{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T21:48:00Z","timestamp":1783028880538,"version":"3.54.6"},"reference-count":43,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T00:00:00Z","timestamp":1666051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Gram-negative bacteria were reported as a significant cause of infections in both community and nosocomial settings. Considered as one of the greatest threats to public health, the spread of bacteria drug resistance and the lack of effective alternative treatment options remains problematic. Herein, we report a promising strategy to combat Gram-negative resistant strains consisting of the combination of a macrolide antibiotic with a polyaminoisoprenyl adjuvant derivative leading to a significant decrease of antibiotic resistance.<\/jats:p>","DOI":"10.3390\/ijms232012457","type":"journal-article","created":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T21:18:02Z","timestamp":1666127882000},"page":"12457","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["An Original and Efficient Antibiotic Adjuvant Strategy to Enhance the Activity of Macrolide Antibiotics against Gram-Negative Resistant Strains"],"prefix":"10.3390","volume":"23","author":[{"given":"Azza","family":"Troudi","sequence":"first","affiliation":[{"name":"Aix Marseille Universit\u00e9, INSERM, SSA, MCT, 13385 Marseille, France"},{"name":"Laboratory of Microorganisms and Active Biomolecules, Department of Biology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis 1068, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3892-4340","authenticated-orcid":false,"given":"Jean Michel","family":"Bolla","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, INSERM, SSA, MCT, 13385 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naouel","family":"Klibi","sequence":"additional","affiliation":[{"name":"Laboratory of Microorganisms and Active Biomolecules, Department of Biology, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis 1068, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9355-8980","authenticated-orcid":false,"given":"Jean Michel","family":"Brunel","sequence":"additional","affiliation":[{"name":"Aix Marseille Universit\u00e9, INSERM, SSA, MCT, 13385 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.2147\/IDR.S173867","article-title":"Antibiotic resistance: A rundown of a global crisis","volume":"11","author":"Aslam","year":"2018","journal-title":"Infect. Drug Resist."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1465-0691.2004.1004.x","article-title":"The need for new antibiotics","volume":"10","author":"Livermore","year":"2004","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1126\/science.1164586","article-title":"Microbiology. Desperately seeking new antibiotics","volume":"321","author":"Payne","year":"2008","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2970","DOI":"10.1111\/j.1462-2920.2009.01972.x","article-title":"The role of antibiotics and antibiotic resistance in nature","volume":"11","author":"Aminov","year":"2009","journal-title":"Environ. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1039\/B916096E","article-title":"Antimicrobial natural products: An update on future antibiotic drug candidates","volume":"27","author":"Saleem","year":"2010","journal-title":"Nat. Prod. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2928","DOI":"10.3389\/fmicb.2018.02928","article-title":"Antibiotic resistance mechanisms in bacteria: Relationships between resistance determinants of antibiotic producers, environmental bacteria, and clinical pathogen","volume":"9","author":"Peterson","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1089\/mdr.2018.0319","article-title":"Multidrugresistant bacteria and alternative methods to control them: An overview","volume":"25","author":"Vivas","year":"2019","journal-title":"Microb. Drug Resist."},{"key":"ref_8","first-page":"1000132","article-title":"Burden of antibiotic resistant gram negative bacterial infections: Evidence and limits","volume":"3","author":"Fiori","year":"2014","journal-title":"J. Med. Microb. Diagn."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s12941-016-0144-2","article-title":"Genetic characterization of TEM-type ESBL-associated antibacterial resistance in Enterobacteriaceae in a tertiary hospital in Ghana","volume":"15","author":"Bonney","year":"2016","journal-title":"Ann. Clin. Microbiol. Antimicrob."},{"key":"ref_10","first-page":"629","article-title":"Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic Analysis","volume":"399","author":"Wagenlehner","year":"2022","journal-title":"Eur. Urol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1089\/mdr.2018.0027","article-title":"Relationship between biofilm formation and antimicrobial resistance in gram-negative bacteria","volume":"25","author":"Cepas","year":"2019","journal-title":"Microb. Drug Resist."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8665","DOI":"10.1021\/acs.jmedchem.8b01781","article-title":"Antibiotic Adjuvants: Make Antibiotics Great Again!","volume":"62","author":"Douafer","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1021\/acs.jmedchem.0c02185","article-title":"Chemical Highlights Supporting the Role of Lipid A in Efficient Biological Adaptation of Gram-Negative Bacteria to External Stresses","volume":"64","author":"Troudi","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1021\/la504407v","article-title":"Effect of divalent cation removal on the structure of Gram-negative bacterial outer membrane models","volume":"31","author":"Clifton","year":"2015","journal-title":"Langmuir"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1128\/jb.128.1.325-336.1976","article-title":"Outer membrane of Gram-negative bacteria. XII. Molecular-sieving function of cell wall","volume":"128","author":"Decad","year":"1976","journal-title":"J. Bacteriol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/0005-2736(76)90182-6","article-title":"Outer membrane of Salmonella typhimurium transmembrane diffusion of some hydrophobic substances","volume":"433","author":"Nikaido","year":"1976","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1128\/MMBR.67.4.593-656.2003","article-title":"Molecular basis of bacterial outer membrane permeability revisited","volume":"67","author":"Nikaido","year":"2003","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1021\/jm700967e","article-title":"Physicochemical properties of antibacterial compounds: Implications for drug discovery","volume":"51","author":"Moser","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/nrd4572","article-title":"ESKAPEing the labyrinth of antibacterial discovery","volume":"14","author":"Tommasi","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2006.0008","DOI":"10.1038\/msb4100050","article-title":"Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: The Keio collection","volume":"2","author":"Baba","year":"2006","journal-title":"Mol. Syst. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e00161-20","DOI":"10.1128\/mBio.00161-20","article-title":"Genetic and chemical-genetic interactions map biogenesis and permeability determinants of the outer membrane of Escherichia coli","volume":"11","author":"Klobucar","year":"2020","journal-title":"mBio"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.chembiol.2010.05.010","article-title":"Chemical genomic approaches to study model microbes","volume":"17","author":"Barker","year":"2010","journal-title":"Chem. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0955-0674(02)00317-4","article-title":"The emerging power of chemical genetics","volume":"14","author":"Specht","year":"2002","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/0006-3002(58)90044-1","article-title":"Lysis of Gram-negative organisms and the role of versene","volume":"30","author":"Repaske","year":"1958","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1128\/mr.56.3.395-411.1992","article-title":"Agents that increase the permeability of the outer membrane","volume":"56","author":"Vaara","year":"1992","journal-title":"Microbiol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e00200-17","DOI":"10.1128\/AAC.00200-17","article-title":"Potentiation of antibiotic activity by a novel cationic peptide: Potency and spectrum of activity of SPR741","volume":"61","author":"Corbett","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1021\/acsinfecdis.9b00159","article-title":"Polymyxin B analog SPR741 potentiates antibiotics against Gram-negative bacteria and uniquely perturbs the outer membrane","volume":"6","author":"French","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/S0140-6736(97)80051-7","article-title":"Peptide antibiotics","volume":"349","author":"Hancock","year":"1997","journal-title":"Lancet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4425","DOI":"10.1021\/bi00587a024","article-title":"Interaction of divalent cations and polymyxin B with lipopolysaccharide","volume":"18","author":"Schindler","year":"1979","journal-title":"Biochemistry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1128\/AAC.27.4.548","article-title":"Binding of polymyxin B nonapeptide to Gram-negative bacteria","volume":"27","author":"Vaara","year":"1985","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4857","DOI":"10.1038\/s41467-018-06488-4","article-title":"Sugar-based bactericides targeting phosphatidylethanolamine-enriched membranes","volume":"19","author":"Dias","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.tibs.2018.06.011","article-title":"How Macrolide Antibiotics Work","volume":"43","author":"Mankin","year":"2018","journal-title":"Trends Biochem. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3109\/1040841X.2015.1136261","article-title":"Macrolide resistance mechanisms in Enterobacteriaceae: Focus on azithromycin","volume":"43","author":"Gomes","year":"2017","journal-title":"Crit. Rev. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.ijantimicag.2017.05.020","article-title":"16-membered macrolide antibiotics: A review","volume":"51","author":"Arsic","year":"2018","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Borselli, D., Lieutaud, A., Thefenne, H., Garnotel, E., Pag\u00e8s, J.-M., Brunel, J.M., and Bolla, J.-M. (2016). Polyamino-isoprenic derivatives block intrinsic resistance of P. aeruginosa to doxycycline and chloramphenicol in vitro. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0154490"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10496","DOI":"10.1021\/acs.jmedchem.0c01335","article-title":"New Polyaminoisoprenyl Antibiotics Enhancers against Two Multidrug-Resistant Gram-Negative Bacteria from Enterobacter and Salmonella Species","volume":"63","author":"Lieutaud","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Troudi, A., Fethi, M., El Asli, M.S., Bolla, J.M., Klibi, N., and Brunel, J.M. (2020). Efficiency of a tetracycline-adjuvant combination against multidrug resistant Pseudomonas aeruginosa Tunisian clinical isolates. Antibiotics, 9.","DOI":"10.3390\/antibiotics9120919"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e02028","DOI":"10.1128\/AAC.02028-20","article-title":"The polyaminoisoprenyl potentiator NV716 revives old disused antibiotics against intracellular forms of infection by Pseudomonas aeruginosa","volume":"65","author":"Wang","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1021\/id500013t","article-title":"A New-Class Antibacterial\u2014Almost. Lessons in Drug Discovery and Development: A Critical Analysis of More than 50 Years of Effort toward ATPase Inhibitors of DNA Gyrase and Topoisomerase IV","volume":"1","author":"Bisacchi","year":"2015","journal-title":"ACS Infect. Dis."},{"key":"ref_40","first-page":"29","article-title":"Analysis of Antimicrobial-Triggered Membrane Depolarization Using Voltage Sensitive Dyes","volume":"4","author":"Gray","year":"2016","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1002\/cbic.201600532","article-title":"Motuporamine Derivatives as Antimicrobial Agents and Antibiotic Enhancers against Resistant Gram-Negative Bacteria","volume":"18","author":"Borselli","year":"2017","journal-title":"Chembiochem"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.jmb.2009.05.064","article-title":"ATP regulates calcium efflux and growth in E. coli","volume":"391","author":"Naseem","year":"2009","journal-title":"J. Mol. Biol."},{"key":"ref_43","first-page":"364","article-title":"Comit\u00e9 de l\u2019Antibiogramme de la Soci\u00e9t\u00e9 Fran\u00e7aise de Microbiologie report 2003","volume":"21","author":"Committee","year":"2003","journal-title":"Int. J. Antimicrob. 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