{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:53:52Z","timestamp":1790801632956,"version":"4.1.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006342","name":"Association Vaincre la Mucoviscidose","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006342","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011773","name":"Conseil r\u00e9gional de Bourgogne-Franche-Comt\u00e9","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011773","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Essential oils (EOs) or their components are widely used by inhalation or nebulization to fight mild respiratory bacterial infections. However, their interaction with antibiotics is poorly known. In this study we evaluated the effects of citral, the main component of lemongrass oil, on <jats:italic>in vitro<\/jats:italic> susceptibility of <jats:italic>Pseudomonas aeruginosa<\/jats:italic> to antibiotics. Exposure of strain PA14 to subinhibitory concentrations of citral increased expression of operons encoding the multidrug efflux systems MexEF-OprN and MexXY\/OprM, and bacterial resistance to anti-pseudomonal antibiotics including imipenem (twofold), gentamicin (eightfold), tobramycin (eightfold), ciprofloxacin (twofold), and colistin (\u2265128-fold). Use of pump deletion mutants showed that in addition to efflux other mechanisms were involved in this citral-induced phenotype. Determination of Zeta potential suggested that citral impairs the cell surface binding of aminoglycosides and colistin used at low concentrations (\u226410 \u03bcg\/mL). Moreover, experiments based on Raman spectroscopy and high-resolution mass spectrometry demonstrated formation of a Schiff base between the aldehyde group of citral and amino-groups of tobramycin and colistin. Chemical synthesis of tobracitryl, the imine compound resulting from condensation of citral and tobramycin, confirmed the loss of antibiotic activity due to adduct formation. Altogether these data point to the potential risk concern of self-medication with EOs containing citral in patients suffering from <jats:italic>P. aeruginosa<\/jats:italic> chronic lung infections and being treated with aerosols of aminoglycoside or colistin.<\/jats:p>","DOI":"10.3389\/fmicb.2021.709838","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T08:26:41Z","timestamp":1625473601000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Negative Impact of Citral on Susceptibility of Pseudomonas aeruginosa to Antibiotics"],"prefix":"10.3389","volume":"12","author":[{"given":"Alexandre","family":"Tetard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Foley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00ebtan L. A.","family":"Mislin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Brunel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estefania","family":"Oliva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Freddy","family":"Torrealba Anzola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Zedet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Cardey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yann","family":"Pellequer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Ramseyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Pl\u00e9siat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Llanes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"21094","DOI":"10.1021\/acsomega.0c02744","article-title":"Individual pKa values of tobramycin, kanamycin B, amikacin, sisomicin, and netilmicin determined by multinuclear NMR spectroscopy.","volume":"5","author":"Alkhzem","year":"2020","journal-title":"ACS Omega"},{"key":"B2","author":"Ausubel","year":"2000","journal-title":"Current Protocols in Molecular Biology."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24183301","article-title":"Anti-Haemophilus activity of selected essential oils detected by TLC-direct bioautography and biofilm inhibition.","volume":"24","author":"Balazs","year":"2019","journal-title":"Molecules"},{"key":"B4","author":"Calhoun","year":"2019","journal-title":"When Oil Meets Air: A New Cause of Hypersensitivity Pneumonitis."},{"key":"B5","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1128\/jb.135.2.324-333.1978","article-title":"Biodegradation of acyclic isoprenoids by Pseudomonas species.","volume":"135","author":"Cantwell","year":"1978","journal-title":"J. Bacteriol."},{"key":"B6","year":"2020","journal-title":"Performance Standards for Antimicrobial Susceptibility Testing"},{"key":"B7","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1111\/j.1365-2672.2007.03353.x","article-title":"Susceptibility and intrinsic tolerance of Pseudomonas aeruginosa to selected plant volatile compounds.","volume":"103","author":"Cox","year":"2007","journal-title":"J. Appl. Microbiol."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.eurpolymj.2019.109290","article-title":"pH-responsive cellulose-based dual drug-loaded hydrogel for wound dressing.","volume":"121","author":"Fan","year":"2019","journal-title":"Eur. Polymer J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.vibspec.2006.12.004","article-title":"A Raman spectroscopy and theoretical study of zinc\u2013cysteine complexation.","volume":"44","author":"Foley","year":"2007","journal-title":"Vib. Spectrosc."},{"key":"B10","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1128\/aac.01252-13","article-title":"Multiple mutations lead to MexXY-OprM-dependent aminoglycoside resistance in clinical strains of Pseudomonas aeruginosa.","volume":"58","author":"Guenard","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"B11","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.phymed.2017.08.016","article-title":"Citral, a monoterpenoid aldehyde interacts synergistically with norfloxacin against methicillin resistant Staphylococcus aureus.","volume":"34","author":"Gupta","year":"2017","journal-title":"Phytomedicine"},{"key":"B12","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1046\/j.1365-2672.1999.00780.x","article-title":"Antimicrobial activity of essential oils and other plant extracts.","volume":"86","author":"Hammer","year":"1999","journal-title":"J. Appl. Microbiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2277","DOI":"10.1099\/mic.0.27957-0","article-title":"Utilization of geraniol is dependent on molybdenum in Pseudomonas aeruginosa: evidence for different metabolic routes for oxidation of geraniol and citronellol.","volume":"151","author":"Hoschle","year":"2005","journal-title":"Microbiology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2012.00012","article-title":"Essential oils in food preservation: mode of action, synergies, and interactions with food matrix components.","volume":"3","author":"Hyldgaard","year":"2012","journal-title":"Front. Microbiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1093\/jac\/47.5.565","article-title":"Antibacterial activity of essential oils and their major constituents against respiratory tract pathogens by gaseous contact.","volume":"47","author":"Inouye","year":"2001","journal-title":"J. Antimicrob. Chemother."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1080\/14786419.2011.557376","article-title":"Anti-quorum sensing activity of essential oils from Colombian plants.","volume":"26","author":"Jaramillo-Colorado","year":"2012","journal-title":"Nat. Prod. Res."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a027029","article-title":"Aminoglycosides: an overview.","volume":"6","author":"Krause","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"76","DOI":"10.3109\/1040841x.2013.763219","article-title":"Synergy between essential oil components and antibiotics: a review.","volume":"40","author":"Langeveld","year":"2014","journal-title":"Crit. Rev. Microbiol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1128\/cmr.00117-14","article-title":"The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria.","volume":"28","author":"Li","year":"2015","journal-title":"Clin. Microbiol. Rev."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2833","DOI":"10.1073\/pnas.0511100103","article-title":"An ordered, nonredundant library of Pseudomonas aeruginosa strain PA14 transposon insertion mutants.","volume":"103","author":"Liberati","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B21","doi-asserted-by":"publisher","first-page":"5676","DOI":"10.1128\/aac.00101-11","article-title":"Role of the efflux system MexEF-OprN in low level resistance of Pseudomonas aeruginosa to ciprofloxacin.","volume":"55","author":"Llanes","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"B22","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1093\/jac\/dkt115","article-title":"Diversity of beta-lactam resistance mechanisms in cystic fibrosis isolates of Pseudomonas aeruginosa: a French multicentre study.","volume":"68","author":"Llanes","year":"2013","journal-title":"J. Antimicrob. Chemother."},{"key":"B23","doi-asserted-by":"publisher","first-page":"3298","DOI":"10.1128\/aac.48.9.3298-3304.2004","article-title":"Expression of the RND-type efflux pump AdeABC in Acinetobacter baumannii is regulated by the AdeRS two-component system.","volume":"48","author":"Marchand","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1320","DOI":"10.1128\/aac.48.4.1320-1328.2004","article-title":"Enhancement of the mexAB-oprM efflux pump expression by a quorum-sensing autoinducer and its cancellation by a regulator, MexT, of the mexEF-oprN efflux pump operon in Pseudomonas aeruginosa.","volume":"48","author":"Maseda","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"B25","first-page":"e969","article-title":"Complete genome assembly of Escherichia coli ATCC 25922, a serotype O6 reference strain.","volume":"2","author":"Minogue","year":"2014","journal-title":"Genome Announc."},{"key":"B26","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.apjtb.2015.09.024","article-title":"Evaluation of antibacterial activity and synergistic effect between antibiotic and the essential oils of some medicinal plants.","volume":"6","author":"Moussaoui","year":"2016","journal-title":"As. Pac. J. Trop. Biomed."},{"key":"B27","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1046\/j.1462-2920.2002.00366.x","article-title":"Complete genome sequence and comparative analysis of the metabolically versatile Pseudomonas putida KT2440.","volume":"4","author":"Nelson","year":"2002","journal-title":"Environ. Microbiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1007\/s00203-018-1485-3","article-title":"Colistin causes profound morphological alteration but minimal cytoplasmic membrane perforation in populations of Escherichia coli and Pseudomonas aeruginosa.","volume":"200","author":"O\u2019Driscoll","year":"2018","journal-title":"Arch. Microbiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1932","DOI":"10.1128\/aem.02334-07","article-title":"Role of the MexAB-OprM efflux pump of Pseudomonas aeruginosa in tolerance to tea tree (Melaleuca alternifolia) oil and its monoterpene components Terpinen-4-ol, 1,8-Cineole, and \u03b1-Terpineol.","volume":"74","author":"Papadopoulos","year":"2008","journal-title":"Appl. Environ. Microbiol."},{"key":"B30","first-page":"861","article-title":"Essential oil from Origanum vulgare completely inhibits the growth of multidrug-resistant cystic fibrosis pathogens.","volume":"11","author":"Pesavento","year":"2016","journal-title":"Nat. Prod. Commun."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.02664","article-title":"MexAB-OprM efflux pump of Pseudomonas aeruginosa offers resistance to carvacrol: a herbal antimicrobial agent.","volume":"10","author":"Pesingi","year":"2019","journal-title":"Front. Microbiol."},{"key":"B32","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-020-59553-8","article-title":"Essential oils against bacterial isolates from cystic fibrosis patients by means of antimicrobial and unsupervised machine learning approaches.","volume":"10","author":"Ragno","year":"2020","journal-title":"Sci. Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"2302","DOI":"10.1128\/aac.02622-15","article-title":"Amino acid substitutions account for most MexS alterations in clinical nfxC mutants of Pseudomonas aeruginosa.","volume":"60","author":"Richardot","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"B34","doi-asserted-by":"publisher","first-page":"3","DOI":"10.4103\/2231-4040.79796","article-title":"Scientific basis for the therapeutic use of Cymbopogon citratus, stapf (Lemon grass).","volume":"2","author":"Shah","year":"2011","journal-title":"J. Adv. Pharm. Technol. Res."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0159006","article-title":"Antimicrobial activity and possible mechanism of action of citral against Cronobacter sakazakii.","volume":"11","author":"Shi","year":"2016","journal-title":"PLoS One"},{"key":"B36","article-title":"Inhibition of Cronobacter sakazakii virulence factors by citral.","volume":"7","author":"Shi","year":"2017","journal-title":"Sci. Rep."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.1128\/jb.187.4.1246-1253.2005","article-title":"Mutations in PA2491 (mexS) promote MexT-dependent mexEF-oprN expression and multidrug resistance in a clinical strain of Pseudomonas aeruginosa.","volume":"187","author":"Sobel","year":"2005","journal-title":"J. Bacteriol."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.00894","article-title":"Attenuation of multiple Vibrio parahaemolyticus virulence factors by citral.","volume":"10","author":"Sun","year":"2019","journal-title":"Front. Microbiol."},{"key":"B39","doi-asserted-by":"crossref","DOI":"10.1155\/2016\/3012462","article-title":"Antimicrobial properties of plant essential oils against human pathogens and their mode of action: an updated review.","volume":"2016","author":"Swamy","year":"2016","journal-title":"Evid. Based Complement Alternat. Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"3732","DOI":"10.1128\/aem.02794-09","article-title":"Variation of physiochemical properties and cell association activity of membrane vesicles with growth phase in Pseudomonas aeruginosa.","volume":"76","author":"Tashiro","year":"2010","journal-title":"Appl. Environ. Microbiol."},{"key":"B41","doi-asserted-by":"crossref","first-page":"e1081","DOI":"10.1128\/AAC.01081-19","article-title":"Cinnamaldehyde induces expression of efflux pumps and multidrug resistance in Pseudomonas aeruginosa.","volume":"63","author":"Tetard","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"B42","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1080\/10412905.2019.1611671","article-title":"Review on the chemical composition of Litsea cubeba essential oils and the bioactivity of its major constituents citral and limonene.","volume":"31","author":"Thielmann","year":"2019","journal-title":"J. Essent. Oil Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1111\/j.1472-765x.2008.02548.x","article-title":"The antimicrobial activity of four commercial essential oils in combination with conventional antimicrobials.","volume":"48","author":"Van Vuuren","year":"2009","journal-title":"Lett. Appl. Microbiol."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0201835","article-title":"Antimicrobial activity of essential oils against multidrug-resistant clinical isolates of the Burkholderia cepacia complex.","volume":"13","author":"Vasireddy","year":"2018","journal-title":"PLoS One"}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.709838\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T08:26:57Z","timestamp":1625473617000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.709838\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,5]]},"references-count":44,"alternative-id":["10.3389\/fmicb.2021.709838"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2021.709838","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,5]]},"article-number":"709838"}}