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A comprehensive method for determining cellular uptake of purine nucleoside phosphorylase and adenylosuccinate synthetase inhibitors by H. pylori.

Autor
Kazazić, Saša
Luić, Marija
Knežević, Petar
Jagusztyn-Krynicka, Elżbieta
Jaźwiec, Radosław
Bzowska, Maria
Ašler, Ivana Leščić
Sabo, Verica Aleksić
Wojtyś, Marta
Data publikacji
2021
Abstrakt (EN)

Due to the growing number of Helicobacter pylori strains resistant to currently available antibiotics, there is an urgent need to design new drugs utilizing different molecular mechanisms than those that have been used up to now. Enzymes of the purine salvage pathway are possible targets of such new antibiotics because H. pylori is not able to synthetize purine nucleotides de novo. The bacterium’s recovery of purines and purine nucleotides from the environment is the only source of these essential DNA and RNA building blocks. We have identified formycins and hadacidin as potent inhibitors of purine nucleoside phosphorylase (PNP) and adenylosuccinate synthetase (AdSS) from H. pylori — two key enzymes of the purine salvage pathway. However, we have found that these compounds are not effective in H. pylori cell cultures. To address this issue, we have developed a universal comprehensive method for assessing H. pylori cell penetration by drug candidates, with three alternative detection assays. These include liquid chromatography tandem mass spectrometry, UV absorption, and inhibition of the target enzyme by the tested compound. Using this approach, we have shown that cellular uptake by H. pylori of formycins and hadacidin is very poor, which reveals why their in vitro inhibition of PNP and AdSS and their effect on H. pylori cell cultures are so different. The cell penetration assessment method developed here will be extremely useful for validating the cellular uptake of other drug candidates, facilitating the design of new potent therapeutic agents against H. pylori.

Słowa kluczowe EN
Helicobacter pylori
Cells penetration by drug candidates
Salvage pathway enzymes
Formycin
Hadacidin
Dyscyplina PBN
nauki fizyczne
Czasopismo
Applied Microbiology and Biotechnology
Tom
105
Zeszyt
20
Strony od-do
7949-7967
ISSN
0175-7598
Data udostępnienia w otwartym dostępie
2021-09-25
Licencja otwartego dostępu
Uznanie autorstwa