{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:48:36Z","timestamp":1791395316360,"version":"4.3.3"},"reference-count":39,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"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>Most clinically used antibiotics exert their effects by targeting essential intracellular components of bacterial cells. Therefore, enhancing their ability to traverse the bacterial envelope is crucial for restoring or improving therapeutic efficacy. We investigated the potential of outer membrane (OM)-disrupting agents\u2014EDTA, NV716, colistin, and squalamine\u2014to potentiate antibiotic activity against the multi-drug-resistant pathogen Pseudomonas aeruginosa. Our objective was to assess the therapeutic value of this strategy while also delineating its limitations by comparing responses across antibiotic classes with diverse chemical structures and pharmacological profiles. Beyond lipophilicity, we analyzed three additional physicochemical descriptors likely to influence OM permeability: molecular surface area, polarizability, and polar surface area. Our findings offer practical insights for the rational design of antibiotic\u2013adjuvant combinations. While each descriptor provides valuable interpretive information, none alone reliably predicts OM-mediated potentiation. Instead, these factors should be viewed collectively within a multidimensional physicochemical profile, where optimal ranges of size, polarity, and lipophilicity act synergistically to enhance antibiotic uptake. By defining a shared multidimensional \u201cresponsive zone,\u201d we propose a framework to guide the selection or design of antibiotics compatible with OM-disrupting strategies, potentially enabling the repurposing of antibiotics limited by poor OM permeability.<\/jats:p>","DOI":"10.3390\/ijms26209844","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:50:16Z","timestamp":1760107816000},"page":"9844","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Permeabilize, but Choose Wisely: Selective Antibiotic Potentiation Through Outer Membrane Disruption in Pseudomonas aeruginosa"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5131-1373","authenticated-orcid":false,"given":"Marine","family":"Novelli","sequence":"first","affiliation":[{"name":"Aix-Marseille Universit\u00e9, INSERM, SSA, MCT, 13385 Marseille, France"}],"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":[[2025,10,10]]},"reference":[{"key":"ref_1","unstructured":"Antimicrobial Resistance Collaborators (2022). Global Burden of Bacterial Antimicrobial Resistance in 2019: A Systematic Analysis. Lancet, 399, 629\u2013655."},{"key":"ref_2","unstructured":"O\u2019Neill, J. (2016). Tackling Drug-Resistant Infections Globally: Final Report and Recommendations, Government of the United Kingdom."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.2147\/IDR.S3545","article-title":"Current and Novel Antibiotics against Resistant Gram-Positive Bacteria","volume":"1","author":"Perez","year":"2008","journal-title":"Infect. Drug Resist."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e56033","DOI":"10.15252\/embr.202256033","article-title":"Fighting Antibiotic Resistance-Strategies and (Pre)Clinical Developments to Find New Antibacterials","volume":"24","author":"Walesch","year":"2023","journal-title":"EMBO Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/j.1476-5381.2011.01250.x","article-title":"Novel Classes of Antibiotics or More of the Same?","volume":"163","author":"Coates","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1021\/acsinfecdis.5b00097","article-title":"Permeability Barrier of Gram-Negative Cell Envelopes and Approaches to Bypass It","volume":"1","author":"Zgurskaya","year":"2015","journal-title":"ACS Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Krishnamoorthy, G., Leus, I.V., Weeks, J.W., Wolloscheck, D., Rybenkov, V.V., and Zgurskaya, H.I. (2017). Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria. mBio, 8.","DOI":"10.1128\/mBio.01172-17"},{"key":"ref_8","doi-asserted-by":"crossref","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":"ref_9","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/978-3-030-18768-2_4","article-title":"Outer Membrane Porins","volume":"92","author":"Masi","year":"2019","journal-title":"Subcell. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5479","DOI":"10.1021\/acs.chemrev.1c00055","article-title":"Structure, Assembly, and Function of Tripartite Efflux and Type 1 Secretion Systems in Gram-Negative Bacteria","volume":"121","author":"Alav","year":"2021","journal-title":"Chem. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.drup.2016.06.007","article-title":"Multidrug Efflux Pumps as Main Players in Intrinsic and Acquired Resistance to Antimicrobials","volume":"28","author":"Blanco","year":"2016","journal-title":"Drug Resist. Updates"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Novelli, M., and Bolla, J.-M. (2024). RND Efflux Pump Induction: A Crucial Network Unveiling Adaptive Antibiotic Resistance Mechanisms of Gram-Negative Bacteria. Antibiotics, 13.","DOI":"10.3390\/antibiotics13060501"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/nyas.14134","article-title":"Permeability Barriers of Gram-Negative Pathogens","volume":"1459","author":"Zgurskaya","year":"2020","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1021\/acs.accounts.0c00843","article-title":"Multidrug Efflux Pumps and the Two-Faced Janus of Substrates and Inhibitors","volume":"54","author":"Zgurskaya","year":"2021","journal-title":"Acc. Chem. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Compagne, N., Vieira Da Cruz, A., M\u00fcller, R.T., Hartkoorn, R.C., Flipo, M., and Pos, K.M. (2023). Update on the Discovery of Efflux Pump Inhibitors against Critical Priority Gram-Negative Bacteria. Antibiotics, 12.","DOI":"10.3390\/antibiotics12010180"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5465","DOI":"10.1021\/acsnano.6b08613","article-title":"Bacterial Outer Membrane Porins as Electrostatic Nanosieves: Exploring Transport Rules of Small Polar Molecules","volume":"11","author":"Bajaj","year":"2017","journal-title":"ACS Nano"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"El Zahed, S.S., French, S., Farha, M.A., Kumar, G., and Brown, E.D. (2021). Physicochemical and Structural Parameters Contributing to the Antibacterial Activity and Efflux Susceptibility of Small-Molecule Inhibitors of Escherichia coli. Antimicrob. Agents Chemother., 65.","DOI":"10.1128\/AAC.01925-20"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mehla, J., Malloci, G., Mansbach, R., L\u00f3pez, C.A., Tsivkovski, R., Haynes, K., Leus, I.V., Grindstaff, S.B., Cascella, R.H., and D\u2019Cunha, N. (2021). Predictive Rules of Efflux Inhibition and Avoidance in Pseudomonas aeruginosa. mBio, 12.","DOI":"10.1128\/mBio.02785-20"},{"key":"ref_19","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_20","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1177\/0885066615619895","article-title":"Antimicrobial Resistance in the Intensive Care Unit: A Focus on Gram-Negative Bacterial Infections","volume":"32","author":"MacVane","year":"2017","journal-title":"J. Intensive Care Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1128\/CMR.00040-09","article-title":"Antibacterial-Resistant Pseudomonas aeruginosa: Clinical Impact and Complex Regulation of Chromosomally Encoded Resistance Mechanisms","volume":"22","author":"Lister","year":"2009","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Santajit, S., and Indrawattana, N. (2016). Mechanisms of Antimicrobial Resistance in ESKAPE Pathogens. Biomed. Res. Int., 2016.","DOI":"10.1155\/2016\/2475067"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e2107644118","DOI":"10.1073\/pnas.2107644118","article-title":"Outer Membrane Permeability: Antimicrobials and Diverse Nutrients Bypass Porins in Pseudomonas aeruginosa","volume":"118","author":"Ude","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1128\/CMR.00030-10","article-title":"Challenges of Antibacterial Discovery","volume":"24","author":"Silver","year":"2011","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.bbapap.2008.11.005","article-title":"Outer Membrane Permeability and Antibiotic Resistance","volume":"1794","author":"Delcour","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0005-2736(99)00256-4","article-title":"Squalamine Is Not a Proton Ionophore","volume":"1464","author":"Selinsky","year":"2000","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Wang, G., Brunel, J.-M., Preusse, M., Mozaheb, N., Willger, S.D., Larrouy-Maumus, G., Baatsen, P., H\u00e4ussler, S., Bolla, J.-M., and Van Bambeke, F. (2022). The Membrane-Active Polyaminoisoprenyl Compound NV716 Re-Sensitizes Pseudomonas aeruginosa to Antibiotics and Reduces Bacterial Virulence. Commun. Biol., 5.","DOI":"10.1038\/s42003-022-03836-5"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s44259-023-00016-1","article-title":"Tackling the Outer Membrane: Facilitating Compound Entry into Gram-negative Bacterial Pathogens","volume":"1","author":"Saxena","year":"2023","journal-title":"Npj Antimicrob. Resist."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Tabcheh, J., Vergalli, J., Davin-R\u00e9gli, A., Ghanem, N., Pages, J.-M., Al-Bayssari, C., and Brunel, J.M. (2023). Rejuvenating the Activity of Usual Antibiotics on Resistant Gram-Negative Bacteria: Recent Issues and Perspectives. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021515"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e65836","DOI":"10.7554\/eLife.65836","article-title":"Colistin Kills Bacteria by Targeting Lipopolysaccharide in the Cytoplasmic Membrane","volume":"10","author":"Sabnis","year":"2021","journal-title":"Elife"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"197","DOI":"10.4103\/0250-474X.33142","article-title":"Atypical Log D Profile of Rifampicin","volume":"69","author":"Singh","year":"2007","journal-title":"Indian. J. Pharm. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"105802","DOI":"10.1016\/j.ejps.2021.105802","article-title":"Rifampicin as an Example of Beyond-Rule-of-5 Compound: Ionization beyond Water and Lipophilicity beyond Octanol\/Water","volume":"161","author":"Ermondi","year":"2021","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10757","DOI":"10.1021\/acsomega.3c00312","article-title":"Antibiotic Adjuvants: A Versatile Approach to Combat Antibiotic Resistance","volume":"8","author":"Dhanda","year":"2023","journal-title":"ACS Omega"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Leus, I.V., Weeks, J.W., Bonifay, V., Shen, Y., Yang, L., Cooper, C.J., Nath, D., Duerfeldt, A.S., Smith, J.C., and Parks, J.M. (2022). Property Space Mapping of Pseudomonas aeruginosa Permeability to Small Molecules. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-12376-1"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1089\/wound.2014.0577","article-title":"EDTA: An Antimicrobial and Antibiofilm Agent for Use in Wound Care","volume":"4","author":"Finnegan","year":"2015","journal-title":"Adv. Wound Care"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"104840","DOI":"10.1016\/j.micpath.2021.104840","article-title":"The Effect of EDTA in Combination with Some Antibiotics against Clinical Isolates of Gram Negative Bacteria in Mansoura, Egypt","volume":"154","author":"Aboelenin","year":"2021","journal-title":"Microb. Pathog."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Troudi, A., Fethi, M., Selim El Asli, M., 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":"3897","DOI":"10.1002\/ejoc.200300167","article-title":"Recent Advances in the Synthesis of Spermine and Spermidine Analogs of the Shark Aminosterol Squalamine","volume":"20","author":"Brunel","year":"2003","journal-title":"Eur. J. Org. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"European Committee for Antimicrobial Susceptibility Testing (EUCAST) of the European Society of Clinical Microbiology and Infectious Dieases (ESCMID) (2000). EUCAST Definitive Document E.DEF 3.1, June 2000: Determination of Minimum Inhibitory Concentrations (MICs) of Antibacterial Agents by Agar Dilution. Clin. Microbiol. Infect., 6, 509\u2013515.","DOI":"10.1046\/j.1469-0691.2000.00142.x"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/9844\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:58:14Z","timestamp":1760108294000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/20\/9844"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,10]]},"references-count":39,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["ijms26209844"],"URL":"https:\/\/doi.org\/10.3390\/ijms26209844","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,10]]}}}