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TARGETING ANTIBIOTIC RESISTANCE
Identification of metallo-ß-lactamase inhibitors
Can the discovery of novel metallo-ß-lactamase inhibitors lead to clinically useful compounds capable of reversing antibiotic resistance?
Bacteria have developed several mechanisms of resistance to antibiotics. The reduced permeability of the cell wall, alterations in target enzymes (penicillin-binding proteins), production of biofilms (vide infra) and production of various forms of ß-lactamase all contribute to the diminishing effectiveness of antibiotics. Metallo-ß-lactamases (MBLs) are zinc metalloenzymes that confer antibiotic resistance to bacteria through the hydrolysis of ß-lactam antibiotics. Pathogens that express the enzyme show significantly reduced susceptibility to carbapenems, such as meropenem and imipenem. This project was initiated by my research group in the Department of Biochemistry at Merck Research Laboratories in 1995 in collaboration with medicinal chemists, molecular modelers, microbiologists and protein crystallographers. We studied carbapenem resistance in the clinical pathogens Bacteroides fragilis and Pseudomonas aeruginosa (P. aeruginosa), as well as methicillin-resistant Staphylococcus aureus (MRSA).
We previously screened over 2,000 compounds (National Cancer Institute Chemical Diversity Set) for inhibition against IMP-1 MBL and have identified several novel compounds that are capable of reversing carbapenem resistance in a laboratory strain of E. coli expressing IMP-1. We have recently extended this approach using a related MBL SPM-1 and are planning to test SPM-1 inhibitors in synergy experiments with meropenem using clinically relevant strains of P. aeruginosa. Our current screen is testing for SPM-1 inhibitors in the Johns Hopkins Clinical Compound Library (see: New Uses for Old Drugs) that includes a collection of FDA drugs. This project involves collaboration with Prof. James Spencer at the University of Bristol, UK. Long range plans include collaboration with pharmacologists to study animal models of infection.