High-throughput tandem-microwell assay for ammonia repositions FDA-Approved drugs to Helicobacter pylori infection
biorxiv(2021)
摘要
To date, little attempt has been made to develop new treatments for Helicobacter pylori ( H. pylori ), although the community is aware of the shortage of treatments for H. pylori . In this study, we developed a 192-tandem-microwell-based high-throughput-assay for ammonia that is a known virulence factor of H. pylori and a product of urease. We could identify few drugs, i.e. panobinostat, dacinostat, ebselen, captan and disulfiram, to potently inhibit the activity of ureases from bacterial or plant species. These inhibitors suppress the activity of urease via substrate-competitive or covalent-allosteric mechanism, but all except captan prevent the antibiotic-resistant H. pylori strain from infecting human gastric cells, with a more pronounced effect than acetohydroxamic acid, a well-known urease inhibitor and clinically used drug for the treatment of bacterial infection. This study offers several bases for the development of new treatments for urease-containing pathogens and to study the mechanism responsible for the regulation of urease activity.
* Abbreviations
:
AHA
: acetohydroxamic acid
CBS
: cystathionine beta-synthase
CSE
: cystathionine γ-lyase
DTT
: dithiothreitol
EBS
: ebselen
FAD
: Foreign Approved Drugs
FDA
: U.S. Food and Drug Administration
H. pylori
: Helicobacter pylori
HPU
: H. pylori urease
HTS
: high-throughput screening
JBU
: jack bean urease
KD
: equilibrium dissociation constant
LB
: Luria-Bertani liquid medium
MICs
: minimum inhibitory concentrations
O. anthropi
: Ochrobactrum anthropi
OAU
: Ochrobactrum anthropic urease
P. mirabilis
: Proteus mirabilis
SPR
: surface plasmon resonance.
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关键词
ammonia,assay,high-throughput,tandem-microwell,fda-approved
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