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Selection and characterization of alanine racemase inhibitors against Aeromonas hydrophila

发布时间：2017-05-26

Yaping Wang1, Chao Yang2, Wen Xue1, Ting Zhang1, Xipei Liu1, Jiansong Ju1, Baohua Zhao1* and Dong Liu1*

BMC Microbiology

(2017) 17:122，DOI: 10.1186/s12866-017-1010-x

Abstract

Background: Combining experimental and computational screening methods has been of keen interest in drug discovery. In the present study, we developed an efficient screening method that has been used to screen 2100small-molecule compounds for alanine racemase Alr-2 inhibitors.

Results:

We identified ten novel nonsubstrate Alr2 inhibitors, of which patulin, homogentisic acid, andhydroquinone were active against Aeromonas hydrophila. The compounds were found to be capable of inhibiting Alr2 to different extents with 50% inhibitory concentrations (IC50) ranging from 6.6 to 17.7 μM. These compounds inhibited the growth of A. hydrophila with minimal inhibitory concentrations (MICs) ranging from 20 to 120 μg/ml. These compounds have no activity on horseradish peroxidase and Damino acid oxidase at a concentration of 50 μM. The MTT assay revealed that homogentisic acid and hydroquinone have minimal cytotoxicity against mammalian cells. The kinetic studies indicated a competitive inhibition of homogentisic acid against Alr2 with an inhibition constant (Ki) of 51.7 μM, while hydroquinone was a noncompetitive inhibitor with a Ki of 212 μM. Molecular docking studies suggested that homogentisic acid binds to the active site of racemase, while hydroquinone lies near the active center of alanine racemase.

Conclusions: Our findings suggested that combining experimental and computational methods could be used for an efficient, large-scale screening of alanine racemase inhibitors against A. hydrophila that could be applied in the development of new antibiotics against A. hydrophila.

连接：http://bmcmicrobiol.biomedcentral.com/articles/10.1186/s12866-017-1010-x