Identification of a potent inhibitor of type II secretion system from Pseudomonas aeruginosa

• Published in: Biochemical and biophysical research communications Vol. 513; no. 3; pp. 688 - 693
• Main Authors: Swietnicki, Wieslaw, Czarny, Anna, Antkowiak, Lukasz, Zaczynska, Ewa, Kolodziejczak, Monika, Sycz, Jordan, Stachowicz, Lukasz, Alicka, Michalina, Marycz, Krzysztof
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.06.2019
• Subjects: ATPase; Cell infection; Inhibition; Pseudomonas aeruginosa; Type II secretion; Type III secretion; Pseudomonas aeruginosa; Type II secretion; Type III secretion; Inhibition; Cell infection; ATPase
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.04.055

Pseudomonas aeruginosa is an opportunistic pathogen infecting human population. The pathogen is becoming a serious health problem due to its ability to evade normal immune response of the host and multiple drug resistance to many antibiotics. The pathogen has 2 major virulence systems of which the type III secretion system (T3SS) is of major concern to humans. A third system, type 2 secretion system (T2SS), is common to bacteria and used to secrete exotoxin A (ExoA) responsible for human cell destruction. To help bypass the drug resistance, a strategy to block the T2SS based on a low similarity between human ATPases and the essential ATPases of the T3SS and T2SS of P. aeruginosa, was used. An in silico-optimized inhibitor of T3SS, made directly from the computer-optimized of previously published compounds and their combinatorial libraries, showed IC50 = 1.3 ± 0.2 μM in the T2SS ExoA secretion blocking test. The compound was non-toxic to human lung epithelial cell line A549 and could block cellular destruction of those cells in a cell infection model at 200 μM for at least 24 h. The compound could be a lead candidate for the development of T2SS virulence blockers of Pseudomonas aeruginosa. •In silico optimization of a chemical library for T3SS PscN ATPase inhibitors identifies inhibitor of T2SS.•Compound is the most potent reported in literature for ExoA secretion inhibition by P. aeruginosa.•Inhibitor is non-toxic to human cells and capable of protecting human cells from destruction by P. aeruginosa secretions.