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. Moreover, in the last decade, only a handful of new antimicrobial agents have been introduced, and these have mostly targeted drug-resistant Gram-positive pathogens such as methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). The goal of this proposal is to develop a high-throughput screening assay to discover and validate small molecule inhibitors of LpxH, an essential enzyme in the lipid A biosynthetic pathway, as novel antibiotics for the treatment of infections caused by multidrug-resistant Gram-negative pathogens.
(Public Health Relevance Statement) The inexorable increase in resistance to multiple antibiotics by Gram-negative pathogens, particularly those in hospitals with high numbers of vulnerable patients, is a major threat to public health. We propose to screen and identify novel inhibitors of LpxH involved in the biosynthesis of lipid A, an essential component of the outer surface of Gram-negative bacteria. We anticipate that these inhibitors will serve as broad-spectrum antibiotics against a variety of clinically important Gram-negative organisms. Because no commercial antibiotics target this pathway, LpxH inhibitors should be refractory to existing compound-specific resistance mechanisms, thus presenting a clear advantage over continuing development of antibiotics against established targets.
