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Alarmone Ap4A is elevated by aminoglycoside antibiotics and enhances their bactericidal activity
Xia Ji1; Jin Zou1; Haibo Peng1; Anne-Sophie Stolle2; Ruiqiang Xie1; Hongjie Zhang1; Bo Peng3,4; John J. Mekalanos2; Jun Zheng1,5
2019-04-19
Source PublicationPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN0027-8424
Volume116Issue:19Pages:9578-9585
AbstractSecond messenger molecules play important roles in the responses to various stimuli that can determine a cell's fate under stress conditions. Here, we report that lethal concentrations of aminoglycoside antibiotics result in the production of a dinucleotide alarmone metabolite-diadenosine tetraphosphate (Ap4A), which promotes bacterial cell killing by this class of antibiotics. We show that the treatment of Escherichia coli with lethal concentrations of kanamycin (Kan) dramatically increases the production of Ap4A. This elevation of Ap4A is dependent on the production of a hydroxyl radical and involves the induction of the Ap4A synthetase lysyl-tRNA synthetase (LysU). Ectopic alteration of intracellular Ap4A concentration via the elimination of the Ap4A phosphatase diadenosine tetraphosphatase (ApaH) and the overexpression of LysU causes over a 5,000-fold increase in bacterial killing by aminoglycosides. This increased susceptibility to aminoglycosides correlates with bacterial membrane disruption. Our findings provide a role for the alarmone Ap4A and suggest that blocking Ap4A degradation or increasing its synthesis might constitute an approach to enhance aminoglycoside killing potency by broadening their therapeutic index and thereby allowing lower nontoxic dosages of these antibiotics to be used in the treatment of multidrug-resistant infections.
KeywordAntibiotic Action Aminoglycoside Kanamycin Diadenosine Tetraphosphate Ap4a Alarmone
DOI10.1073/pnas.1822026116
Indexed BySCI
Language英语
WOS Research AreaScience & Technology - Other Topics
WOS SubjectMultidisciplinary Sciences
WOS IDWOS:000467226400060
PublisherNATL ACAD SCIENCES, 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
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Cited Times [WOS]:7   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorJohn J. Mekalanos; Jun Zheng
Affiliation1.Faculty of Health Sciences, University of Macau, Macau SAR, China
2.Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115
3.School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China
4.Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China
5.Institute of Translational Medicine, University of Macau, Macau SAR, China
First Author AffilicationFaculty of Health Sciences
Corresponding Author AffilicationFaculty of Health Sciences;  University of Macau
Recommended Citation
GB/T 7714
Xia Ji,Jin Zou,Haibo Peng,et al. Alarmone Ap4A is elevated by aminoglycoside antibiotics and enhances their bactericidal activity[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2019,116(19):9578-9585.
APA Xia Ji.,Jin Zou.,Haibo Peng.,Anne-Sophie Stolle.,Ruiqiang Xie.,...&Jun Zheng.(2019).Alarmone Ap4A is elevated by aminoglycoside antibiotics and enhances their bactericidal activity.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,116(19),9578-9585.
MLA Xia Ji,et al."Alarmone Ap4A is elevated by aminoglycoside antibiotics and enhances their bactericidal activity".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 116.19(2019):9578-9585.
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