LpxC Inhibitors for Gram-Negative Infections

Background

Infection by Gram‑negative bacteria such as Pseudomonas aeruginosa, β‑lactamase producing (ESBL) Enterobacteriaceae, and Acinetobacter baumannii is a major health problem, especially in the case of hospital‑acquired infections. Current estimates indicate that Pseudomonas aeruginosa is responsible for about 10% of all hospital-acquired infections such as pneumonia, urinary tract infections, intra‑abdominal infections, and catheter‑associated bloodstream infections. In addition, there is an increasing level of resistance to current antibiotic therapies, which severely limits treatment options. An increasing rate of multidrug-resistant (MDR) Pseudomonas strains (from 4% in 1992 to 14% in 2002) has led to the use of drugs such as polymyxin that have serious side effects. Compared to infections caused by non‑resistant strains, resistant and MDR pathogens increase the average length of hospital stay by about 5 days and 17 days, respectively. Gram‑negative bacteria are unique in that their outer membrane contains lipopolysaccharide (LPS), which is essential for bacterial viability. Lipid A is the major lipid component of LPS, and inhibition of Lipid A biosynthesis is lethal to bacteria. LpxC is the enzyme that catalyzes the first committed step in the Lipid A biosynthetic pathway, and it is a suitable target for the development of antibiotics.

Technology

Researchers at Stony Brook University have developed inhibitors of the LpxC enzyme with improved safety profiles compared to existing compounds. This is achieved by synthesizing inhibitors that dissociate slowly from LpxC and have extended activity at low drug concentrations so that they can be administered at lower doses. The result is reduced exposure to antibiotics, decreased side effects, increased compliance, and reduced drug resistance. Thus, long residence time inhibitors of LpxC are realized to treat serious infections caused by MDR‑pathogens with minimized impact on the microbiome.