ABSTRACTThe spread of multidrug or extensively drug-resistant Gram-negative bacteria is a serious public health issue. There are too few new antibiotics in development to combat the threat of multidrug-resistant infections, and consequently the rate of increasing antibiotic resistance is outpacing the drug development process. This fundamentally threatens our ability to treat common infectious diseases. Fosfomycin (FOM) has an established track record of safety in humans and is highly active againstEscherichia coli, including multidrug-resistant strains. However, many other Gram-negative pathogens, including the “priority pathogens”Klebsiella pneumoniaeandPseudomonas aeruginosa, are inherently resistant to FOM due to the chromosomalfosAgene, which directs expression of a metal-dependent glutathioneS-transferase (FosA) that metabolizes FOM. In this study, we describe the discovery and biochemical and structural characterization of ANY1 (3-bromo-6-[3-(3-bromo-2-oxo-1H-pyrazolo[1,5-a]pyrimidin-6-yl)-4-nitro-1H-pyrazol-5-yl]-1H-pyrazolo[1,5-a]pyrimidin-2-one), a small-molecule active-site inhibitor of FosA. Importantly, ANY1 potentiates FOM activity in representative Gram-negative pathogens. Collectively, our study outlines a new strategy to expand FOM activity to a broader spectrum of Gram-negative pathogens, including multidrug-resistant strains.
P1-080: UPDATING OF NEW STRATEGY FOR TREATING AD: SPECIFIC DEGRADATION OF ACHE BY A SMALL MOLECULE