{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T05:36:58Z","timestamp":1792647418210,"version":"4.5.0"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T00:00:00Z","timestamp":1674518400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Methicillin-resistant <jats:italic>Staphylococcus aureus<\/jats:italic> (MRSA) has now become a major nosocomial pathogen bacteria and resistant to many antibiotics. Therefore, Development of novel approaches to combat the disease is especially important. The present study aimed to provide a novel approach involving the use of nucleotide-mediated metabolic reprogramming to tackle intractable methicillin-resistant <jats:italic>S. aureus<\/jats:italic> (MRSA) infections.<\/jats:p><jats:p><jats:bold>Objective:<\/jats:bold> This study aims to explore the bacterial effects and mechanism of uracil and gentamicin in <jats:italic>S. aureus.<\/jats:italic><\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Antibiotic bactericidal assays was used to determine the synergistic bactericidal effect of uracil and gentamicin. How did uracil regulate bacterial metabolism including the tricarboxylic acid (TCA) cycle by GC-MS-based metabolomics. Next, genes and activity of key enzymes in the TCA cycle, PMF, and intracellular aminoglycosides were measured. Finally, bacterial respiration, reactive oxygen species (ROS), and ATP levels were also assayed in this study.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> In the present study, we found that uracil could synergize with aminoglycosides to kill MRSA (USA300) by 400-fold. Reprogramming metabolomics displayed uracil reprogrammed bacterial metabolism, especially enhanced the TCA cycle to elevate NADH production and proton motive force, thereby promoting the uptake of antibiotics. Furthermore, uracil increased cellular respiration and ATP production, resulting the generation of ROS. Thus, the combined activity of uracil and antibiotics induced bacterial death. Inhibition of the TCA cycle or ROS production could attenuate bactericidal efficiency. Moreover, uracil exhibited bactericidal activity in cooperation with aminoglycosides against other pathogenic bacteria. In a mouse mode of MRSA infection, the combination of gentamicin and uracil increased the survival rate of infected mice.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Our results suggest that uracil enhances the activity of bactericidal antibiotics to kill Gram-positive bacteria by modulating bacterial metabolism.<\/jats:p>","DOI":"10.3389\/fphar.2023.1133685","type":"journal-article","created":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T05:15:00Z","timestamp":1674537300000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":52,"title":["Uracil restores susceptibility of methicillin-resistant Staphylococcus aureus to aminoglycosides through metabolic reprogramming"],"prefix":"10.3389","volume":"14","author":[{"given":"Lvyuan","family":"Fan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyu","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilin","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Pang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhai","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guozhu","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubin","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1038\/nature10069","article-title":"Metabolite-enabled eradication of bacterial persisters by aminoglycosides","volume":"473","author":"Allison","year":"2011","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1548","DOI":"10.1021\/bi500074w","article-title":"Regulation of the expression of the \u03b2-lactam antibiotic-resistance determinants in methicillin-resistant Staphylococcus aureus (MRSA)","volume":"53","author":"Bl\u00e1zquez","year":"2014","journal-title":"Biochemistry"},{"key":"B3","doi-asserted-by":"publisher","first-page":"847634","DOI":"10.3389\/fmicb.2022.847634","article-title":"Repressed central carbon metabolism and its effect on related metabolic pathways in cefoperazone\/sulbactam-resistant Pseudomonas aeruginosa","volume":"13","author":"Chen","year":"2022","journal-title":"Front. Microbiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1016\/j.fsi.2014.08.008","article-title":"N-acetylglucosamine enhances survival ability of tilapias infected by Streptococcus iniae","volume":"40","author":"Cheng","year":"2014","journal-title":"Fish. Shellfish Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e00437-13","DOI":"10.1128\/mBio.00437-13","article-title":"A dysfunctional tricarboxylic acid cycle enhances fitness of Staphylococcus epidermidis during \u03b2-lactam stress","volume":"4","author":"Chittezham Thomas","year":"2013","journal-title":"mBio"},{"key":"B6","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1007\/s11306-022-01903-w","article-title":"Exogenous metabolite feeding on altering antibiotic susceptibility in gram-negative bacteria through metabolic modulation: A review","volume":"18","author":"Chung","year":"2022","journal-title":"Metabolomics"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e1007697","DOI":"10.1371\/journal.ppat.1007697","article-title":"Host metabolites stimulate the bacterial proton motive force to enhance the activity of aminoglycoside antibiotics","volume":"15","author":"Crabbe","year":"2019","journal-title":"PLoS Pathog."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e01608-17","DOI":"10.1128\/AAC.01608-17","article-title":"Metabolic mitigation of Staphylococcus aureus vancomycin intermediate-level susceptibility","volume":"62","author":"Gardner","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"B9","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/j.meegid.2013.03.013","article-title":"Staphylococcus aureus toxins\u2013their functions and genetics","volume":"21","author":"Grumann","year":"2014","journal-title":"Infect. Genet. Evol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"29701","DOI":"10.1074\/jbc.M114.584979","article-title":"The catabolite control protein E (CcpE) affects virulence determinant production and pathogenesis of Staphylococcus aureus","volume":"289","author":"Hartmann","year":"2014","journal-title":"J. Biol. Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1038\/s41564-017-0037-y","article-title":"Contribution of reactive oxygen species to thymineless death in Escherichia coli","volume":"2","author":"Hong","year":"2017","journal-title":"Nat. Microbiol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"823332","DOI":"10.3389\/fvets.2021.823332","article-title":"Selection of the amino acid and saccharide that increase the tetracycline susceptibility of Vibrio splendidus","volume":"8","author":"Jiang","year":"2021","journal-title":"Front. Vet. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"7265","DOI":"10.1007\/s10853-021-05776-7","article-title":"Polymeric approach to combat drug-resistant methicillin-resistant Staphylococcus aureus","volume":"56","author":"Kanth","year":"2021","journal-title":"J. Mater Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.kjms.2017.08.001","article-title":"Distribution of genes encoding resistance to aminoglycoside modifying enzymes in methicillin-resistant Staphylococcus aureus (MRSA) strains","volume":"33","author":"Khosravi","year":"2017","journal-title":"Kaohsiung J. Med. Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/j.cell.2007.06.049","article-title":"A common mechanism of cellular death induced by bactericidal antibiotics","volume":"130","author":"Kohanski","year":"2007","journal-title":"Cell"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1016\/j.drudis.2022.03.015","article-title":"Unraveling antimicrobial resistance using metabolomics","volume":"27","author":"Kok","year":"2022","journal-title":"Drug Discov. Today"},{"key":"B17","doi-asserted-by":"publisher","first-page":"e302321","DOI":"10.1128\/spectrum.02327-21","article-title":"Nitrite promotes ROS production to potentiate cefoperazone-sulbactam-mediated elimination to lab-evolved and clinical-evolved Pseudomonas aeruginosa","volume":"10","author":"Kuang","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"B18","doi-asserted-by":"publisher","first-page":"18033","DOI":"10.1038\/nrdp.2018.33","article-title":"Methicillin-resistant Staphylococcus aureus","volume":"4","author":"Lee","year":"2018","journal-title":"Nat. Rev. Dis. Prim."},{"key":"B19","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1007\/BF00831539","article-title":"Bacterial resistance to uncouplers","volume":"26","author":"Lewis","year":"1994","journal-title":"J. Bioenerg. Biomembr."},{"key":"B20","doi-asserted-by":"publisher","first-page":"4295","DOI":"10.1111\/1462-2920.15021","article-title":"Metabolic mechanism of colistin resistance and its reverting in Vibrio alginolyticus","volume":"22","author":"Li","year":"2020","journal-title":"Environ. Microbiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"417","DOI":"10.2147\/IDR.S179639","article-title":"Metabolic mechanism of ceftazidime resistance in Vibrio alginolyticus","volume":"12","author":"Liu","year":"2019","journal-title":"I Infect. Drug Resist"},{"key":"B22","doi-asserted-by":"publisher","first-page":"104915","DOI":"10.1016\/j.micpath.2021.104915","article-title":"Emerging resistance mechanisms for 4 types of common anti-MRSA antibiotics in Staphylococcus aureus: A comprehensive review","volume":"156","author":"Liu","year":"","journal-title":"Microb. Pathog."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1902227","DOI":"10.1002\/advs.201902227","article-title":"Metformin restores tetracyclines susceptibility against multidrug resistant bacteria","volume":"7","author":"Liu","year":"","journal-title":"Adv. Sci. (Weinh)."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2593","DOI":"10.2147\/IDR.S263225","article-title":"Cysteine potentiates bactericidal antibiotics activity against Gram-negative bacterial persisters","volume":"13","author":"Liu","year":"","journal-title":"Infect. Drug Resist"},{"key":"B25","doi-asserted-by":"publisher","first-page":"622798","DOI":"10.3389\/fmicb.2021.622798","article-title":"Thymine sensitizes gram-negative pathogens to antibiotic killing","volume":"12","author":"Liu","year":"","journal-title":"Front. Microbiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"8173","DOI":"10.1073\/pnas.1509743112","article-title":"Antibiotic efficacy is linked to bacterial cellular respiration","volume":"112","author":"Lobritz","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B27","doi-asserted-by":"publisher","first-page":"eaba0862","DOI":"10.1126\/science.aba0862","article-title":"Clinically relevant mutations in core metabolic genes confer antibiotic resistance","volume":"371","author":"Lopatkin","year":"2021","journal-title":"Science"},{"key":"B28","doi-asserted-by":"publisher","first-page":"583468","DOI":"10.3389\/fdgth.2021.583468","article-title":"Digital insights into nucleotide metabolism and antibiotic treatment failure","volume":"3","author":"Lopatkin","year":"2021","journal-title":"Front. Digit. Health"},{"key":"B29","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1021\/acsinfecdis.1c00559","article-title":"n-Butanol potentiates subinhibitory aminoglycosides against bacterial persisters and multidrug-resistant MRSA by rapidly enhancing antibiotic uptake","volume":"8","author":"Lv","year":"2022","journal-title":"ACS Infect. Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"6976","DOI":"10.1128\/AEM.01576-14","article-title":"The fatty acid signaling molecule cis-2-decenoic acid increases metabolic activity and reverts persister cells to an antimicrobial-susceptible state","volume":"80","author":"Marques","year":"2014","journal-title":"Appl. Environ. Microbiol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"567","DOI":"10.2147\/IDR.S142397","article-title":"Antimicrobial use of reactive oxygen therapy: Current insights","volume":"11","author":"Memar","year":"2018","journal-title":"Infect. Drug Resist"},{"key":"B32","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.chembiol.2016.12.015","article-title":"Carbon sources tune antibiotic susceptibility in Pseudomonas aeruginosa via tricarboxylic acid cycle control","volume":"24","author":"Meylan","year":"2017","journal-title":"Cell Chem. Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"606","DOI":"10.3390\/antibiotics11050606","article-title":"Recent developments in methicillin-resistant Staphylococcus aureus (MRSA) treatment: A review","volume":"11","author":"Nandhini","year":"2022","journal-title":"Antibiot. (Basel)"},{"key":"B34","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/(sici)1097-0320(19990101)35:1<55::aid-cyto8>3.0.co;2-2","article-title":"Accurate flow cytometric membrane potential measurement in bacteria using diethyloxacarbocyanine and a ratiometric technique","volume":"35","author":"Novo","year":"1999","journal-title":"Cytometry"},{"key":"B35","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1007\/s13238-015-0185-x","article-title":"Functional metabolomics: From biomarker discovery to metabolome reprogramming","volume":"6","author":"Peng","year":"","journal-title":"Protein Cell"},{"key":"B36","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.cmet.2015.01.008","article-title":"Exogenous alanine and\/or glucose plus kanamycin kills antibiotic-resistant bacteria","volume":"21","author":"Peng","year":"","journal-title":"Cell Metab."},{"key":"B37","doi-asserted-by":"publisher","first-page":"112801","DOI":"10.1016\/j.ejmech.2020.112801","article-title":"Therapeutic potential of uracil and its derivatives in countering pathogenic and physiological disorders","volume":"207","author":"Ramesh","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"B38","doi-asserted-by":"publisher","first-page":"7854","DOI":"10.1021\/acs.chemrev.6b00174","article-title":"Recent trends in nucleotide synthesis","volume":"116","author":"Roy","year":"2016","journal-title":"Chem. Rev."},{"key":"B39","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1016\/j.bbabio.2014.03.017","article-title":"Characterization of the type 2 NADH: Menaquinone oxidoreductases from Staphylococcus aureus and the bactericidal action of phenothiazines","volume":"1837","author":"Schurig-Briccio","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"B40","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1021\/ac051437y","article-title":"Xcms: Processing mass spectrometry data for metabolite profiling using nonlinear peak alignment, matching, and identification","volume":"78","author":"Smith","year":"2006","journal-title":"Anal. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/j.cmet.2019.06.009","article-title":"Bacterial metabolism and antibiotic efficacy","volume":"30","author":"Stokes","year":"2019","journal-title":"Cell Metab."},{"key":"B42","doi-asserted-by":"publisher","first-page":"103562","DOI":"10.1016\/j.jprot.2019.103562","article-title":"The depressed P cycle contributes to the acquisition of ampicillin resistance in Edwardsiella piscicida","volume":"212","author":"Su","year":"2020","journal-title":"J. Proteomics"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.1021\/pr501285f","article-title":"Fructose restores susceptibility of multidrug-resistant Edwardsiella tarda to kanamycin","volume":"14","author":"Su","year":"2015","journal-title":"J. Proteome Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"E1578","DOI":"10.1073\/pnas.1714645115","article-title":"Pyruvate cycle increases aminoglycoside efficacy and provides respiratory energy in bacteria","volume":"115","author":"Su","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B45","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1128\/mr.51.4.439-457.1987","article-title":"Bacterial uptake of aminoglycoside antibiotics","volume":"51","author":"Taber","year":"1987","journal-title":"Microbiol. Rev."},{"key":"B46","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.ajem.2016.10.058","article-title":"Linezolid versus vancomycin for nosocomial pneumonia due to methicillin-resistant Staphylococcus aureus in the elderly: A retrospective cohort analysis: Effectiveness of linezolid in the elderly","volume":"35","author":"Takada","year":"2017","journal-title":"Am. J. Emerg. Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"800442","DOI":"10.3389\/fmicb.2021.800442","article-title":"Glucose-potentiated amikacin killing of cefoperazone\/sulbactam resistant Pseudomonas aeruginosa","volume":"12","author":"Tang","year":"2021","journal-title":"Front. Microbiol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1016\/j.tim.2016.12.008","article-title":"The role of reactive oxygen species in antibiotic-mediated killing of bacteria","volume":"25","author":"Van Acker","year":"2017","journal-title":"Trends Microbiol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1021\/acs.jproteome.0c00725","article-title":"Metabolites in the TCA cycle promote resistance to chloramphenicol of Edwardsiella tarda","volume":"20","author":"Wang","year":"2020","journal-title":"J. Proteome Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"839808","DOI":"10.3389\/fphar.2022.839808","article-title":"Antibiotic combination therapy: A strategy to overcome bacterial resistance to aminoglycoside antibiotics","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/nprot.2007.521","article-title":"Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances","volume":"3","author":"Wiegand","year":"2008","journal-title":"Nat. Protoc."},{"key":"B52","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1021\/ac0713510","article-title":"Visualization of GC\/TOF-MS-based metabolomics data for identification of biochemically interesting compounds using OPLS class models","volume":"80","author":"Wiklund","year":"2008","journal-title":"Anal. Chem."},{"key":"B53","doi-asserted-by":"publisher","first-page":"fnv040","DOI":"10.1093\/femsle\/fnv040","article-title":"Exogenous glycine and serine promote growth and antifungal activity of Penicillium citrinum W1 from the south-west Indian Ocean","volume":"362","author":"Wu","year":"2015","journal-title":"FEMS Microbiol. Lett."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1016\/j.cell.2019.04.016","article-title":"A white-box machine learning approach for revealing antibiotic mechanisms of action","volume":"177","author":"Yang","year":"2019","journal-title":"Cell"},{"key":"B55","doi-asserted-by":"publisher","first-page":"146885","DOI":"10.1016\/j.scitotenv.2021.146885","article-title":"Polystyrene microplastics induce metabolic disturbances in marine medaka (Oryzias melastigmas) liver","volume":"782","author":"Ye","year":"","journal-title":"Sci. Total Environ."},{"key":"B56","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.jprot.2018.05.006","article-title":"Identification and efficacy of glycine, serine and threonine metabolism in potentiating kanamycin-mediated killing of Edwardsiella piscicida","volume":"183","author":"Ye","year":"2018","journal-title":"J. Proteomics"},{"key":"B57","doi-asserted-by":"publisher","first-page":"654783","DOI":"10.3389\/fmicb.2021.654783","article-title":"Reactive oxygen species-related ceftazidime resistance is caused by the pyruvate cycle perturbation and reverted by Fe3+ in Edwardsiella tarda","volume":"12","author":"Ye","year":"","journal-title":"Front. Microbiol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"4724","DOI":"10.1111\/1462-2920.14811","article-title":"Reduced redox\u2010dependent mechanism and glucose\u2010mediated reversal in gentamicin\u2010resistant Vibrio alginolyticus","volume":"21","author":"Zhang","year":"2019","journal-title":"Environ. Microbiol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"4367","DOI":"10.1111\/1462-2920.15085","article-title":"Reduced ROS\u2010mediated antibiotic resistance and its reverting by glucose in Vibrio alginolyticus","volume":"22","author":"Zhang","year":"2020","journal-title":"Environ. Microbiol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"eabj0716","DOI":"10.1126\/scitranslmed.abj0716","article-title":"Glutamine promotes antibiotic uptake to kill multidrug-resistant uropathogenic bacteria","volume":"13","author":"Zhao","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"B61","doi-asserted-by":"publisher","first-page":"2525","DOI":"10.1038\/s41467-022-30272-0","article-title":"Modulating the evolutionary trajectory of tolerance using antibiotics with different metabolic dependencies","volume":"13","author":"Zheng","year":"2022","journal-title":"Nat. Commun."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1133685\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,24]],"date-time":"2023-01-24T05:15:03Z","timestamp":1674537303000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1133685\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,24]]},"references-count":61,"alternative-id":["10.3389\/fphar.2023.1133685"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1133685","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,24]]},"article-number":"1133685"}}