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Wieslaw Swietnicki

Nursing 2017 Speaker -  Wieslaw Swietnicki

Title: Type III secretion inhibitors of EPEC

Wieslaw Swietnicki

Inst Imm Exp Ther PAS, Poland

Biography

Dr. Swietnicki is a researcher working on bacterial virulence systems. He uses his skills to study the function of type III virulence system from pathogenic bacteria. The knowledge is applied to develop strategies to design small molecule therapies selective for pathogens. The strategy was applied to target virulence of Yersinia pestis, causative agent of bubonic and pneumonic plague, and enteropathogenic E. coli (EPEC), causative agent of human diarrhea.

Dr. Swietnicki got his M.Sc. in Chemistry at the University of Wroclaw, PL in 1983 and Ph.D. in Biochemistry and Molecular Biology at the University of Florida, Gainesville, FL in 1995. He presently works at the Institute of Immunology and Experimental Therapy of the Polish Academy of Science in Wroclaw, PL developing a novel vaccine against a human pathogen.

Abstract

Enteropathogenic E. coli (EPEC) is a human pathogen using type III secretion system for delivery of proteins directly into the human host. The system contains a single ATPase, EscN, which is essential for uncoupling of proteins from their complexes with chaperones before the delivery. The structure of EscN ATPase (PDB code: 2obm) was used to screen computationally for small molecule inhibitors blocking its active site. Two lead candidates were examined but only one, Compound 54, was selected for further optimization. After extended QSAR optimization, two derivatives were found to be competitive inhibitors of EscN capable of blocking ATPase activity with a Ki below 50 µM. One candidate, WEN05-03, with a Ki=16±2 µM, was also minimally toxic to mammalian cells as determined by other assays. In the cell infection model of HeLa cells with EPEC, Compound WEN05-03 completely blocked actin cluster formation at 100 µM concentration, when analyzed by confocal microscopy. The second best inhibitor of EscN ATPase activity was WEN04-34 with a Ki=46±2 µM. However, the compound was highly toxic to the BALB/3T3 cell line. In summary, the work identifies a compound blocking bacterial ATPase in its active site without causing cellular toxicity to the host cells. It is the first report showing feasibility of using bacterial virulence system ATPase as a target for safe, non-toxic compounds and offering a proof-of-concept for non-antibiotic alternatives.