A new therapy against MDR bacteria by in silico virtual screening of Pseudomonas aeruginosa LpxC inhibitors

Abstract

Multidrug-resistant (MDR) bacteria are a significant threat to communities worldwide. MDR Pseudomonas aeruginosa is, a pathogen resistant to most therapies, can cause serious conditions such as endocarditis and pneumonia. The development of an antibiotic is needed before current treatments fail. We targeted LpxC, a key protein for biosynthesizing lipid A of lipopolysaccharide, by in silico virtual screening of current approved therapies. In our first prediction, ZINC000001587011, also known as brequinar, had a low binding energy, high bioavailability, but an unfavorably high calculated octanol-water partition coefficient (cLogP), which signifies poor solubility in water. We performed functional group modification to decrease the high cLogP. Finally, after going through virtual screening of 20,000 candidates and 30 derivatives of ZINC000001587011, we propose that N11 might have the most potential against P. aeruginosa lipid A synthesis, making it a potential treatment for MDR P. aeruginosa.