Alanine racemase a promising Helicobacter pylori drug target inhibited by propanoic acid

Abstract

Eradication of Helicobacter pylori, the class 1 carcinogen, faces several obstacles, which demand alternative options to conventional drug development methods. Alanine racemase (Alr) was proposed as H. pylori drug target, inhibited by propanoic acid (PA), in a previous in silico study. We investigated the possible treatment of H. pylori infection through Alr inhibition. A new model of H. pylori Alr was built, validated, and the binding of PA to the active site was modelled via molecular docking with a good docking score. PA minimum inhibitory concentration (MIC) against H. pylori ATCC 43504 and six H. pylori clinical isolates ranged from 312.5 to 416.7 ± 180 μg/ml and remained unchanged after 14 serial passages in increasing PA concentrations. The minimum bactericidal concentration of PA was 625 μg/ml. Selective Alr inhibition was confirmed by a significant PA MIC increase with increasing d-alanine concentrations. Similar PA MIC in other tested pathogens was recorded (312.5-625 μg/ml). PA lacked cytotoxicity in tested cell lines and efficiently eradicated H. pylori in a rat infection model. In conclusion, Alr is a promising broad-spectrum drug target, inhibited by PA without resistance development by repeated exposure for 14 serial passages.

Keywords: Alanine racemase; Helicobacter pylori; Propanoic acid.