Grant: Project Grant

Antibiotic resistance is one of the most urgent health challenges of our time. Among antibiotics, beta-lactams are the most widely used, making up more than half of global antibiotic use. Within this group, carbapenems are often the "last resort" drugs used to treat life-threatening infections caused by multidrug-resistant bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. Unfortunately, these antibiotics are now under threat. Certain resistance genes, called carbapenemases, break down nearly all beta-lactam antibiotics, including carbapenems. As these genes spread globally, our ability to treat dangerous infections is becoming increasingly limited. Although some carbapenemases, such as KPC enzymes, have been extensively studied, we still know very little about their deeper genetic makeup, how they emerged, and how they may continue to evolve against new antibiotics. In this project, we will study the cluster of carbapenemases to reveal the mechanisms that enable carbapenemase activity. Specifically, we will: (1) reconstruct evolutionary trees and ancestral sequences to explore the diversity of carbapenemases, (2) identify the genetic changes that allowed carbapenemase activity to emerge, and (3) systematically explore mutational effects and evolutionary potential of clinically important carbapenemases. By combining advanced computational tools with high-throughput laboratory experiments, this research will provide a comprehensive understanding of how carbapenemases originate and evolve. Our findings will help predict how resistance genes may adapt to new antibiotics and inhibitors, offering critical insights for the development of next-generation therapies and strategies to combat antimicrobial resistance.