Grant: Project Grant

Bacteria, such as P. aeruginosa. E. coli, K. pneumonia, and A. baumannii, can cause serious infectious diseases, including pneumonia, urinary tract infections, and diarrhea. During the past decade, the increasingly rapid spread of bacteria that are resistant to multiple antibiotics has become a real threat to our health systems. A major underlying cause for bacterial resistance is the action of a group of enzymes called beta-lactamases, which destroy beta-lactam antibiotics. Our overall understanding of those enzymes is still limited despite extensive studies in the past decades. We must develop our comprehensive understanding of beta-lactamases, in particular, 'hidden' potentials and limitations of the reservoir of beta-lactam resistance that provide future resistance, in particular, our newly developed last resort antibiotics. In this research project, we aim to develop a comprehensive understanding for beta-lactamases. In particular, we will investigate evolutionary potentials and limitations of beta-lactam 'resistome' against newly developed clinical and preclinical beta-lactam antibiotics and lactamase inhibitors. We will combine large scale bioinformatics and cutting-edge genetic technology to unveil the sequence-function relationships for all four major classes of beta-lactamases (class A, B, C and D), with an emphasis on beta-lactamases that have been spread among pathogens and non-pathogenic environmental microbes. We will also conduct high-throughput beta-lactamase characterizations and experimental evolution to unveil evolutionary potentials and limitations of several major clinically associated beta-lactamase types. Our research program will greatly advance our understanding of beta-lactamases, and the information obtained in this research will be used to develop robust surveillance programs and mitigation strategies for controlling and preventing further evolution and dissemination of beta-lactamases.