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      Nitrite Promotes ROS Production to Potentiate Cefoperazone-Sulbactam-Mediated Elimination to Lab-Evolved and Clinical-Evolved Pseudomonas aeruginosa

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          ABSTRACT

          Cefoperazone-sulbactam (SCF)-resistant Pseudomonas aeruginosa poses a big challenge in the use of SCF to treat infection caused by the pathogen. We have recently shown exogenous nitrite-enabled killing of naturally and artificially evolved Pseudomonas aeruginosa strains (AP-R CLIN-EVO and AP-R LAB-EVO, respectively) by SCF. However, the underlying mechanism is unknown. Here, reprogramming metabolomics was adopted to investigate how nitrite enhanced the SCF-mediated killing efficacy. Nitrite-reprogrammed metabolome displayed an activated pyruvate cycle (P cycle), which was confirmed by elevated activity of pyruvate dehydrogenase (PDH), α-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase. The activated P cycle provided NADH for the electron transport chain and thereby increased reactive oxygen species (ROS), which potentiated SCF to kill AP-R CLIN-EVO and AP-R LAB-EVO. The nitrite-enabled killing of AP-R CLIN-EVO and AP-R LAB-EVO by SCF was inhibited by PDH inhibitor furfural and ROS scavenger N-Acetyl-L-cysteine but promoted by ROS promoter Fe 3+. SCF alone could not induce ROS, but SCF-mediated killing efficacy was enhanced by ROS. In addition, the present study demonstrated that nitrite repressed antioxidants, which were partly responsible for the elevated ROS. These results reveal a nitrite-reprogrammed metabolome mechanism by which AP-R CLIN-EVO and AP-R LAB-EVO sensitivity to SCF is elevated.

          IMPORTANCE Antibiotic-resistant Pseudomonas aeruginosa has become a real concern in hospital-acquired infections, especially in critically ill and immunocompromised patients. Understanding antibiotic resistance mechanisms and developing novel control measures are highly appreciated. We have recently shown that a reduced nitrite-dependent NO biosynthesis contributes to cefoperazone-sulbactam (SCF) resistance, which is reverted by exogenous nitrite, in both naturally and artificially evolved P. aeruginosa strains (AP-R CLIN-EVO and AP-R LAB-EVO, respectively). However, the mechanism is unknown. The present study reports that the nitrite-enabled killing of AP-R CLIN-EVO and AP-R LAB-EVO by SCF is attributed to the promoted production of reactive oxygen species (ROS). Nitrite activates the pyruvate cycle to generate NADH for the electron transport chain, which in turn promotes ROS generation. Nitrite-potentiated SCF-mediated killing is decreased by pyruvate dehydrogenase inhibitor furfural and ROS scavenger N-Acetyl-L-cysteine but increased by ROS promoter Fe 3+. Furthermore, SCF-mediated killing is promoted by H 2O 2 in a dose-dependent manner. In addition, the combination of nitrite and H 2O 2 greatly enhances SCF-mediated killing. These results not only disclose a nitrite-ROS-potentiated SCF-mediated killing, but also show SCF-mediated killing is dependent upon ROS.

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          MetaboLights: a resource evolving in response to the needs of its scientific community

          Abstract MetaboLights is a database for metabolomics studies, their raw experimental data and associated metadata. The database is cross-species and cross-technique and it covers metabolite structures and their reference spectra as well as their biological roles and locations. MetaboLights is the recommended metabolomics repository for a number of leading journals and ELIXIR, the European infrastructure for life science information. In this article, we describe the significant updates that we have made over the last two years to the resource to respond to the increasing amount and diversity of data being submitted by the metabolomics community. We refreshed the website and most importantly, our submission process was completely overhauled to enable us to deliver a far more user-friendly submission process and to facilitate the growing demand for reproducibility and integration with other ‘omics. Metabolomics resources and data are available under the EMBL-EBI’s Terms of Use via the web at https://www.ebi.ac.uk/metabolights and under Apache 2.0 at Github (https://github.com/EBI-Metabolights/).
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            Exogenous alanine and/or glucose plus kanamycin kills antibiotic-resistant bacteria.

            Multidrug-resistant bacteria are an increasingly serious threat to human and animal health. However, novel drugs that can manage infections by multidrug-resistant bacteria have proved elusive. Here we show that glucose and alanine abundances are greatly suppressed in kanamycin-resistant Edwardsiella tarda by GC-MS-based metabolomics. Exogenous alanine or glucose restores susceptibility of multidrug-resistant E. tarda to killing by kanamycin, demonstrating an approach to killing multidrug-resistant bacteria. The mechanism underlying this approach is that exogenous glucose or alanine promotes the TCA cycle by substrate activation, which in turn increases production of NADH and proton motive force and stimulates uptake of antibiotic. Similar results are obtained with other Gram-negative bacteria (Vibrio parahaemolyticus, Klebsiella pneumoniae, Pseudomonas aeruginosa) and Gram-positive bacterium (Staphylococcus aureus), and the results are also reproduced in a mouse model for urinary tract infection. This study establishes a functional metabolomics-based strategy to manage infection by antibiotic-resistant bacteria.
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              Potentiating antibacterial activity by predictably enhancing endogenous microbial ROS production

              The ever-increasing incidence of antibiotic-resistant infections combined with a weak pipeline of new antibiotics has created a global public health crisis 1 . Accordingly, novel strategies for enhancing our antibiotic arsenal are needed. As antibiotics kill bacteria in part by inducing reactive oxygen species (ROS) 2–4 , we reasoned that targeting microbial ROS production might potentiate antibiotic activity. Here we show that ROS production can be predictably enhanced in Escherichia coli, increasing the bacteria’s susceptibility to oxidative attack. We developed an ensemble, genome-scale metabolic modeling approach capable of predicting ROS production in E. coli. The metabolic network was systematically perturbed and its flux distribution analyzed to identify targets predicted to increase ROS production. In silico–predicted targets were experimentally validated and shown to confer increased susceptibility to oxidants. Validated targets also increased susceptibility to killing by antibiotics. This work establishes a systems-based method to tune ROS production in bacteria and demonstrates that increased microbial ROS production can potentiate killing by oxidants and antibiotics.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                Microbiol Spectr
                Microbiol Spectr
                spectrum
                Microbiology Spectrum
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                2165-0497
                5 July 2022
                Jul-Aug 2022
                5 July 2022
                : 10
                : 4
                : e02327-21
                Affiliations
                [a ] The Third Affiliated Hospital and State Key Laboratory of Bio-Control, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Sun Yat-sen Universitygrid.12981.33, , University City, Guangzhou, People’s Republic of China
                [b ] Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
                Riverside University Health System, Medical Center – University of California
                Author notes

                The authors declare no conflict of interest.

                Author information
                https://orcid.org/0000-0003-2600-4838
                https://orcid.org/0000-0002-9239-0434
                Article
                02327-21 spectrum.02327-21
                10.1128/spectrum.02327-21
                9430864
                35863024
                39e50166-e278-4c3d-8f92-e6a3376f3671
                Copyright © 2022 Kuang et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 26 November 2021
                : 15 June 2022
                Page count
                supplementary-material: 0, Figures: 10, Tables: 1, Equations: 0, References: 41, Pages: 17, Words: 7798
                Funding
                Funded by: Bureau of Science and Information Technology of Guangzhou Municipality | Guangzhou Municipal Science and Technology Project (Guangzhou Science and Technology Plan), FundRef https://doi.org/10.13039/501100010256;
                Award ID: 201904020042
                Award Recipient :
                Funded by: National Natural Science Foundation of China (NSFC), FundRef https://doi.org/10.13039/501100001809;
                Award ID: 82170014
                Award Recipient :
                Categories
                Research Article
                antimicrobial-chemotherapy, Antimicrobial Chemotherapy
                Custom metadata
                July/August 2022

                pseudomonas aeruginosa,antibiotic resistance,cefoperazone-sulbactam,electron transport chain,nitrite,reprogramming metabolomics,the pyruvate cycle

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