Thursday, November 21, 2024
11/21/2024
Project Summary The environment is a primary determinant of bacterial growth and behavior. It impacts not only metabolism and growth rate, but also morphology, development, and antibiotic susceptibility. Our research centers on the essential processes that coordinate cell growth and cell cycle progression with the environment. In bacteria these processes are critical, maximizing proliferative potential across a wide physicochemical landscape. Defects in these processes can be catastrophic, impairing growth, reducing viability, and rendering cells hypersensitive to antimicrobials. The increasing prevalence of antibiotic resistant pathogens provides a powerful motivation for our work. Understanding how bacteria adapt to the physicochemical environment should reveal novel approaches for the treatment of bacterial pathogens and identify targets for the development of next-generation therapeutics. In this this effort we employ evolutionarily distinct organisms including two Gram-negative Gammaproteobacteria: the model organism Escherichia coli and the pathogen Klebsiella pneumoniae. In 2019 K. pneumoniae was the third leading cause of global deaths due to or associated with antibiotic resistance (Lancet, 2022). The cell envelope is vital to bacterial viability, required as both a permeability barrier and a buttress against turgor pressure. Exposed to the environment, essential cell envelope processes must remain functional across a large range of conditions. Understanding the factors that underlie and preserve cell envelope integrity is a primary research focus. Extending our finding that functional redundancy amongst E. coli cell wall enzymes ensures robust growth across pH values, we will use single molecule techniques and biochemistry to illuminate the impact of pH on the activity of individual PBP transpeptidases in situ. These enzymes play a critical role in peptidoglycan cross linking and are the target of beta-lactam antibiotics. We will also identify factors underlying pH-mediated changes in cell wall synthase activity and beta-lactam resistance in K. pneumoniae. As part of a broader effort to understand the mechanisms coordinating cell envelope biogenesis with cell growth and cell cycle progression, we will elucidate the essential role of the outer membrane component lipopolysaccharide (LPS) in E. coli biology. Finally, building on our longstanding interest in the relationship between nutrient availability and cell morphology, we will characterize the mechanisms governing a newly identified starvation-mediated stress response, cytoplasmic condensation, and identify the effector(s) responsible for the positive relationship between the starvation-associated alarmone, ppGpp, and cell division. We are aided in these endeavors by our multidisciplinary approach that employs a diverse array of techniques, as well as an extensive network of close colleagues and collaborators with whom we enjoy a free exchange of reagents and ideas. These advantages allow us to answer previously intractable questions in physiology and homeostatic control that are relevant to organisms throughout the tree of life.
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