{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T16:53:30Z","timestamp":1774630410963,"version":"3.50.1"},"reference-count":87,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH\/NIAID)\n\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/044zkrt47","award":["R44AI174351"],"award-info":[{"award-number":["R44AI174351"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Objectives: Multidrug-resistant (MDR) Pseudomonas aeruginosa represents a major clinical challenge, driven in part by resistance\u2013nodulation\u2013division (RND) efflux pumps that reduce intracellular antibiotic concentrations and limit the efficacy of many antibacterial agents, including fluoroquinolones. The aim of this study was to identify and characterize TXA11114 as a small-molecule efflux pump inhibitor (EPI) capable of restoring the activity of the fluoroquinolone levofloxacin against MDR P. aeruginosa. Methods: The antibacterial activity of the TXA11114\u2013levofloxacin combination was evaluated using minimum inhibitory concentration (MIC) assays against panels of clinical isolates. Mechanistic studies included levofloxacin accumulation assays, ethidium bromide accumulation assays, outer-membrane permeability measurements, and whole-genome sequencing of mutants with altered potentiation phenotypes. In vivo efficacy was evaluated in murine thigh and lung infection models, while preliminary safety and drug-like properties were assessed using cytotoxicity assays and in vitro ADME profiling. Results: The TXA11114\u2013levofloxacin combination produced &gt; 1 log10 CFU reductions in bacterial burden in murine thigh and lung infection models, exceeding the activity of levofloxacin monotherapy. TXA11114 markedly potentiated levofloxacin activity, producing substantial reductions in levofloxacin MIC values across multiple MDR clinical isolates, and also enhanced the activity of several additional efflux pump substrates, including \u03b2-lactams, tetracyclines, chloramphenicol, and trimethoprim\u2013sulfamethoxazole. Mechanistic experiments demonstrated increased intracellular accumulation of efflux substrates without evidence of nonspecific membrane disruption, and mutations in ompH were associated with altered potentiation phenotypes. Conclusions: The TXA11114\u2013levofloxacin combination produced significantly greater bacterial reductions than levofloxacin monotherapy in murine infection models. Levofloxacin was selected because fluoroquinolone resistance in P. aeruginosa is frequently driven by efflux-mediated mechanisms. While this study focused on levofloxacin potentiation, future work will evaluate additional efflux pump substrates and further define the molecular target of TXA11114.<\/jats:p>","DOI":"10.3390\/antibiotics15040346","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T15:45:42Z","timestamp":1774626342000},"page":"346","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TXA11114: Discovery of an In Vivo Efficacious Efflux Pump Inhibitor (EPI) That Potentiates Levofloxacin Against Pseudomonas aeruginosa"],"prefix":"10.3390","volume":"15","author":[{"given":"Jesus D.","family":"Rosado-Lugo","sequence":"first","affiliation":[{"name":"TAXIS Pharmaceuticals, Inc., Monmouth Junction, NJ 08852, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pratik","family":"Datta","sequence":"additional","affiliation":[{"name":"TAXIS Pharmaceuticals, Inc., Monmouth Junction, NJ 08852, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2946-4477","authenticated-orcid":false,"given":"Ahmad","family":"Altiti","sequence":"additional","affiliation":[{"name":"TAXIS Pharmaceuticals, Inc., Monmouth Junction, NJ 08852, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongzheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"TAXIS Pharmaceuticals, Inc., Monmouth Junction, NJ 08852, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Lu","sequence":"additional","affiliation":[{"name":"TAXIS Pharmaceuticals, Inc., Monmouth Junction, NJ 08852, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Yuan","sequence":"additional","affiliation":[{"name":"TAXIS Pharmaceuticals, Inc., Monmouth Junction, NJ 08852, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ajit K.","family":"Parhi","sequence":"additional","affiliation":[{"name":"TAXIS Pharmaceuticals, Inc., Monmouth Junction, NJ 08852, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref_1","unstructured":"CDC (2019). Antibiotic Resistance Threats in the United States, 2019."},{"key":"ref_2","unstructured":"Centers for Disease Control and Prevention (2024). Antimicrobial Resistance Threats in the United States, 2021\u20132022."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3934\/microbiol.2018.3.482","article-title":"An overview of the antimicrobial resistance mechanisms of bacteria","volume":"4","author":"Reygaert","year":"2018","journal-title":"AIMS Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Yuan, Y., Rosado-Lugo, J.D., Zhang, Y., Datta, P., Sun, Y., Cao, Y., Banerjee, A., and Parhi, A.K. (2021). Evaluation of Heterocyclic Carboxamides as Potential Efflux Pump Inhibitors in Pseudomonas aeruginosa. Antibiotics, 11.","DOI":"10.3390\/antibiotics11010030"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1007\/s40265-021-01635-6","article-title":"The Epidemiology and Pathogenesis and Treatment of Pseudomonas aeruginosa Infections: An Update","volume":"81","author":"Reynolds","year":"2021","journal-title":"Drugs"},{"key":"ref_6","unstructured":"Spencer, J., and Chukwuma, U. (2018). Annual Surveillance Summary: Pseudomonas aeruginosa Infections in the Military Health System (MHS), 2017, (NMCPHC-EDC-TR-379-2018)."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1517\/17460441.2012.688949","article-title":"Understanding efflux in Gram-negative bacteria: Opportunities for drug discovery","volume":"7","author":"Schweizer","year":"2012","journal-title":"Expert. Opin. Drug Discov."},{"key":"ref_8","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_9","first-page":"255","article-title":"Multidrug efflux pumps and antimicrobial resistance in Pseudomonas aeruginosa and related organisms","volume":"3","author":"Poole","year":"2001","journal-title":"J. Mol. Microbiol. Biotechnol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"59","DOI":"10.2174\/1568026013395605","article-title":"Multidrug efflux in Pseudomonas aeruginosa: Components, mechanisms and clinical significance","volume":"1","author":"Poole","year":"2001","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Serra, C., Bouharkat, B., Tir Touil-Meddah, A., Guenin, S., and Mullie, C. (2019). MexXY Multidrug Efflux System Is More Frequently Overexpressed in Ciprofloxacin Resistant French Clinical Isolates Compared to Hospital Environment Ones. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.00366"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1080\/17460441.2018.1514386","article-title":"The development of efflux pump inhibitors to treat Gram-negative infections","volume":"13","author":"Blanco","year":"2018","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"702","DOI":"10.2174\/1389450116666151001103948","article-title":"Efflux Pump Inhibitors: A Novel Approach to Combat Efflux-Mediated Drug Resistance in Bacteria","volume":"17","author":"Wang","year":"2016","journal-title":"Curr. Drug Targets"},{"key":"ref_14","first-page":"e25952","article-title":"Investigation of OprD Porin Protein Levels in Carbapenem-Resistant Pseudomonas aeruginosa Isolates","volume":"8","author":"Terzi","year":"2015","journal-title":"Jundishapur J. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.ijmm.2011.10.001","article-title":"Structure and function of OprD protein in Pseudomonas aeruginosa: From antibiotic resistance to novel therapies","volume":"302","author":"Li","year":"2012","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1080\/21505594.2016.1222343","article-title":"The global epidemiology of carbapenemase-producing Enterobacteriaceae","volume":"8","author":"Doi","year":"2017","journal-title":"Virulence"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"396","DOI":"10.15585\/mmwr.mm6713e1","article-title":"Vital signs: Containment of novel multidrug-resistant organisms and resistance mechanisms-United States, 2006\u20132017","volume":"67","author":"Woodworth","year":"2018","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1128\/AAC.45.1.105-116.2001","article-title":"Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: Novel agents for combination therapy","volume":"45","author":"Lomovskaya","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.molmed.2005.06.006","article-title":"Inhibitors of efflux pumps in Gram-negative bacteria","volume":"11","author":"Pages","year":"2005","journal-title":"Trends Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.1016\/S0960-894X(03)00556-0","article-title":"Conformationally-restricted analogues of efflux pump inhibitors that potentiate the activity of levofloxacin in Pseudomonas aeruginosa","volume":"13","author":"Renau","year":"2003","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7087","DOI":"10.1016\/j.bmc.2007.07.039","article-title":"MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 7: Highly soluble and in vivo active quaternary ammonium analogue D13-9001, a potential preclinical candidate","volume":"15","author":"Yoshida","year":"2007","journal-title":"Bioorganic Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1128\/AAC.01866-13","article-title":"Characterization of a novel pyranopyridine inhibitor of the AcrAB efflux pump of Escherichia coli","volume":"58","author":"Opperman","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.bcp.2005.12.008","article-title":"Practical applications and feasibility of efflux pump inhibitors in the clinic\u2014A vision for applied use","volume":"71","author":"Lomovskaya","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e01934-17","DOI":"10.1128\/JCM.01934-17","article-title":"CLSI Methods Development and Standardization Working Group of the Subcommittee on Antimicrobial Susceptibility Testing. CLSI Methods Development and Standardization Working Group Best Practices for Evaluation of Antimicrobial Susceptibility Tests","volume":"56","author":"Humphries","year":"2018","journal-title":"J. Clin. Microbiol."},{"key":"ref_25","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_26","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1093\/jac\/dky208","article-title":"Revitalizing the drug pipeline: AntibioticDB, an open access database to aid antibacterial research and development","volume":"73","author":"Farrell","year":"2018","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.2174\/0929867323666160304150522","article-title":"Current Advances in Developing Inhibitors of Bacterial Multidrug Efflux Pumps","volume":"23","author":"Mahmood","year":"2016","journal-title":"Curr. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Xu, F., Xie, Y., Yu, W., and Wang, Z. (2026). Breaking the outer membrane barrier: Structure, targets, and antimicrobial strategies for Gram-negative bacteria. Front. Microbiol., 17.","DOI":"10.3389\/fmicb.2026.1734749"},{"key":"ref_30","unstructured":"TAXIS Pharmaceuticals Inc (2020). Tackling resistance in multidrug-resistant bacterial infections. Biopharma Deal., 14, B23."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Rosado-Lugo, J.D., Datta, P., Sun, Y., Cao, Y., Banerjee, A., Yuan, Y., and Parhi, A.K. (2022). Evaluation of a Conformationally Constrained Indole Carboxamide as a Potential Efflux Pump Inhibitor in Pseudomonas aeruginosa. Antibiotics, 11.","DOI":"10.3390\/antibiotics11060716"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2939","DOI":"10.1021\/jm051262k","article-title":"Application of the Goldilocks effect to the design of potent and selective inhibitors of phenylethanolamine N-methyltransferase: Balancing pKa and steric effects in the optimization of 3-methyl-1,2,3,4-tetrahydroisoquinoline inhibitors by beta-fluorination","volume":"49","author":"Grunewald","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3786","DOI":"10.1021\/jm500317a","article-title":"Matched molecular pair analysis: Significance and the impact of experimental uncertainty","volume":"57","author":"Kramer","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/bs.pmch.2014.11.001","article-title":"Fluorine in medicinal chemistry","volume":"54","author":"Swallow","year":"2015","journal-title":"Prog. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1124\/jpet.301.2.427","article-title":"Three-dimensional quantitative structure-activity relationship for inhibition of human ether-a-go-go-related gene potassium channel","volume":"301","author":"Ekins","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4872","DOI":"10.1016\/j.bmcl.2008.07.071","article-title":"Physiochemical drug properties associated with in vivo toxicological outcomes","volume":"18","author":"Hughes","year":"2008","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1002\/cmdc.200700221","article-title":"A composite model for HERG blockade","volume":"3","author":"Kramer","year":"2008","journal-title":"ChemMedChem"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.bmcl.2016.11.085","article-title":"Amine promiscuity and toxicology analysis","volume":"27","author":"Lee","year":"2017","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1021\/tx200211v","article-title":"Improving drug candidates by design: A focus on physicochemical properties as a means of improving compound disposition and safety","volume":"24","author":"Meanwell","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.2174\/15680266113139990036","article-title":"Recent developments in computational prediction of HERG blockage","volume":"13","author":"Wang","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1021\/ci050450g","article-title":"Quantitative structure-activity relationship studies on inhibition of HERG potassium channels","volume":"46","author":"Yoshida","year":"2006","journal-title":"J. Chem. Inf. Model."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.4155\/bio.09.128","article-title":"Mechanisms of amine accumulation in, and egress from, lysosomes","volume":"1","author":"Goldman","year":"2009","journal-title":"Bioanalysis"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1128\/AAC.43.5.1003","article-title":"Aminoglycosides: Nephrotoxicity","volume":"43","author":"Tulkens","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"8315","DOI":"10.1021\/acs.jmedchem.5b00258","article-title":"Applications of Fluorine in Medicinal Chemistry","volume":"58","author":"Gillis","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1080\/14756360701425014","article-title":"The role of fluorine in medicinal chemistry","volume":"22","author":"Shah","year":"2007","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3527","DOI":"10.1039\/B307563J","article-title":"4-Fluorinated L-lysine analogs as selective i-NOS inhibitors: Methodology for introducing fluorine into the lysine side chain","volume":"1","author":"Hallinan","year":"2003","journal-title":"Org. Biomol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"4573","DOI":"10.1016\/0040-4020(96)00137-8","article-title":"Total synthesis of pseudodistomin C, a sphingosine-related piperidine alkaloid from tunicate Pseudodistoma kanoko","volume":"52","author":"Doi","year":"1996","journal-title":"Tetrahedron"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1021\/jo00109a008","article-title":"Hunt Symmetric Allylboration of 2-N,3-O-Isopropylidene-N-Boc-L-serinal: Diastereoselective Synthesis of the Calicheamicin \u03b31I Amino Sugar","volume":"60","author":"William","year":"1995","journal-title":"J. Org. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1021\/jm9904755","article-title":"A new class of conformationally rigid analogues of 4-amino-5-halopentanoic acids, potent inactivators of aminobutyric acid aminotransferase","volume":"43","author":"Qiu","year":"2000","journal-title":"J. Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1016\/j.bmcl.2009.01.076","article-title":"4,4-Difluorinated analogues of L-arginine and NG-hydroxy-L-arginine as mechanistic probes for nitric oxide synthase","volume":"19","author":"Martin","year":"2009","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"8625","DOI":"10.1016\/S0040-4039(01)01866-4","article-title":"A concise synthesis of l-4,4-difluoroglutamine","volume":"42","author":"Meffre","year":"2001","journal-title":"Tetrahedron Lett."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3202","DOI":"10.1128\/AAC.47.10.3202-3207.2003","article-title":"Contribution of the MexXY multidrug transporter to aminoglycoside resistance in Pseudomonas aeruginosa clinical isolates","volume":"47","author":"Sobel","year":"2003","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"dlab179","DOI":"10.1093\/jacamr\/dlab179","article-title":"A panel of diverse Pseudomonas aeruginosa clinical isolates for research and development","volume":"3","author":"Lebreton","year":"2021","journal-title":"JAC Antimicrob. Resist."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"fnw166","DOI":"10.1093\/femsle\/fnw166","article-title":"Mutations in NalC induce MexAB-OprM overexpression resulting in high level of aztreonam resistance in environmental isolates of Pseudomonas aeruginosa","volume":"363","author":"Braz","year":"2016","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Choudhury, D., Ghose, A., Dhar Chanda, D., Das Talukdar, A., Dutta Choudhury, M., Paul, D., Maurya, A.P., Chakravarty, A., and Bhattacharjee, A. (2016). Premature Termination of MexR Leads to Overexpression of MexAB-OprM Efflux Pump in Pseudomonas aeruginosa in a Tertiary Referral Hospital in India. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0151308"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/ismej.2011.122","article-title":"Quorum quenching quandary: Resistance to antivirulence compounds","volume":"6","author":"Maeda","year":"2012","journal-title":"ISME J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1128\/AAC.45.2.480-484.2001","article-title":"Carbapenem resistance mechanisms in Pseudomonas aeruginosa clinical isolates","volume":"45","author":"Pai","year":"2001","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1007\/s00203-016-1215-7","article-title":"Overexpression of MexAB-OprM efflux pump in carbapenem-resistant Pseudomonas aeruginosa","volume":"198","author":"Pan","year":"2016","journal-title":"Arch. Microbiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1128\/AAC.01581-12","article-title":"Quantitative contributions of target alteration and decreased drug accumulation to Pseudomonas aeruginosa fluoroquinolone resistance","volume":"57","author":"Bruchmann","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1093\/jac\/dkh505","article-title":"Reduction of the fitness burden of quinolone resistance in Pseudomonas aeruginosa","volume":"55","author":"Kugelberg","year":"2005","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"275","DOI":"10.2147\/IDR.S147581","article-title":"Mutations in the gyrA, parC, and mexR genes provide functional insights into the fluoroquinolone-resistant Pseudomonas aeruginosa isolated in Vietnam","volume":"11","author":"Nguyen","year":"2018","journal-title":"Infect. Drug Resist."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Stiefel, P., Schmidt-Emrich, S., Maniura-Weber, K., and Ren, Q. (2015). Critical aspects of using bacterial cell viability assays with the fluorophores SYTO9 and propidium iodide. BMC Microbiol., 15.","DOI":"10.1186\/s12866-015-0376-x"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Zack, K.M., Sorenson, T., and Joshi, S.G. (2024). Types and Mechanisms of Efflux Pump Systems and the Potential of Efflux Pump Inhibitors in the Restoration of Antimicrobial Susceptibility, with a Special Reference to Acinetobacter baumannii. Pathogens, 13.","DOI":"10.3390\/pathogens13030197"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1021\/acsinfecdis.9b00221","article-title":"Lysine-Based Small Molecule Sensitizes Rifampicin and Tetracycline against Multidrug-Resistant Acinetobacter baumannii and Pseudomonas aeruginosa","volume":"6","author":"Konai","year":"2020","journal-title":"ACS Infect. Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e0095121","DOI":"10.1128\/Spectrum.00951-21","article-title":"Repurposing Approved Drugs as Fluoroquinolone Potentiators to Overcome Efflux Pump Resistance in Staphylococcus aureus","volume":"9","author":"Mahey","year":"2021","journal-title":"Microbiol. Spectr."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e00910-20","DOI":"10.1128\/AAC.00910-20","article-title":"Use of a Fluorescence-Based Assay to Measure Escherichia coli Membrane Potential Changes in High Throughput","volume":"64","author":"Hudson","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_67","doi-asserted-by":"crossref","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":"ref_68","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.meegid.2014.03.018","article-title":"Role of efflux pumps: MexAB-OprM and MexXY(-OprA), AmpC cephalosporinase and OprD porin in non-metallo-beta-lactamase producing Pseudomonas aeruginosa isolated from cystic fibrosis and burn patients","volume":"24","author":"Aghazadeh","year":"2014","journal-title":"Infect. Genet. Evol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0378-1097(03)00882-6","article-title":"Detection of an IS21 insertion sequence in the mexR gene of Pseudomonas aeruginosa increasing beta-lactam resistance","volume":"230","author":"Boutoille","year":"2004","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"6844","DOI":"10.1128\/AAC.03681-14","article-title":"Mutation-driven beta-lactam resistance mechanisms among contemporary ceftazidime-nonsusceptible Pseudomonas aeruginosa isolates from U.S. hospitals","volume":"58","author":"Castanheira","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1089\/mdr.1998.4.257","article-title":"Mechanisms of quinolone resistance in clinical strains of Pseudomonas aeruginosa","volume":"4","author":"Jalal","year":"1998","journal-title":"Microb. Drug Resist."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1128\/AAC.48.5.1797-1802.2004","article-title":"Clinical strains of Pseudomonas aeruginosa overproducing MexAB-OprM and MexXY efflux pumps simultaneously","volume":"48","author":"Llanes","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_73","first-page":"140","article-title":"The Evaluation of Antibiotic Resistance and nalB Mutants in Pseudomonas eruginosa Isolated from Burnt Patients of Shohada Mehrab Yazd Hospital Burn Ward","volume":"9","author":"Moosavi","year":"2020","journal-title":"Rep. Biochem. Mol. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s11274-018-2465-0","article-title":"Mutational analyses of regulatory genes, mexR, nalC, nalD and mexZ of mexAB-oprM and mexXY operons, in efflux pump hyperexpressing multidrug-resistant clinical isolates of Pseudomonas aeruginosa","volume":"34","author":"Suresh","year":"2018","journal-title":"World J. Microbiol. Biotechnol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1126\/science.288.5469.1251","article-title":"High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection","volume":"288","author":"Oliver","year":"2000","journal-title":"Science"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/0014-5793(90)80169-J","article-title":"Bacterial \u2018histone-like protein I\u2019 (HLP-I) is an outer membrane constituent?","volume":"262","author":"Hirvas","year":"1990","journal-title":"FEBS Lett."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.1128\/AAC.00035-09","article-title":"Genomewide identification of genetic determinants of antimicrobial drug resistance in Pseudomonas aeruginosa","volume":"53","author":"Dotsch","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1021\/pr050159g","article-title":"Proteomic analysis of the sarcosine-insoluble outer membrane fraction of Pseudomonas aeruginosa responding to ampicillin, kanamycin, and tetracycline resistance","volume":"4","author":"Peng","year":"2005","journal-title":"J. Proteome Res."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Babu, M., Diaz-Mejia, J.J., Vlasblom, J., Gagarinova, A., Phanse, S., Graham, C., Yousif, F., Ding, H., Xiong, X., and Nazarians-Armavil, A. (2011). Genetic interaction maps in Escherichia coli reveal functional crosstalk among cell envelope biogenesis pathways. PLoS Genet., 7.","DOI":"10.1371\/journal.pgen.1002377"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1016\/j.bbamcr.2013.10.014","article-title":"Folding mechanisms of periplasmic proteins","volume":"1843","author":"Goemans","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"4987","DOI":"10.1002\/pmic.200800288","article-title":"Identification of potential substrate proteins for the periplasmic Escherichia coli chaperone Skp","volume":"8","author":"Jarchow","year":"2008","journal-title":"Proteomics"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1128\/JB.182.6.1754-1756.2000","article-title":"AcrD of Escherichia coli is an aminoglycoside efflux pump","volume":"182","author":"Rosenberg","year":"2000","journal-title":"J. Bacteriol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1038\/nsmb828","article-title":"Structure of the periplasmic chaperone Skp suggests functional similarity with cytosolic chaperones despite differing architecture","volume":"11","author":"Dommel","year":"2004","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/s12929-020-00678-3","article-title":"A synthetic peptide sensitizes multi-drug-resistant Pseudomonas aeruginosa to antibiotics for more than two hours and permeabilizes its envelope for twenty hours","volume":"27","author":"Shahrour","year":"2020","journal-title":"J. Biomed. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.molcel.2004.07.023","article-title":"Crystal structure of Skp, a prefoldin-like chaperone that protects soluble and membrane proteins from aggregation","volume":"15","author":"Walton","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"932","DOI":"10.3390\/pharmaceutics3040932","article-title":"Ionic channels as targets for drug design: A review on computational methods","volume":"3","year":"2011","journal-title":"Pharmaceutics"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"e0015521","DOI":"10.1128\/AEM.00155-21","article-title":"Antifungal Azoles as Tetracycline Resistance Modifiers in Staphylococcus aureus","volume":"87","author":"Mahey","year":"2021","journal-title":"Appl. Environ. Microbiol."}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/15\/4\/346\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T16:03:47Z","timestamp":1774627427000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/15\/4\/346"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":87,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["antibiotics15040346"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics15040346","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]}}}