovery of natural antimicrobials for food safety and infectious disease treatments

Combating antibiotic resistance requires continual discovery and development of new antibiotics, or adjuvants that increase the efficacies of current antibiotics. We employ both culture-based and culture-independent approaches to identify novel antimicrobials from diverse environmental and food fermentation microbiota. Active projects address the following themes:

• Develop biocontrol agents for foodborne pathogens, such as Listeria monocytogenes, from the food microbiota and food-grade microorganisms
• Discover novel antimicrobials from various microbiota for treatment of infectious diseases in humans and animals