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Analysis of the oxidative stress regulon identifies soxS as a genetic target for resistance reversal in multi-drug resistant Klebsiella pneumoniae

View ORCID ProfileJoão Anes, Katherine Dever, Athmanya Eshwar, View ORCID ProfileScott Nguyen, Yu Cao, View ORCID ProfileSathesh K Sivasankaran, Sandra Sakalauskaitė, Angelika Lehner, Stéphanie Devineau, Rimantas Daugelavičius, Séamus Fanning, View ORCID ProfileShabarinath Srikumar
doi: https://doi.org/10.1101/2020.08.21.262022
João Anes
1UCD-Centre for Food Safety, UCD School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin D04 V1W8, Ireland
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Katherine Dever
1UCD-Centre for Food Safety, UCD School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin D04 V1W8, Ireland
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Athmanya Eshwar
3Institute for Food Safety and Hygiene, University of Zurich, Zurich, Switzerland
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Scott Nguyen
1UCD-Centre for Food Safety, UCD School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin D04 V1W8, Ireland
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Yu Cao
1UCD-Centre for Food Safety, UCD School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin D04 V1W8, Ireland
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Sathesh K Sivasankaran
4Genome Informatics Facility, Iowa State University, 448 Bessy Hall, Ames, IA, 50011, USA
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Sandra Sakalauskaitė
5Department of Biochemistry, Faculty of Natural Sciences, Vytautas Magnus University, Kaunas, Lithuania
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Angelika Lehner
3Institute for Food Safety and Hygiene, University of Zurich, Zurich, Switzerland
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Stéphanie Devineau
6Université de Paris, Unit of Functional and Adaptive Biology (BFA), UMR8251, CNRS, 75013 Paris, France
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Rimantas Daugelavičius
5Department of Biochemistry, Faculty of Natural Sciences, Vytautas Magnus University, Kaunas, Lithuania
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Séamus Fanning
1UCD-Centre for Food Safety, UCD School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin D04 V1W8, Ireland
7Institute for Global Food Security, Queen’s University Belfast, Chlorine Gardens, Belfast BT5 6AG, United Kingdom
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Shabarinath Srikumar
1UCD-Centre for Food Safety, UCD School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin D04 V1W8, Ireland
2Department of Food, Nutrition, and Health, College of Food and Agriculture, United Arab Emirates University, Al Ain, UAE
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  • For correspondence: ssrikumar@uaeu.ac.ae
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Abstract

In bacteria, the defense system deployd to counter oxidative stress is orchestrated by three transcriptional factors – SoxS, SoxR, and OxyR. Although the regulon that these factors control is known in many bacteria, similar data is not available for Klebsiella pneumoniae. To address this data gap, oxidative stress was artificially induced in K. pneumoniae MGH 78578 using paraquat and the corresponding oxidative stress regulon recorded using RNA-seq. The soxS gene was significantly induced during oxidative stress and a knock-out mutant was constructed, to explore its functionality. The wild-type and mutant were grown in the presence of paraquat and subjected to RNA-seq to elucidate the soxS regulon in K. pneumoniae MGH78578. Genes that are commonly regulated both in the oxidative stress regulon and soxS regulon were identified and denoted as the ‘oxidative SoxS regulon’ – these included a stringent group of genes specifically regulated by SoxS. Efflux pump encoding genes such as acrAB-tolC, acrE, and global regulators such as marRAB were identified as part of this regulon. Consequently, the isogenic soxS mutant was found to exhibit a reduction in the minimum bactericidal concentration against tetracycline compared to that of the wild type. Impaired efflux activity, allowing tetracycline to be accumulated in the cytoplasm to bactericidal levels, was further evaluated using a tetraphenylphosphonium (TPP+) accumulation assay. The soxS mutant was also susceptible to tetracycline in vivo, in a zebrafish embryo model. We conclude that the soxS gene could be considered as a genetic target against which an inhibitor could be developed in the future and used in combinatorial therapy with tetracycline to combat infections associated with multi-drug resistant K. pneumoniae.

Competing Interest Statement

The authors have declared no competing interest.

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Analysis of the oxidative stress regulon identifies soxS as a genetic target for resistance reversal in multi-drug resistant Klebsiella pneumoniae
João Anes, Katherine Dever, Athmanya Eshwar, Scott Nguyen, Yu Cao, Sathesh K Sivasankaran, Sandra Sakalauskaitė, Angelika Lehner, Stéphanie Devineau, Rimantas Daugelavičius, Séamus Fanning, Shabarinath Srikumar
bioRxiv 2020.08.21.262022; doi: https://doi.org/10.1101/2020.08.21.262022
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Analysis of the oxidative stress regulon identifies soxS as a genetic target for resistance reversal in multi-drug resistant Klebsiella pneumoniae
João Anes, Katherine Dever, Athmanya Eshwar, Scott Nguyen, Yu Cao, Sathesh K Sivasankaran, Sandra Sakalauskaitė, Angelika Lehner, Stéphanie Devineau, Rimantas Daugelavičius, Séamus Fanning, Shabarinath Srikumar
bioRxiv 2020.08.21.262022; doi: https://doi.org/10.1101/2020.08.21.262022

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