Lindsey Backman

Question 

How do bacteria within the human microbiome, which are essential to human health, protect the enzymes they rely on for survival? 

Approach

Bacteria are constantly engaged in interspecies warfare to outcompete other microbes, including consuming niche nutrients that other bacteria cannot metabolize or possessing protective abilities that enable survival in extreme environments. With the global increase of antibiotic-resistant pathogens, there is a critical need for developing new antibiotics. The Backman lab aims to identify and elucidate strategies that bacteria employ to outcompete other species and proliferate, potentially leading to new antibiotic targets.
 
Backman’s graduate work focused on investigating new members of the glycyl radical enzyme (GRE) superfamily which catalyze key metabolic reactions in anaerobic bacteria and are abundant in the human gut microbiome. Her primary graduate project focused on characterizing a new GRE, hydroxyproline dehydratase (HypD), which uniquely enables anaerobes such as the commonly antibiotic-resistant pathogen Clostridioides difficile to consume hydroxyproline, an abundant metabolite, and thereby to outcompete commensal bacteria. Backman solved the first structures of HypD and performed biochemical experiments that led to a proposed enzymatic mechanism for HypD, which will enable structure-based inhibitor design. As HypD chemistry is niche to a subset of bacteria within the human microbiome, designing antibiotics that target HypD could afford an opportunity to specifically fight C. difficile without simultaneously killing all commensal bacteria.
 
At the Whitehead Institute, the Backman lab will explore a different competitive advantage: tactics that enable anaerobic pathogens to thrive amidst oxidative stress. Such strategies are particularly important for pathogens and disease-associated bacteria, as infections and inflammation trigger host inflammatory response pathways associated with high levels of oxidative stress. The Backman lab will utilize structural, biochemical, and genetic methods to identify and interrogate strategies that protect oxygen-vulnerable enzymes in anaerobic pathogens. Putative survival strategies that they will investigate are the uses of bacterial microcompartments (BMCs) to protect GREs from oxidative stress and GRE enzyme repair systems. Beyond uncovering mechanisms for anaerobic persistence in an oxygen-rich world, these studies will reveal novel, specific antibiotic targets and could eventually lead to the engineering of effective probiotics that employ such oxygen-resistant strategies.

Bio

Backman received her PhD in chemistry from MIT in 2022, having earned a bachelor of science in chemistry, summa cum laude, from the University of Florida in 2015. As an undergraduate, she received honors including the University of Florida Presidential Service and University Scholars awards. She also participated in HHMI’s Exceptional Research Opportunities Program (EXROP) and its Capstone Award program – which both enable students from underrepresented backgrounds to work with a university professor to pursue summer research projects. Through those programs and the MIT Summer Research Program, she worked for two summers as a research assistant in the lab of Catherine Drennan, MIT professor of chemistry and biology and HHMI Investigator, who subsequently became Backman’s PhD advisor.