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Microbiology spectrum

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Crizotinib Shows Antibacterial Activity against Gram-Positive Bacteria by Reducing ATP Production and Targeting the CTP Synthase PyrG

Published:8 June 2022 DOI: 10.1128/spectrum.00884-22
Yun-Dan Zheng,?Tairan Zhong,?Haiming Wu,?Nan Li,?Zuye Fang,?Linlin Cao,?Xingfeng Yin,?Qing-Yu He,?R. Ge,?Xuesong Sun

Abstract

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. 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.

Substances (6)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Crizotinib 877399-52-5 C21H22Cl2FN5O 617 suppliers $5.00-$1963.50
Crizotinib 877399-52-5 C21H22Cl2FN5O 617 suppliers $5.00-$1963.50
Crizotinib 877399-52-5 C21H22Cl2FN5O 617 suppliers $5.00-$1963.50
Crizotinib 877399-52-5 C21H22Cl2FN5O 617 suppliers $5.00-$1963.50
Crizotinib 877399-52-5 C21H22Cl2FN5O - Inquiry
Crizotinib 877399-52-5 C21H22Cl2FN5O - Inquiry

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