{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T04:32:08Z","timestamp":1787632328404,"version":"build-2736575974"},"reference-count":114,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Background: The efflux system is one of the resistance mechanisms that bacteria use to reduce the effectiveness of antibiotics, leading to the development of multidrug resistance. To evaluate other treatment choices, esomeprazole (ESO), omeprazole (OME), pantoprazole (PAN), vitamin D (VD), and vitamin K (VK) were tested for potential efflux pump (EP)-inhibiting activity. Methods: The minimum inhibitory concentrations (MICs) of the tested drugs were determined against K. pneumoniae ATCC 51503 and P. aeruginosa PAO1. Quantitative estimation of the EP-inhibiting activity of the tested medications was phenotypically investigated with a semi-automated fluorometric system and genotypically confirmed by real-time polymerase chain reaction (RT-PCR). Data were confirmed through docking study. Results: K. pneumoniae ATCC 51503 and P. aeruginosa PAO1 were positive efflux standard strains. VD and VK revealed an MICVD of 625\u20131250 \u00b5g\/mL and MICVK of 2500\u20135000 \u00b5g\/mL, lower than what was detected for PPIs (MICPPIs = 16,000\u201332,000 \u00b5g\/mL). Vitamins showed powerful anti-efflux activity with remarkable ethidium bromide accumulation in K. pneumoniae ATCC 51503 and P. aeruginosa PAO1. Also, VD and VK significantly lowered the MIC of ciprofloxacin by 64-fold. On the molecular level, OME showed a notable decrease in the relative expression of the efflux-encoding genes acrB and mexA by 91.5% and 99.7% in ATCC 51503 and PAO1, respectively. Conclusion: This study highlights the anti-efflux activity of ESO, OME, PAN, VD, and VK against the tested Gram-negative strains. Hence, these PPIs and vitamins could be valuable adjuvant treatments to enhance the effectiveness of curing infections caused by MDR strains.<\/jats:p>","DOI":"10.3390\/microorganisms13061227","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T11:12:57Z","timestamp":1748344377000},"page":"1227","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Antimicrobial and Anti-Efflux Machinery of FDA-Approved Proton Pump Inhibitors and Vitamins Against Klebsiella pneumoniae and Pseudomonas aeruginosa"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6381-1906","authenticated-orcid":false,"given":"Lekaa L.","family":"Lutfi","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"},{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0420-4364","authenticated-orcid":false,"given":"Moataz A.","family":"Shaldam","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El Sheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3044-6102","authenticated-orcid":false,"given":"Mona I.","family":"Shaaban","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soha Lotfy","family":"Elshaer","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Duval, R.E., Grare, M., and Demore, B. (2019). Fight Against Antimicrobial Resistance: We Always Need New Antibacterials but for Right Bacteria. Molecules, 24.","DOI":"10.3390\/molecules24173152"},{"key":"ref_2","unstructured":"Tacconelli, E. (2024, January 22). Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development. Available online: https:\/\/remed.org\/wp-content\/uploads\/2017\/03\/lobal-priority-list-of-antibiotic-resistant-bacteria-2017.pdf."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Saleh, N.M., Ezzat, H., El-Sayyad, G.S., and Zedan, H. (2024). Regulation of overexpressed efflux pump encoding genes by cinnamon oil and trimethoprim to abolish carbapenem-resistant Acinetobacter baumannii clinical strains. BMC Microbiol., 24.","DOI":"10.1186\/s12866-024-03194-8"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"AbuTaha, S.A., Al-Kharraz, T., Belkebir, S., Abu Taha, A., and Zyoud, S.E.H. (2022). Patterns of microbial resistance in bloodstream infections of hemodialysis patients: A cross-sectional study from Palestine. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-21979-7"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.tim.2021.05.001","article-title":"Efflux pumps in Mycobacterium tuberculosis and their inhibition to tackle antimicrobial resistance","volume":"30","author":"Laws","year":"2022","journal-title":"Trends Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e0051421","DOI":"10.1128\/AAC.00514-21","article-title":"Update on Multidrug Resistance Efflux Pumps in Acinetobacter spp","volume":"65","author":"Kornelsen","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"195","DOI":"10.4155\/fmc.15.173","article-title":"An overview of bacterial efflux pumps and computational approaches to study efflux pump inhibitors","volume":"8","author":"Jamshidi","year":"2016","journal-title":"Future Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/s41579-018-0048-6","article-title":"Multidrug efflux pumps: Structure, function and regulation","volume":"16","author":"Du","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e00303-23","DOI":"10.1128\/iai.00303-23","article-title":"Klebsiella pneumoniae TolC contributes to antimicrobial resistance, exopolysaccharide production, and virulence","volume":"91","author":"Bina","year":"2023","journal-title":"Infect. Immun."},{"key":"ref_10","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_11","doi-asserted-by":"crossref","first-page":"104789","DOI":"10.1016\/j.micpath.2021.104789","article-title":"Expression of RND efflux pumps mediated antibiotic resistance in Pseudomonas aeruginosa clinical strains","volume":"153","author":"Rahbar","year":"2021","journal-title":"Microb. Pathog."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"102544","DOI":"10.1016\/j.jiph.2024.102544","article-title":"The influence of efflux pump, outer membrane permeability and \u03b2-lactamase production on the resistance profile of multi, extensively and pandrug resistant Klebsiella pneumoniae","volume":"17","author":"Hussein","year":"2024","journal-title":"J. Infect. Public Health"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ardebili, A., Talebi, M., Azimi, L., and Rastegar Lari, A. (2014). Effect of Efflux Pump Inhibitor Carbonyl Cyanide 3-Chlorophenylhydrazone on the Minimum Inhibitory Concentration of Ciprofloxacin in Acinetobacter baumannii Clinical Isolates. Jundishapur J. Microbiol., 7.","DOI":"10.5812\/jjm.8691"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/ja.2016.15","article-title":"In vitro characterization and inhibition of the interaction between ciprofloxacin and berberine against multidrug-resistant Klebsiella pneumoniae","volume":"69","author":"Zhou","year":"2016","journal-title":"J. Antibiot."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/apm.13015","article-title":"Quercetin inhibits carbapenemase and efflux pump activities among carbapenem-resistant Gram-negative bacteria","volume":"128","author":"Pal","year":"2020","journal-title":"Apmis"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sun, L., Sun, L., Li, X., Hu, X., Wang, X., Nie, T., Zhang, Y., and You, X. (2021). A Novel Tigecycline Adjuvant ML-7 Reverses the Susceptibility of Tigecycline-Resistant Klebsiella pneumoniae. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.809542"},{"key":"ref_17","first-page":"194","article-title":"An efflux pump (MexAB-OprM) of Pseudomonas aeruginosa is associated with antibacterial activity of Epigallocatechin-3-gallate (EGCG)","volume":"36","author":"Kanagaratnam","year":"2017","journal-title":"Phytomedicine Int. J. Phytother. Phytopharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2978","DOI":"10.1167\/iovs.19-27200","article-title":"Glycyrrhizin use for multi-drug resistant Pseudomonas aeruginosa: In vitro and in vivo studies","volume":"60","author":"Hazlett","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1021\/acsinfecdis.1c00281","article-title":"A Microbe-Derived Efflux Pump Inhibitor of the Resistance-Nodulation-Cell Division Protein Restores Antibiotic Susceptibility in Escherichia coli and Pseudomonas aeruginosa","volume":"8","author":"Tambat","year":"2022","journal-title":"ACS Infect. Dis."},{"key":"ref_20","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_21","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_22","doi-asserted-by":"crossref","unstructured":"Zhang, S., Wang, J., and Ahn, J. (2023). Advances in the Discovery of Efflux Pump Inhibitors as Novel Potentiators to Control Antimicrobial-Resistant Pathogens. Antibiotics, 12.","DOI":"10.3390\/antibiotics12091417"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"100164","DOI":"10.1016\/j.medidd.2023.100164","article-title":"Bac-EPIC: A web interface for developing novel efflux pump inhibitor compounds targeting Escherichia coli","volume":"20","author":"Pandey","year":"2023","journal-title":"Med. Drug Discov."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e00951-21","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_25","doi-asserted-by":"crossref","unstructured":"Abdel-Karim, S.A.M., El-Ganiny, A.M.A., El-Sayed, M.A., and Abbas, H.A.A. (2022). Promising FDA-approved drugs with efflux pump inhibitory activities against clinical isolates of Staphylococcus aureus. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0272417"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Cui, Z.H., He, H.L., Zheng, Z.J., Yuan, Z.Q., Chen, Y., Huang, X.Y., Ren, H., Zhou, Y.F., Zhao, D.H., and Fang, L.X. (2023). Phentolamine Significantly Enhances Macrolide Antibiotic Antibacterial Activity against MDR Gram-Negative Bacteria. Antibiotics, 12.","DOI":"10.3390\/antibiotics12040760"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e01675-17","DOI":"10.1128\/AAC.01675-17","article-title":"Vitamin D Compounds Are Bactericidal against Streptococcus mutans and Target the Bacitracin-Associated Efflux System","volume":"62","author":"Saputo","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Tintino, S.R., Souza, V.C.A., Silva, J.M.A., Oliveira-Tintino, C.D.D.M., Pereira, P.S., Leal-Balbino, T.C., Pereira-Neves, A., Siqueira-Junior, J.P., da Costa, J.G.M., and Rodrigues, F.F.G. (2020). Effect of Vitamin K3 Inhibiting the Function of NorA Efflux Pump and Its Gene Expression on Staphylococcus aureus. Membranes, 10.","DOI":"10.3390\/membranes10060130"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ramatla, T., Mokgokong, P., Lekota, K., and Thekisoe, O. (2024). Antimicrobial resistance profiles of Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae strains isolated from broiler chickens. Food Microbiol., 120.","DOI":"10.1016\/j.fm.2024.104476"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Al-Ouqaili, M.T., Khalaf, E.A., and Al-Kubaisy, S.H. (2020). DNA Sequence Analysis of BlaVEB Gene Encoding Multi-drug Resistant and Extended-spectrum \u03b2-lactamases Producer Isolates of Enterobacteriaceae and Pseudomonas aeruginosa. Open Microbiol. J., 14.","DOI":"10.2174\/1874285802014010040"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1093\/qjmed\/hcx148","article-title":"An outbreak of community-acquired Pseudomonas aeruginosa pneumonia in a setting of high water stress","volume":"110","author":"John","year":"2017","journal-title":"QJM Int. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"114006","DOI":"10.1016\/j.ijheh.2022.114006","article-title":"Prevalence of ESKAPE pathogens in the environment: Antibiotic resistance status, community-acquired infection and risk to human health","volume":"244","author":"Denissen","year":"2022","journal-title":"Int. J. Hyg. Environ. Health"},{"key":"ref_33","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_34","doi-asserted-by":"crossref","first-page":"100666","DOI":"10.1016\/j.genrep.2020.100666","article-title":"Efflux pumps of Gram-negative bacteria in brief","volume":"20","author":"Auda","year":"2020","journal-title":"Gene Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.resmic.2018.05.003","article-title":"Structure and mechanism of bacterial tripartite efflux pumps","volume":"169","author":"Neuberger","year":"2018","journal-title":"Res. Microbiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5597","DOI":"10.1021\/acs.chemrev.0c01137","article-title":"The Whole Is Bigger than the Sum of Its Parts: Drug Transport in the Context of Two Membranes with Active Efflux","volume":"121","author":"Rybenkov","year":"2021","journal-title":"Chem. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1111\/j.1574-6976.2011.00290.x","article-title":"Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria","volume":"36","author":"Nikaido","year":"2012","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e3168","DOI":"10.7717\/peerj.3168","article-title":"Mode of action of the 2-phenylquinoline efflux inhibitor PQQ4R against Escherichia coli","volume":"5","author":"Machado","year":"2017","journal-title":"PeerJ"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"106251","DOI":"10.1016\/j.ijantimicag.2020.106251","article-title":"RamA upregulates multidrug resistance efflux pumps AcrAB and OqxAB in Klebsiella pneumoniae","volume":"57","author":"Xu","year":"2021","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.2217\/fmb.14.66","article-title":"Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance","volume":"9","author":"Blair","year":"2014","journal-title":"Future Microbiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2460","DOI":"10.1002\/med.21591","article-title":"Efflux pump inhibitors of clinically relevant multidrug resistant bacteria","volume":"39","author":"Lamut","year":"2019","journal-title":"Med. Res. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6360","DOI":"10.1128\/AAC.03535-14","article-title":"Identification of Acinetobacter baumannii serum-associated antibiotic efflux pump inhibitors","volume":"58","author":"Blanchard","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_43","unstructured":"CLSI (2021). M100 Performance Standards for Antimicrobial Susceptibility Testing, Clinical Laboratory and Standards Institute. [31st ed.]."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s40261-020-00963-x","article-title":"Proton Pump Inhibitors are Risk Factors for Viral Infections: Even for COVID-19?","volume":"40","author":"Charpiat","year":"2020","journal-title":"Clin. Drug Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1136\/gutjnl-2020-322248","article-title":"Severe clinical outcomes of COVID-19 associated with proton pump inhibitors: A nationwide cohort study with propensity score matching","volume":"70","author":"Lee","year":"2021","journal-title":"Gut"},{"key":"ref_46","unstructured":"Lewis, I., and James, S. (2024, January 22). Performance Standards for Antimicrobial Susceptibility Testing. Available online: https:\/\/clsi.org\/shop\/standards\/m100\/."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Abdulaal, W.H., Alhakamy, N.A., Asseri, A.H., Radwan, M.F., Ibrahim, T.S., Okbazghi, S.Z., Abbas, H.A., Mansour, B., Shoun, A.A., and Hegazy, W.A.H. (2024). Redirecting pantoprazole as a metallo-beta-lactamase inhibitor in carbapenem-resistant Klebsiella pneumoniae. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1366459"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1111\/1751-7915.13807","article-title":"Armeniaspirol A: A novel anti-Helicobacter pylori agent","volume":"15","author":"Jia","year":"2022","journal-title":"Microb. Biotechnol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e01921-20","DOI":"10.1128\/AAC.01921-20","article-title":"Dihydrotanshinone I Is Effective against Drug-Resistant Helicobacter pylori In Vitro and In Vivo","volume":"65","author":"Luo","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Sadiq, S., Rana, N.F., Zahid, M.A., Zargaham, M.K., Tanweer, T., Batool, A., Naeem, A., Nawaz, A., Rizwan Ur, R., and Muneer, Z. (2020). Virtual Screening of FDA-Approved Drugs against LasR of Pseudomonas aeruginosa for Antibiofilm Potential. Molecules, 25.","DOI":"10.3390\/molecules25163723"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Mdanda, S., Baijnath, S., Shobo, A., Singh, S.D., Maguire, G.E.M., Kruger, H.G., Arvidsson, P.I., Naicker, T., and Govender, T. (2017). Lansoprazole-sulfide, pharmacokinetics of this promising anti-tuberculous agent. Biomed. Chromatogr. BMC, 31.","DOI":"10.1002\/bmc.4035"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1128\/AAC.01306-05","article-title":"Synthesis of omeprazole analogues and evaluation of these as potential inhibitors of the multidrug efflux pump NorA of Staphylococcus aureus","volume":"51","author":"Vidaillac","year":"2007","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.jgar.2018.01.005","article-title":"Evaluation of synergistic antimicrobial effect of vitamins (A, B1, B2, B6, B12, C, D, E and K) with antibiotics against resistant bacterial strains","volume":"13","author":"Shahzad","year":"2018","journal-title":"J. Glob. Antimicrob. Resist."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1556\/1886.2020.00020","article-title":"Vitamin E as promising adjunct treatment option in the combat of infectious diseases caused by bacterial including multi-drug resistant pathogens\u2014Results from a comprehensive literature survey","volume":"10","author":"Hartmann","year":"2020","journal-title":"Eur. J. Microbiol. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Patti, G., Pellegrino, C., Ricciardi, A., Novara, R., Cotugno, S., Papagni, R., Guido, G., Totaro, V., De Iaco, G., and Romanelli, F. (2021). Potential Role of Vitamins A, B, C, D and E in TB Treatment and Prevention: A Narrative Review. Antibiotics, 10.","DOI":"10.3390\/antibiotics10111354"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1556\/1886.2019.00014","article-title":"Antimicrobial and Immune-Modulatory Effects of Vitamin D Provide Promising Antibiotics-Independent Approaches to Tackle Bacterial Infections\u2014Lessons Learnt from a Literature Survey","volume":"9","author":"Golpour","year":"2019","journal-title":"Eur. J. Microbiol. Immunol."},{"key":"ref_57","first-page":"1278","article-title":"The Antimicrobial Activity of Combination of Vitamin D3 and Omega-3 against Pathogenic Microorganisms","volume":"28","author":"Abdulrazzaq","year":"2024","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/BF01489010","article-title":"Studies on the antimicrobial effect of vitamin D (author\u2019s trans.)","volume":"55","author":"Feindt","year":"1977","journal-title":"Klin. Wochenschr."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.sjbs.2015.09.004","article-title":"Menadione (vitamin K) enhances the antibiotic activity of drugs by cell membrane permeabilization mechanism","volume":"24","author":"Andrade","year":"2017","journal-title":"Saudi J. Biol. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Lee, M.H., Yang, J.Y., Cho, Y., Woo, H.J., Kwon, H.J., Kim, D.H., Park, M., Moon, C., Yeon, M.J., and Kim, H.W. (2019). Inhibitory Effects of Menadione on Helicobacter pylori Growth and Helicobacter pylori-Induced Inflammation via NF-\u03baB Inhibition. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051169"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"220","DOI":"10.4161\/derm.3.4.15027","article-title":"Antimicrobial implications of vitamin D","volume":"3","author":"Youssef","year":"2011","journal-title":"Derm. Endocrinol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Kim, E.W., Teles, R.M.B., Haile, S., Liu, P.T., and Modlin, R.L. (2018). Vitamin D status contributes to the antimicrobial activity of macrophages against Mycobacterium leprae. PLoS Neglected Trop. Dis., 12.","DOI":"10.1371\/journal.pntd.0006608"},{"key":"ref_63","first-page":"100111","article-title":"Riboflavin as a promising antimicrobial agent? A multi-perspective review","volume":"3","author":"Farah","year":"2022","journal-title":"Curr. Res. Microb. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Hassuna, N.A., Rabie, E.M., Mahd, W.K.M., Refaie, M.M.M., Yousef, R.K.M., and Abdelraheem, W.M. (2023). Antibacterial effect of vitamin C against uropathogenic E. coli in vitro and in vivo. BMC Microbiol., 23.","DOI":"10.1186\/s12866-023-02856-3"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"91","DOI":"10.5152\/eurasianjmed.2024.23145","article-title":"Vitamins Can Increase Antibiotic Effects Against Multidrug-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii in an In Vitro Infection Model","volume":"56","author":"Celebi","year":"2024","journal-title":"Eurasian J. Med."},{"key":"ref_66","unstructured":"Proton Pump Inhibitors (2012). LiverTox: Clinical and Research Information on Drug-Induced Liver Injury."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/fsn3.3787","article-title":"Pharmacokinetics of vitamin dosage forms: A complete overview","volume":"12","author":"Sugandhi","year":"2024","journal-title":"Food Sci. Nutr."},{"key":"ref_68","unstructured":"Asif, A., and Farooq, N. (2025). Vitamin D Toxicity, StatPearls Publishing."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1093\/nutrit\/nuab061","article-title":"Vitamin K\u2014Sources, physiological role, kinetics, deficiency, detection, therapeutic use, and toxicity","volume":"80","author":"Mladenka","year":"2022","journal-title":"Nutr. Rev."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Paixao, L., Rodrigues, L., Couto, I., Martins, M., Fernandes, P., de Carvalho, C.C., Monteiro, G.A., Sansonetty, F., Amaral, L., and Viveiros, M. (2009). Fluorometric determination of ethidium bromide efflux kinetics in Escherichia coli. J. Biol. Eng., 3.","DOI":"10.1186\/1754-1611-3-18"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"729","DOI":"10.2174\/138945008785747789","article-title":"The AcrB efflux pump: Conformational cycling and peristalsis lead to multidrug resistance","volume":"9","author":"Seeger","year":"2008","journal-title":"Curr. Drug Targets"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1021\/acsinfecdis.4c00091","article-title":"Extending the Potency and Lifespan of Antibiotics: Inhibitors of Gram-Negative Bacterial Efflux Pumps","volume":"10","author":"Duffey","year":"2024","journal-title":"ACS Infect Dis"},{"key":"ref_73","unstructured":"Mulli\u00e9, C., Bouharkat, B., Guiheneuf, R., Serra, C., Touil-Meddah, A.T., and Sonnet, P. (2017). Efflux Pumps in Acinetobacter Baumannii: Role in Antibiotic Resistance and Interest of Efflux Pump Inhibitors as Additional Therapeutic Weapons. Antimicrobial Research: Novel Bioknowledge and Educational Programs, Formatex Research Center."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e2215512120","DOI":"10.1073\/pnas.2215512120","article-title":"The human proton pump inhibitors inhibit Mycobacterium tuberculosis rifampicin efflux and macrophage-induced rifampicin tolerance","volume":"120","author":"Lake","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Lu, M., Yan, H., Yu, C., Yuan, L., and Sun, S. (2020). Proton pump inhibitors act synergistically with fluconazole against resistant Candida albicans. Sci. Rep., 10.","DOI":"10.1038\/s41598-019-57174-4"},{"key":"ref_76","first-page":"245","article-title":"Repurposing pantoprazole and haloperidol as efflux pump inhibitors in azole resistant clinical Candida albicans and non-albicans isolates","volume":"30","author":"Kamel","year":"2022","journal-title":"Saudi Pharm. J. SPJ Off. Publ. Saudi Pharm. Soc."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"306","DOI":"10.12669\/pjms.332.11778","article-title":"Effects of domperidone in combination with omeprazole in the treatment of chronic superficial gastritis","volume":"33","author":"Wang","year":"2017","journal-title":"Pak. J. Med. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Chowdhury, N., Suhani, S., Purkaystha, A., Begum, M.K., Raihan, T., Alam, M.J., Islam, K., and Azad, A.K. (2019). Identification of AcrAB-TolC Efflux Pump Genes and Detection of Mutation in Efflux Repressor AcrR from Omeprazole Responsive Multidrug-Resistant Escherichia coli Isolates Causing Urinary Tract Infections. Microbiol. Insights, 12.","DOI":"10.1177\/1178636119889629"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3237","DOI":"10.2147\/DDDT.S113556","article-title":"Homology modeling, molecular dynamics, and virtual screening of NorA efflux pump inhibitors of Staphylococcus aureus","volume":"10","author":"Bhaskar","year":"2016","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"129","DOI":"10.4103\/ijmr.IJMR_2079_17","article-title":"Efflux pump inhibitors for bacterial pathogens: From bench to bedside","volume":"149","author":"Sharma","year":"2019","journal-title":"Indian J. Med. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1093\/jac\/dkac044","article-title":"Adaptation of clinical isolates of Klebsiella pneumoniae to the combination of niclosamide with the efflux pump inhibitor phenyl-arginine-\u03b2-naphthylamide (Pa\u03b2N): Co-resistance to antimicrobials","volume":"77","author":"Pacios","year":"2022","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"73","DOI":"10.2174\/157489112799829710","article-title":"Bacterial efflux pumps involved in multidrug resistance and their inhibitors: Rejuvinating the antimicrobial chemotherapy","volume":"7","author":"Bhardwaj","year":"2012","journal-title":"Recent Pat. Anti-Infect. Drug Discov."},{"key":"ref_83","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_84","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1021\/acsinfecdis.6b00167","article-title":"Reviving antibiotics: Efflux pump inhibitors that interact with AcrA, a membrane fusion protein of the AcrAB-TolC multidrug efflux pump","volume":"3","author":"Abdali","year":"2017","journal-title":"ACS Infect. Dis."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1093\/femsre\/fuz014","article-title":"Antibiotic resistance breakers: Current approaches and future directions","volume":"43","author":"Laws","year":"2019","journal-title":"FEMS Microbiol Rev"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/nature13205","article-title":"Structure of the AcrAB-TolC multidrug efflux pump","volume":"509","author":"Du","year":"2014","journal-title":"Nature"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1128\/AAC.00715-09","article-title":"Klebsiella pneumoniae AcrAB efflux pump contributes to antimicrobial resistance and virulence","volume":"54","author":"Padilla","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Shu, R., Liu, G., Xu, Y., Liu, B., Huang, Z., and Wang, H. (2024). AcrAB Efflux Pump Plays a Crucial Role in Bile Salts Resistance and Pathogenesis of Klebsiella pneumoniae. Antibiotics, 13.","DOI":"10.3390\/antibiotics13121146"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Morita, Y., Tomida, J., and Kawamura, Y. (2012). MexXY multidrug efflux system of Pseudomonas aeruginosa. Front. Microbiol., 3.","DOI":"10.3389\/fmicb.2012.00408"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.jiph.2017.09.016","article-title":"Role of MexAB-OprM and MexXY-OprM efflux pumps and class 1 integrons in resistance to antibiotics in burn and Intensive Care Unit isolates of Pseudomonas aeruginosa","volume":"11","author":"Goli","year":"2018","journal-title":"J. Infect. Public Health"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"285","DOI":"10.2147\/IDR.S233808","article-title":"Molecular Epidemiology and Mechanisms of High-Level Resistance to Meropenem and Imipenem in Pseudomonas aeruginosa","volume":"13","author":"Hassuna","year":"2020","journal-title":"Infect. Drug Resist."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Lorusso, A.B., Carrara, J.A., Barroso, C.D.N., Tuon, F.F., and Faoro, H. (2022). Role of Efflux Pumps on Antimicrobial Resistance in Pseudomonas aeruginosa. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415779"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"709","DOI":"10.3390\/applmicrobiol3030049","article-title":"The Effect of Antibiotic Treatment and Gene Expression of Mex B Efflux Transporters on the Resistance in Pseudomonas Aeruginosa Biofilms","volume":"3","author":"Kello","year":"2023","journal-title":"Appl. Microbiol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3782","DOI":"10.1128\/AEM.00239-15","article-title":"Polyphenolic extract from maple syrup potentiates antibiotic susceptibility and reduces biofilm formation of pathogenic bacteria","volume":"81","author":"Maisuria","year":"2015","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"106397","DOI":"10.1016\/j.micpath.2023.106397","article-title":"Effect of piperine on the inhibitory potential of MexAB-OprM efflux pump and imipenem resistance in carbapenem-resistant Pseudomonas aeruginosa","volume":"185","author":"Liu","year":"2023","journal-title":"Microb. Pathog."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3509","DOI":"10.1073\/pnas.1602472113","article-title":"Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives","volume":"113","author":"Sjuts","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_97","unstructured":"Washington, W., Allen, S., and Janda, W. (2006). Koneman\u2019s Color Atlas and Textbook of Diagnostic Microbiology, Lippincott Williams and Wilkins."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Iranpour, D., Hassanpour, M., Ansari, H., Tajbakhsh, S., Khamisipour, G., and Najafi, A.J.B. (2015). Phylogenetic groups of Escherichia coli strains from patients with urinary tract infection in Iran based on the new Clermont phylotyping method. Biomed. Res. Int., 2015.","DOI":"10.1155\/2015\/846219"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1093\/jac\/dkp186","article-title":"Correlation of the expression of acrB and the regulatory genes marA, soxS and ramA with antimicrobial resistance in clinical isolates of Klebsiella pneumoniae endemic to New York City","volume":"64","author":"Bratu","year":"2009","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Lutfi, L.L., Shaaban, M.I., and Elshaer, S.L. (2024). Vitamin D and vitamin K1 as novel inhibitors of biofilm in Gram-negative bacteria. BMC Microbiol., 24.","DOI":"10.1186\/s12866-024-03293-6"},{"key":"ref_101","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_102","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.micpath.2014.07.008","article-title":"Aspirin is an efficient inhibitor of quorum sensing, virulence and toxins in Pseudomonas aeruginosa","volume":"74","author":"Shaaban","year":"2014","journal-title":"Microb. Pathog."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.ijantimicag.2007.12.015","article-title":"Demonstration of intrinsic efflux activity of Escherichia coli K-12 AG100 by an automated ethidium bromide method","volume":"31","author":"Viveiros","year":"2008","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Gillespie, S.H., and McHugh, T.D. (2010). Evaluation of Efflux Activity of Bacteria by a Semi-automated Fluorometric System. Antibiotic Resistance Protocols, Humana Press. [2nd ed.].","DOI":"10.1007\/978-1-60327-279-7"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Parish, T., and Roberts, D.M. (2015). Measuring Efflux and Permeability in Mycobacteria. Mycobacteria Protocols, Springer.","DOI":"10.1007\/978-1-4939-2450-9"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1089\/adt.2016.752","article-title":"An experimental model for the rapid screening of compounds with potential use against mycobacteria","volume":"14","author":"Costa","year":"2016","journal-title":"Assay Drug Dev. Technol."},{"key":"ref_107","first-page":"769","article-title":"Biological activity of twenty-three hydantoin derivatives on intrinsic efflux pump system of Salmonella enterica serovar Enteritidis NCTC 13349","volume":"25","author":"Machado","year":"2011","journal-title":"In Vivo"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1128\/AAC.01482-12","article-title":"Role of the Mmr efflux pump in drug resistance in Mycobacterium tuberculosis","volume":"57","author":"Rodrigues","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Machado, D., Coelho, T.S., Perdigao, J., Pereira, C., Couto, I., Portugal, I., Maschmann, R.D.A., Ramos, D.F., von Groll, A., and Rossetti, M.L.J.F. (2017). Interplay between mutations and efflux in drug resistant clinical isolates of Mycobacterium tuberculosis. Front. Microbiol., 8.","DOI":"10.3389\/fmicb.2017.00711"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Machado, D., Perdig\u00e3o, J., Portugal, I., Pieroni, M., Silva, P.A., Couto, I., and Viveiros, M.J.A. (2018). Efflux activity differentially modulates the levels of isoniazid and rifampicin resistance among multidrug resistant and monoresistant Mycobacterium tuberculosis strains. Antibiotics, 7.","DOI":"10.3390\/antibiotics7010018"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212 \u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e00659-23","DOI":"10.1128\/mbio.00659-23","article-title":"Cryo-EM Structures of the Klebsiella pneumoniae AcrB Multidrug Efflux Pump","volume":"14","author":"Zhang","year":"2023","journal-title":"mBio"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"4948","DOI":"10.1038\/s41467-020-18770-5","article-title":"Antibiotic export by MexB multidrug efflux transporter is allosterically controlled by a MexA-OprM chaperone-like complex","volume":"11","author":"Glavier","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/6\/1227\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:41:38Z","timestamp":1760031698000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/13\/6\/1227"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,27]]},"references-count":114,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["microorganisms13061227"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms13061227","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,27]]}}}