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Mechanisms and Clinical Significance of β-Lactam Tolerance in Gram-negative Pathogens

Antibiotic treatment failure is an increasingly widespread burden on human health that poses one of the most significant threats to planetary life. Treatment failure is often due to the development of antibiotic resistance. A complete comprehension of the factors that promote the development, and particularly the dissemination, of antibiotic resistance is still lacking. Nonetheless, evidence suggests that antibiotic “tolerance” – the ability of a microorganism to sustain viability for extended time periods in the presence of antibiotics – is an important stepping stone towards frank resistance. This project, a collaborative effort between the Dörr Laboratory in Ithaca, and the Westblade Laboratory at Weill Cornell Medicine in NYC, is focused on β-lactam tolerance in nosocomial Gram-negative pathogens such as Klebsiella pneumoniae and Enterobacter cloacae. Using a diverse toolset encompassing genetic, biochemical and clinical microbiology methods, we will interrogate the metabolic state and the genetic circuitry underlying β-lactam tolerance in clinically important Gram-negative pathogens. Furthermore, we will probe the connection between tolerance and the development of overt β-lactam resistance (e.g., acquisition of β-lactamases, which are enzymes that degrade β-lactams). Ultimately, we hope to uncover novel targets for antitolerance agents that could serve as adjuvants to improve the efficacy of β-lactam antibiotics, which are among our most important antibiotics.

This project is a collaboration between the Doerr, and Lars Westblade (Weill Cornell Medicine) labs.