Aurintricarboxylic acid structure modifications lead to reduction of inhibitory properties against virulence factor YopH and higher cytotoxicity

Abstract

Yersinia sp. bacteria owe their viability and pathogenic virulence to the YopH factor, which is a highly active bacterial protein tyrosine phosphatase. Inhibition of YopH phosphatase results in the lack of Yersinia sp. pathogenicity. We have previously described that aurintricarboxylic acid inhibits the activity of YopH at nanomolar concentrations and represents a unique mechanism of YopH inactivation due to a redox process. This work is a continuation of our previous studies. Here we show that modifications of the structure of aurintricarboxylic acid reduce the ability to inactivate YopH and lead to higher cytotoxicity. In the present paper we examine the inhibitory properties of aurintricarboxylic acid analogues, such as eriochrome cyanine R (ECR) and pararosaniline. Computational docking studies we report here indicate that ATA analogues are not precluded to bind in the YopH active site and in all obtained binding conformations ECR and pararosaniline bind to YopH active site. The free binding energy calculations show that ECR has a stronger binding affinity to YopH than pararosaniline, which was confirmed by experimental YopH enzymatic activity studies. We found that ATA analogues can reversibly reduce the enzymatic activity of YopH, but possess weaker inhibitory properties than ATA. The ATA analogues induced inactivation of YopH is probably due to oxidative mechanism, as pretreatment with catalase prevents from inhibition. We also found that ATA analogues significantly decrease the viability of macrophage cells, especially pararosaniline, while ATA reveals only slight effect on cell viability.

Bacterial Protein Tyrosine Phosphatases as Possible Targets for Antimicrobial Therapies in Response to Antibiotic Resistance

“…Not only oxidants can induce inhibition of PTPs via oxidation mechanism, but ROS generating compounds such as aurintricarboxylic acid (ATA) can as well. ATA is believed to be a nontoxic compound, and it is still one of the most active inhibitors of the YopH virulence factor from Yersinia bacteria, with IC50 equal to 10 nM (presented in Table 1 ) [ 56 ].…”

Inhibitors of Protein Tyrosine Phosphatase PTP1B With Anticancer Potential

“…Such correlation was obsevered related to aurintricarboxylic acid (ATA) which reveals high inhibitory effect on PTP1B (47). However, the experiments conducted on other tyrosine phosphatase YopH has shown that the analogs of ATA are weaker inhibitors than their precursor (48).…”