AUTHOR=Ibrahim Kareem A. , Kashef Mona T. , Elkhamissy Tharwat R. , Ramadan Mohammed A. , Helmy Omneya M. 

TITLE=Aspartate α-decarboxylase a new therapeutic target in the fight against Helicobacter pylori infection

JOURNAL=Frontiers in Microbiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.1019666

DOI=10.3389/fmicb.2022.1019666

ISSN=1664-302X

ABSTRACT=<p>Effective eradication therapy for <italic>Helicobacter pylori</italic> is a worldwide demand. Aspartate α-decarboxylase (ADC) was reported as a drug target in <italic>H</italic>. <italic>pylori</italic>, in an <italic>in silico</italic> study, with malonic acid (MA) as its inhibitor. We evaluated eradicating <italic>H</italic>. <italic>pylori</italic> infection through ADC inhibition and the possibility of resistance development. MA binding to ADC was modeled <italic>via</italic> molecular docking. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of MA were determined against <italic>H</italic>. <italic>pylori</italic> ATCC 43504, and a clinical <italic>H</italic>. <italic>pylori</italic> isolate. To confirm selective ADC inhibition, we redetermined the MIC in the presence of products of the inhibited enzymatic pathway: β-alanine and pantothenate. HPLC was used to assay the enzymatic activity of <italic>H</italic>. <italic>pylori</italic> 6x-his tagged ADC in the presence of different MA concentrations. <italic>H</italic>. <italic>pylori</italic> strains were serially exposed to MA for 14 passages, and the MICs were determined. Cytotoxicity in different cell lines was tested. The efficiency of ADC inhibition in treating <italic>H</italic>. <italic>pylori</italic> infections was evaluated using a Sprague–Dawley (SD) rat infection model. MA spectrum of activity was determined in different pathogens. MA binds to <italic>H</italic>. <italic>pylori</italic> ADC active site with a good docking score. The MIC of MA against <italic>H</italic>. <italic>pylori</italic> ranged from 0.5 to 0.75 mg/mL with MBC of 1.5 mg/mL. Increasing β-alanine and pantothenate concentrations proportionally increased MA MIC. The 6x-his tagged ADC activity decreased by increasing MA concentration. No resistance to ADC inhibition was recorded after 14 passages; MA lacked cytotoxicity in all tested cell lines. ADC inhibition effectively eradicated <italic>H</italic>. <italic>pylori</italic> infection in SD rats. MA had MIC between 0.625 to 1.25 mg/mL against the tested bacterial pathogens. In conclusion, ADC is a promising target for effectively eradicating <italic>H</italic>. <italic>pylori</italic> infection that is not affected by resistance development, besides being of broad-spectrum presence in different pathogens. MA provides a lead molecule for the development of an anti-helicobacter ADC inhibitor. This provides hope for saving the lives of those at high risk of infection with the carcinogenic <italic>H</italic>. <italic>pylori</italic>.</p>