FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4282943119> ?p ?o ?g. }

• W4282943119 abstract "Infections caused by drug-resistant bacteria are a serious threat to public health worldwide, and the discovery of novel antibacterial compounds is urgently needed. Here, we screened an FDA-approved small-molecule library and found that crizotinib possesses good antimicrobial efficacy against Gram-positive bacteria. Crizotinib was found to increase the survival rate of mice infected with bacteria and decrease pulmonary inflammation activity in an animal model. Furthermore, it showed synergy with clindamycin and gentamicin. Importantly, the Gram-positive bacteria showed a low tendency to develop resistance to crizotinib. Mechanistically, quantitative proteomics and biochemical validation experiments indicated that crizotinib exerted its antibacterial effects by reducing ATP production and pyrimidine metabolism. A drug affinity responsive target stability study suggested crizotinib targets the CTP synthase PyrG, which subsequently disturbs pyrimidine metabolism and eventually reduces DNA synthesis. Subsequent molecular dynamics analysis showed that crizotinib binding occurs in close proximity to the ATP binding pocket of PyrG and causes loss of function of this CTP synthase. Crizotinib is a promising antimicrobial agent and provides a novel choice for the development of treatment for Gram-positive infections. IMPORTANCE Infections caused by drug-resistant bacteria are a serious problem worldwide. Therefore, there is an urgent need to find novel drugs with good antibacterial activity against multidrug-resistant bacteria. In this study, we found that a repurposed drug, crizotinib, exhibits excellent antibacterial activity against drug-resistant bacteria both in vivo and in vitro via suppressing ATP production and pyrimidine metabolism. Crizotinib was found to disturb pyrimidine metabolism by targeting the CTP synthase PyrG, thus reducing DNA synthesis. This unique mechanism of action may explain the decreased development of resistance by Staphylococcus aureus to crizotinib. This study provides a potential option for the treatment of drug-resistant bacterial infections in the future." @default.
• W4282943119 created "2022-06-16" @default.
• W4282943119 creator A5012921461 @default.
• W4282943119 creator A5014990417 @default.
• W4282943119 creator A5015105154 @default.
• W4282943119 creator A5015792001 @default.
• W4282943119 creator A5037172649 @default.
• W4282943119 creator A5039808325 @default.
• W4282943119 creator A5049351533 @default.
• W4282943119 creator A5054489408 @default.
• W4282943119 creator A5064098179 @default.
• W4282943119 creator A5079606810 @default.
• W4282943119 date "2022-06-29" @default.
• W4282943119 modified "2023-10-16" @default.
• W4282943119 title "Crizotinib Shows Antibacterial Activity against Gram-Positive Bacteria by Reducing ATP Production and Targeting the CTP Synthase PyrG" @default.
• W4282943119 cites W1527200958 @default.
• W4282943119 cites W1599268777 @default.
• W4282943119 cites W1762020366 @default.
• W4282943119 cites W1878404532 @default.
• W4282943119 cites W2016562927 @default.
• W4282943119 cites W2020165280 @default.
• W4282943119 cites W2035496446 @default.
• W4282943119 cites W2070719504 @default.
• W4282943119 cites W2094406744 @default.
• W4282943119 cites W2135581618 @default.
• W4282943119 cites W2150424194 @default.
• W4282943119 cites W2151150074 @default.
• W4282943119 cites W2155864378 @default.
• W4282943119 cites W2161045767 @default.
• W4282943119 cites W2189116376 @default.
• W4282943119 cites W2288575926 @default.
• W4282943119 cites W2314649741 @default.
• W4282943119 cites W2396885775 @default.
• W4282943119 cites W2510790150 @default.
• W4282943119 cites W2543256771 @default.
• W4282943119 cites W2547702745 @default.
• W4282943119 cites W2598265731 @default.
• W4282943119 cites W2779019546 @default.
• W4282943119 cites W2793324329 @default.
• W4282943119 cites W2884025824 @default.
• W4282943119 cites W2898596231 @default.
• W4282943119 cites W2899841051 @default.
• W4282943119 cites W2912673401 @default.
• W4282943119 cites W2913573831 @default.
• W4282943119 cites W2997915563 @default.
• W4282943119 cites W3007479390 @default.
• W4282943119 cites W3022216217 @default.
• W4282943119 cites W3025009713 @default.
• W4282943119 cites W3033371523 @default.
• W4282943119 cites W3082153070 @default.
• W4282943119 cites W3109703375 @default.
• W4282943119 cites W3138434603 @default.
• W4282943119 cites W3154414784 @default.
• W4282943119 cites W3160241186 @default.
• W4282943119 cites W3160418806 @default.
• W4282943119 cites W3208274994 @default.
• W4282943119 doi "https://doi.org/10.1128/spectrum.00884-22" @default.
• W4282943119 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35674439" @default.
• W4282943119 hasPublicationYear "2022" @default.
• W4282943119 type Work @default.
• W4282943119 citedByCount "3" @default.
• W4282943119 countsByYear W42829431192022 @default.
• W4282943119 countsByYear W42829431192023 @default.
• W4282943119 crossrefType "journal-article" @default.
• W4282943119 hasAuthorship W4282943119A5012921461 @default.
• W4282943119 hasAuthorship W4282943119A5014990417 @default.
• W4282943119 hasAuthorship W4282943119A5015105154 @default.
• W4282943119 hasAuthorship W4282943119A5015792001 @default.
• W4282943119 hasAuthorship W4282943119A5037172649 @default.
• W4282943119 hasAuthorship W4282943119A5039808325 @default.
• W4282943119 hasAuthorship W4282943119A5049351533 @default.
• W4282943119 hasAuthorship W4282943119A5054489408 @default.
• W4282943119 hasAuthorship W4282943119A5064098179 @default.
• W4282943119 hasAuthorship W4282943119A5079606810 @default.
• W4282943119 hasBestOaLocation W42829431193 @default.
• W4282943119 hasConcept C126322002 @default.
• W4282943119 hasConcept C181199279 @default.
• W4282943119 hasConcept C185592680 @default.
• W4282943119 hasConcept C200159599 @default.
• W4282943119 hasConcept C2776232967 @default.
• W4282943119 hasConcept C2776476023 @default.
• W4282943119 hasConcept C2779422266 @default.
• W4282943119 hasConcept C2779634585 @default.
• W4282943119 hasConcept C2780104969 @default.
• W4282943119 hasConcept C4937899 @default.
• W4282943119 hasConcept C523546767 @default.
• W4282943119 hasConcept C54355233 @default.
• W4282943119 hasConcept C55493867 @default.
• W4282943119 hasConcept C71924100 @default.
• W4282943119 hasConcept C86803240 @default.
• W4282943119 hasConcept C89423630 @default.
• W4282943119 hasConcept C98274493 @default.
• W4282943119 hasConceptScore W4282943119C126322002 @default.
• W4282943119 hasConceptScore W4282943119C181199279 @default.
• W4282943119 hasConceptScore W4282943119C185592680 @default.
• W4282943119 hasConceptScore W4282943119C200159599 @default.
• W4282943119 hasConceptScore W4282943119C2776232967 @default.
• W4282943119 hasConceptScore W4282943119C2776476023 @default.
• W4282943119 hasConceptScore W4282943119C2779422266 @default.
• W4282943119 hasConceptScore W4282943119C2779634585 @default.

• next