Every year in the United States alone, an estimated 2 million infections and 25,000 deaths are caused by bacteria that are resistant to antibiotics. In addition to this staggering toll on human health, the annual economic impact of these infections is estimated to be an equally astounding $20-35 billion. Moreover, the unfavorable economics of antimicrobial development have led many pharmaceutical companies to either scale back or to entirely eliminate their antibiotic development efforts. The escalating futility of existing antibiotic therapies, combined with a dwindling development pipeline, is threatening to plunge civilization back into the pre-antibiotic era, where routine cuts can lead to life-threatening infections. Our research program addresses the growing threat of drug-resistant human pathogens through several distinct, yet inter-related and cohesive approaches.
NATURAL PRODUCT BIOSYNTHESIS
The first major aim of our work is to better understand natural product (NP) biosynthesis. NPs are “privileged” molecular scaffolds that account for the majority antimicrobials approved for clinical use around the world. Many bacterial NPs are constructed by multifunctional enzyme assemblies that require protein-protein interactions (PPIs) to maintain catalytic efficiency and to steer product structural fidelity during the course of the multi-step biosynthetic process. Understanding the nature of these PPIs facilitates rational manipulation of NP biosynthesis for synthetic biology and molecular engineering purposes. Our lab capitalizes on several emerging biochemical and biophysical techniques to provide a unique perspective into the role of PPIs in NP biosynthesis. Our studies define relationships between molecular interactions and enzymatic catalysis, inform engineering efforts, and inspire similar approaches to uncover the biosynthetic rules for many classes of NPs. We are also interested in the discovery and characterization of new natural products. Click here for more information about this project.
UNDERSTANDING BACTERIAL BIOFILMS
Our second major research aim focuses on a different aspect of bacterial infections. Many pathogens are difficult to treat with existing antimicrobials due to their propensity to form biofilms. One strategy to combat these pathogens would be to interfere with the biochemical processes that help to establish and maintain growth in the biofilm state. The hypothesis is that coaxing the organism out of the biofilm state will render the organism more susceptible to traditional antibiotics. Along these lines, we are interested in the fundamental mechanisms of biofilm biogenesis – especially those mechanisms that involve protein-protein interaction networks. The experimental tools developed during the course of this work could potentially lead to new molecules for the dispersion of biofilms, and will be broadly applicable for studying many other fundamental processes in bacteria, such as membrane biogenesis and maintenance, nutrient acquisition, and protein quality control. Click here for more information about this project.
BACTERIAL PROTEIN SECRETION MECHANISMS
Another focus in our lab is to develop new methods for peptide delivery into Gram-negative bacterial cells. The outer membranes of Gram-negative bacteria are typically impervious to molecules larger than approximately 500 Da. Robust methods for circumventing this barrier will open avenues for the application of unique antimicrobials, such as peptide based inhibitors of protein-protein interactions. This work will harness and exploit several natural secretion systems used by Gram-negative bacteria to deliver effector molecules to neighboring cells. Our work includes a basic science component geared towards understanding the mechanism of the secretion machineries and their capacity for manipulation, as well as a translational component geared towards engineering vehicles for peptide delivery to target specific cells. Click here for more information about this project.
Altogether, our research contributes to a fundamentally new molecular mechanistic understanding of natural product biosynthesis and bacterial physiology. Once the biological principles are illuminated, this knowledge can be exploited to devise strategies to treat antibiotic resistant microbes, as well as to replenish our rapidly diminishing arsenal of effective antimicrobial agents.