LpxH Inhibitors as Novel Therapeutics Against Multidrug-resistant Enterobacterales

Project Summary/Abstract An alarming number of Gram-negative nosocomial pathogens have acquired resistance to nearly all currently available antibiotics, making it very difficult to treat patients effectively. Although a handful of new antimicrobial agents have been approved by the FDA recently, they have mostly targeted drug-resistant Gram-positive pathogens. Thus, new antibiotics targeting unexploited pathways are desperately needed to stem the tide of multidrug-resistant Gram-negative bacteria that are becoming a major threat to the public health. The goal of this proposal is to develop small molecule inhibitors of LpxH, an essential enzyme in the lipid A biosynthetic pathway, as novel antibiotics for the treatment of Gram-negative bacterial infections caused by multidrug- resistant Enterobacterales, such as the extended-spectrum -lactamase (ESBL)-producing Enterobacterales and carbapenem-resistant Enterobacterales (CREs), that pose serious threats to the public health. Preliminary data have demonstrated our expertise in developing and optimizing small molecule inhibitors of LpxH based on structural insights and ligand dynamics information and have established the in vivo efficacy of a promising new LpxH inhibitor in rescuing mice with lethal Klebsiella pneumoniae infection. Leveraging our accumulated knowledge and demonstrable success in LpxH inhibitor development, we propose to design and synthesize potent LpxH inhibitors with optimal drug-like properties. At the completion of the project, we anticipate having developed a lead LpxH inhibitor with potent antibiotic activity against multidrug-resistant Enterobacterales (such as E. coli and K. pneumoniae) and having demonstrated its safety and efficacy in the murine sepsis model. The successful execution of the proposed studies will establish the therapeutic potential of LpxH-targeting antibiotics and set the stage for accelerated clinical development.