Abstract
Antibiotic resistance is an important public health problem today, causing increased morbidity and mortality. Resistance to antibiotics in bacteria can develop by various mechanisms such as a change in the target site of the drug, a change in the outer membrane permeability, enzymatic defusing of the drug and efflux of the antimicrobial compound. Some bacteria have the potential to develop resistance to more than one drug by using several mechanisms together. One of the important resistance mechanisms of bacteria is active efflux pumps (EPs). EPs are pump proteins found in all cell types, located in the cell membrane. They are responsible for the excretion of various intracellular and extracellular substances (antibiotics, etc.) out of the cell. There is much research on various antimicrobials that cause antibiotic resistance in Gram negative rods, but studies on EPs are relatively few. Due to the concern that antibiotics will be insufficient in the treatment of diseases, a good understanding of EPs and the discovery of new EP inhibitors will shed light on the future of humanity. In this review, the structure of bacterial EPs in Gram negative bacteria, the role of EPs in multidrug resistance, the importance of EP inhibitors in the fight against antibiotic resistance and the phenotypic and genotypic detection methods of EPs are discussed.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Data available on request from the authors.
Change history
03 June 2023
A Correction to this paper has been published: https://doi.org/10.1007/s00203-023-03588-8
References
Abbas H, Shaker G, Khattab R, Askoura M (2021) A new role of metformin as an efflux pump inhibitor in klebsiella pneumonia. J Microbiol Biotechnol Food Sci 11:1–8. https://doi.org/10.15414/jmbfs.4232
Abdallah A, el Azawy D, Mohammed H, el Maghraby H (2021) Expression of Mex AB-Opr M efflux pump system and meropenem resistance in Pseudomonas aeruginosa isolated from surgical intensive care unit. Microbes Infect Dis. https://doi.org/10.21608/mid.2021.92720.1187
Abdi SN, Ghotaslou R, Ganbarov K et al (2020) Acinetobacter baumannii efflux pumps and antibiotic resistance. Infect Drug Resist 13:423–434. https://doi.org/10.2147/IDR.S228089
Abushaheen MA, Muzaheed, Fatani AJ, et al (2020) Antimicrobial resistance, mechanisms and its clinical significance. Disease-a-Month. https://doi.org/10.1016/j.disamonth.2020.100971
Adzitey F (2015) Antibiotic classes and antibiotic susceptibility of bacterial isolates from selected poultry; a mini review. World’s Vet J 5:36–41
Akçay Özlüer P (2016) Kinolon Dirençli Escherıchıa Colı Klinik İzolatlarında Plazmidik Direnç Mekanizmalarının Araştırılması. Adnan Menderes Üniversitesi
Al Rashed N, Joji R, Saeed N, Bindayna K (2020) Detection of overexpression of efflux pump expression in fluoroquinolone-resistant Pseudomonas aeruginosa isolates. Int J Appl Basic Med Res 10:37. https://doi.org/10.4103/ijabmr.ijabmr_90_19
Alav I, Sutton JM, Rahman KM (2018) Role of bacterial efflux pumps in biofilm formation. J Antimicrob Chemother 73:2003–2020. https://doi.org/10.1093/jac/dky042
Albayrak Ö (2018) Escherichia Coli ve Klebsiella Pneumoniae İzolatlarında Karbapenem Direnci ve Dirençten Sorumlu Enzimlerin Araştırılması. Master Thesis, Afyon Kocatepe University,
Al-Otaibi FE, Bukhari EE, Badr M, Alrabiaa AA (2016) Prevalence and risk factors of Gram-negative bacilli causing blood stream infection in patients with malignancy. Saudi Med J 37:9. https://doi.org/10.1553/smj.2016.9.14211
Altınöz E, Altuner EM (2019) Antibiotic resistance and efflux pumps. Int J Innov Res Rev (INJIRR) 3:1–9
Altıntop Pınar Karbapenemlere Direnç Gösteren Gram Negatif Bakterilerde Metallo-Beta-Laktamaz Enziminin Fenotipik Olarak Araştırılması. Çukurova University, PhD thesis, Adana, 2015
Alvarez-Ortega C, Olivares J, Martínez JL et al (2013) RND multidrug efflux pumps: what are they good for? Front Microbiol. https://doi.org/10.3389/fmicb.2013.00007
Ardebili A, Talebi M, Azimi L, 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. https://doi.org/10.5812/jjm.8691
Ardehali SH, Azimi T, Fallah F et al (2019) Role of efflux pumps in reduced susceptibility to tigecycline in Acinetobacter baumannii. New Microbes New Infect. https://doi.org/10.1016/j.nmni.2019.100547
Askoura M, Mattawa W (2011) Efflux pump inhibitors (EPIs) as new antimicrobial agents against Pseudomonas aeruginosa. Libyan J Med. https://doi.org/10.3402/ljm.v6i0.5870
Ayaz M, Ullah F, Sadiq A et al (2019) Synergistic interactions of phytochemicals with antimicrobial agents: Potential strategy to counteract drug resistance. Chem Biol Interact 308:294–303. https://doi.org/10.1016/j.cbi.2019.05.050
Aygül A (2015) Antibiyotik Direncinde Dışa Atım Sistemlerinin ve Dirençle Mücadelede Dışa Atım Pompa İnhibitörlerinin Önemi. Ege Üniversity Faculity of Pharmacy, İzmir 278–291
Baddour LM, Dayer MJ, Thornhill MH (2019) Fluoroquinolone use and associated adverse drug events in England. J Infect 78:249–259. https://doi.org/10.1016/J.JINF.2018.11.001
Beikmohammadi H, Viesy S, Kaviani R, Pouladi I (2022) Detection of efflux pump genes conferring multidrug resistance in clinical isolates of Acinetobacter baumannii in Tehran province. Rev Med Microbiol 33:31–36. https://doi.org/10.1097/MRM.0000000000000255
Bevan ER, Jones AM, Hawkey PM (2017) Global epidemiology of CTX-M b-lactamases: temporal and geographical shifts in genotype. J Antimicrob Chemother 72:2145–2155. https://doi.org/10.1093/jac/dkx146
Blair JMA, Richmond GE, Piddock LJV (2014) Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. Future Microbiol 9:1165–1177. https://doi.org/10.2217/FMB.14.66
Blair JMA, Webber MA, Baylay AJ et al (2015) Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol 13:42–51. https://doi.org/10.1038/nrmicro3380
Blázquez J, Couce A, Rodríguez-Beltrán J, Rodríguez-Rojas A (2012) Antimicrobials as promoters of genetic variation. Curr Opin Microbiol 15:561–569. https://doi.org/10.1016/J.MIB.2012.07.007
Bogdan-Ioan Coculescu (2009) Antimicrobial resistance induced by genetic changes. J Med Life 2:114–123
Bulut A (2014) Enterobacteriaceae Üyelerinde Karbapenem Direnci Ve Dirençten Sorumlu Enzimlerin Varlığının Araştırılması. Afyon Kocatepe Üniversitesi
Bush K, Bradford PA (2020) Epidemiology of β-lactamase-producing pathogens. Clin Microbiol Rev. https://doi.org/10.1128/CMR.00047-19
Bush K, Jacoby GA (2010) Updated functional classification of β-lactamases. Antimicrob Agents Chemother 54:969–976. https://doi.org/10.1128/AAC.01009-09
Centers for Disease Control and Prevention: antibiotic resistance threats in the United States, 2019. Atlanta, GA. https://www.cdc.gov/drugresistance/national-estimates.html. Accessed 1 Apr 2023.
Cox G, Wright GD (2013) Intrinsic antibiotic resistance: mechanisms, origins, challenges and solutions. Int J Med Microbiol 303:287–292. https://doi.org/10.1016/J.IJMM.2013.02.009
Coyne S, Courvalin P, Périchon B (2011) Efflux-mediated antibiotic resistance in Acinetobacter spp. Antimicrob Agents Chemother 55:947–953. https://doi.org/10.1128/AAC.01388-10
Dağlar D, Öngüt G (2012) Genişlemiş Spektrumlu Beta-Laktamazlar (GSBL) ve Tanı Yöntemleri extended spectrum beta-lactamases (ESBLs) and identification methods. İnönü Üniversitesi Sağlık Bilimleri Dergisi 1:1–9
Dal T, Sinan Dal M, Ağır İ (2012) Acinetobacter baumannii’de Antibiyotik Direnci ve AdeABC Aktif Pompa Sistemleri: Literatürün Gözden Geçirilmesi. 137–148
Davies J (2010) Origins and evolution of antibiotic resistance. Microbiologia 12:9–16. https://doi.org/10.1128/mmbr.00016-10
De Oliveira DMP, Forde BM, Kidd TJ et al (2020) Antimicrobial resistance in ESKAPE pathogens. Clin Microbiol Rev 33:1–49. https://doi.org/10.1128/CMR
Fajardo A, Martínez-Martín N, Mercadillo M et al (2018) The neglected intrinsic resistome of bacterial pathogens. PLoS One 3:1–6. https://doi.org/10.1371/journal.pone.0001619
Friedman ND, Temkin E, Carmeli Y (2016) The negative impact of antibiotic resistance. Clin Microbiol Infect 22:416–422. https://doi.org/10.1016/j.cmi.2015.12.002
Gao Y, Dutta S, Wang X (2022) Serendipitous discovery of a highly active and selective resistance-modifying agent for colistin-resistant gram-negative bacteria. ACS Omega 7:12442–12446. https://doi.org/10.1021/acsomega.2c01530
Giamarellou H, Poulakou G (2009) Multidrug-resistant gram-negative infections what are the treatment options? Drugs 69:1879–1901
Graham DW, Polissi A, Basu S et al (2016) Escherichia coli β-lactamases: what really matters. Front Microbiol. https://doi.org/10.3389/fmicb.2016.00417
Hasdemir UO, Chevalier J, Nordmann P, Pagès JM (2004) Detection and prevalence of active drug efflux mechanism in various multidrug-resistant Klebsiella pneumoniae strains from Turkey. J Clin Microbiol 42:2701–2706. https://doi.org/10.1128/JCM.42.6.2701-2706.2004
Hutchings M, Truman A, Wilkinson B (2019) Antibiotics: past, present and future. Curr Opin Microbiol 51:72–80
Jacoby GA (2009) AmpC Β-lactamases. Clin Microbiol Rev 22:161–182. https://doi.org/10.1128/CMR.00036-08
Jernigan JA, Hatfield KM, Wolford H et al (2020) Multidrug-resistant bacterial infections in U.S. Hospitalized Patients, 2012–2017. N Engl J Med 382:1309–1319. https://doi.org/10.1056/nejmoa1914433
Karacan B (2019) İnvaziv Klebsıella Pneumonıae İzolatlarının Tigesiklin Direncinde Efluks Pompasının Rolü. Marmara Univesity, Master Thesis,İstanbul
Kayiş U (2019) Antimikrobiyal Direnç Mekanizmalari. Aydın Sağlık Dergisi 5:1–12
Kaynak Onurdaǧ F, Kayiş U, Ökten S (2021) Effect of Phenylalanine-arginine-beta-naphthylamide to Ciprofloxacin Minimum Inhibitory Concentration Values and Expression of Efflux Pump System Genes in Acinetobacter baumannii Isolates. Mikrobiyol Bul 55:285–299. https://doi.org/10.5578/MB.20219801
Kor S-B, Tou B-S-Y, Chieng C-K-L et al (2014) RND efflux pump genes and integrons in Acinetobacter baumannii from Malaysia Distribution of the multidrug efflux pump genes adeA, adeI, adeJ, adeY and integrons in clinical isolates of Acinetobacter baumannii from Malay-sian hospitals. Biomed Res 25:143–148
Kumar S, Mukherjee MM, Varela MF (2013) Modulation of bacterial multidrug resistance efflux pumps of the major facilitator superfamily. Int J Bacteriol. https://doi.org/10.1155/2013/204141
Kumar V, Shriram V, Paul A, Thakur M (Eds) (2022) Antimicrobial resistance: Underlying mechanisms and therapeutic approaches (1st ed.)
Lambert PA (2005) Bacterial resistance to antibiotics: modified target sites. Adv Drug Deliv Rev 57:1471–1485. https://doi.org/10.1016/J.ADDR.2005.04.003
Lee Ventola C (2015) The antibiotic resistance crisis. Causes Threats 40:277–283
Li X-Z, Nikaido H (2009) Efflux-mediated drug resistance in bacteria: an update. Drugs 69:1555–1623. https://doi.org/10.2165/11317030-000000000-00000
Li XZ, Plésiat P, Nikaido H (2015) The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev 28:337–418. https://doi.org/10.1128/CMR.00117-14
Li R, Han Y, Zhou Y et al (2017) Tigecycline susceptibility and molecular resistance mechanisms among clinical Klebsiella pneumoniae strains isolated during non-tigecycline treatment. Microb Drug Resist 23:139–146. https://doi.org/10.1089/MDR.2015.0258
Lima R, Del Fiol FS, Balcão VM (2019) Prospects for the use of new technologies to combat multidrug-resistant bacteria. Front Pharmacol 10:692. https://doi.org/10.3389/fphar.2019.00692
Lin YT, Huang YW, Huang HH et al (2016) In vivo evolution of tigecycline-non-susceptible Klebsiella pneumoniae strains in patients: relationship between virulence and resistance. Int J Antimicrob Agents 48:485–491. https://doi.org/10.1016/j.ijantimicag.2016.07.008
Lomovskaya O, Watkins WJ (2001) Efflux pumps: their role in antibacterial drug discovery. Curr Med Chem 8:1699–1711
Marchetti ML, Errecalde J, Mestorino N (2012) Effect of 1-(1-naphthylmethyl)-piperazine on antimicrobial agent susceptibility in multidrug-resistant isogenic and veterinary Escherichia coli field strains. J Med Microbiol 61:786–792. https://doi.org/10.1099/jmm.0.040204-0
Martinez JL (2014) General principles of antibiotic resistance in bacteria. Drug Discov Today Technol 11:33–39. https://doi.org/10.1016/J.DDTEC.2014.02.001
Matamoros-Recio A, Franco-Gonzalez JF, Forgione RE et al (2021) Understanding the antibacterial resistance: computational explorations in bacterial membranes. ACS Omega 6:6041–6054
Meletis G (2016) Carbapenem resistance: overview of the problem and future perspectives. Ther Adv Infect Dis 3:15–21
Moehring R, Anderson DJ, Calderwood SB, Bloom A (2022) Gram-negative bacillary bacteremia in adults. Diabetes Murra 23:31
Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, Morgan DR (1995) Manual of Clinical Microbiology (1th edn). Page 121
Ni W, Li Y, Guan J et al (2016) Effects of efflux pump inhibitors on colistin resistance in multidrug-resistant gram-negative bacteria. Antimicrob Agents Chemother 60:3115–3118. https://doi.org/10.1128/AAC.00248-16
Pazarlı O, Cömert F, Külah C et al (2017) The evaluation of resistance genes and gene mutations in quinolone resistant Escherichia coli and Klebsiella spp. isolates. Turk Mikrobiyol Cemiy Derg. https://doi.org/10.5222/tmcd.2017.176
Poole K, Zgurskaya H, Misra R et al (2015) Recent advances toward a molecular mechanism of efflux pump inhibition. Front Microbiol 6:1–16. https://doi.org/10.3389/fmicb.2015.00421
Redgrave LS, Sutton SB, Webber MA, Piddock LJV (2014) Fluoroquinolone resistance: mechanisms, impact on bacteria, and role in evolutionary success. Trends Microbiol 22:438–445. https://doi.org/10.1016/j.tim.2014.04.007
Reygaert WC (2018) An overview of the antimicrobial resistance mechanisms of bacteria. AIMS Microbiol 4:482–501. https://doi.org/10.3934/microbiol.2018.3.482
Saabir F, Hussain A, Mulani M et al (2022) Efflux pump and its inhibitors: cause and cure for multidrug resistance. J Appl Biol Biotechnol 10:177–194. https://doi.org/10.7324/JABB.2022.100322
Şahin K, Altan G (2019) Kinolon Dirençli Escherichia coli İzolatlarında Diğer Antibiyotiklere Direnç Oranlarının Araştırılması. Strategic Health Res 3:197–202. https://doi.org/10.34084/bshr.611956
Schweizer HP (2012) Understanding efflux in Gram-negative bacteria: opportunities for drug discovery. Expert Opin Drug Discov 7:633–642. https://doi.org/10.1517/17460441.2012.688949
Şenol A, Özer Balın Ş (2021) Yoğun Bakım Üniteleri’nde Sık Görülen Enfeksiyonlar, Gram-negatif Mikroorganizmalar, Antibiyotik Direnci. KSU Med J 16:35–39. https://doi.org/10.17517/ksutfd.671762
Sharma A, Sharma R, Bhattacharyya T et al (2017) Fosfomycin resistance in Acinetobacter baumannii is mediated by efflux through a major facilitator superfamily (MFS) transporter-AbaF. J Antimicrob Chemother 72:68–74. https://doi.org/10.1093/jac/dkw382
Sheng ZK, Hu F, Wang W et al (2014) Mechanisms of tigecycline resistance among Klebsiella pneumoniae clinical isolates. Antimicrob Agents Chemother 58:6982–6985. https://doi.org/10.1128/AAC.03808-14
Singh T, Dar SA, Das S, Haque S (2020) Importance of efflux pumps in subjugating antibiotic resistance. In: Prashant K, Sidharth C, Arunava D (eds) Drug discovery targeting drug-resistant bacteria. Elsevier Inc., p 273–299
Sreekantan AP, Rajan PP, Mini M, Kumar P (2022) Multidrug efflux pumps in bacteria and efflux pump inhibitors. Postępy Mikrobiol - Adv Microbiol. https://doi.org/10.2478/am-2022-0009
Sun J, Deng Z, Yan A (2014) Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. Biochem Biophys Res Commun 453:254–267. https://doi.org/10.1016/J.BBRC.2014.05.090
Tamura N, Murakami S, Oyama Y et al (2005) Direct interaction of multidrug efflux transporter AcrB and outer membrane channel TolC detected via site-directed disulfide cross-linking. Biochemistry 44:11115–11121. https://doi.org/10.1021/BI050452U
Tanrıverdi Çaycı Y, Bıyık İ, Çınar C, Birinci A (2020) Antimicrobial resistance of carbapenem-resistant enterobacteriaceae isolates between the years of 2015–2018. Turk Mikrobiyol Cemiy Derg 50:134–140. https://doi.org/10.5222/tmcd.2020.134
Tekin A (2014) Enterobacteriaceae Suşlarında Karbapenem Direncinin Fenotipik ve Genotipik Olarak Tanımlanması. İstanbul Bilim Üniversity, PhD Thesis, İstanbul
Temel A, Eraç B (2020) A global threat: Acinetobacter baumannii infections, current condition in antimicrobial resistance and alternative treatment approaches. Turk Hijyen Ve Deneysel Biyoloji Dergisi 77:367–378. https://doi.org/10.5505/TurkHijyen.2019.04764
Vivas R, Barbosa AAT, Dolabela SS, Jain S (2019) Multidrug-resistant bacteria and alternative methods to control them: an overview. Microb Drug Resist 25:890–908. https://doi.org/10.1089/MDR.2018.0319
Webber MA, Piddock LJv (2003) The importance of efflux pumps in bacterial antibiotic resistance. J Antimicrob Chemother 51:9–11. https://doi.org/10.1093/jac/dkg050
Weston N, Sharma P, Ricci V, Piddock LJV (2018) Regulation of the AcrAB-TolC efflux pump in Enterobacteriaceae. Res Microbiol 169:425–431. https://doi.org/10.1016/j.resmic.2017.10.005
World Health Organization (WHO), 2020. Avaliable at: https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance. Accessed 1 Apr 2023
Xing L, Barnie PA, Su Z, Xu H (2014) Development of efflux pumps and inhibitors (EPIs) in A. baumanii. Clin Microbiol. https://doi.org/10.4172/2327-5073.1000135
Yılmaz ÖG (2017) Antibiotics: pharmacokinetics, toxicity, resistance and multidrug efflux pumps. Biochem Pharmacol 133:43–62. https://doi.org/10.1016/J.BCP.2016.10.005
Yoshiaki Gu (2020) Raising awareness of antimicrobialresistance: comment on‘Reducingexpectations for antibiotics in primary care: a randomised experiment to test theresponse to fear based messages aboutantimicrobial resistance. GuBMC Med. https://doi.org/10.1186/s12916-020-01553-6
Zeng B, Wang H, Zou L et al (2010) Evaluation and target validation of indole derivatives as inhibitors of the AcrAB-TolC efflux pump. Biosci Biotechnol Biochem 74:2237–2241. https://doi.org/10.1271/bbb.100433
Zhong X, Xu H, Chen D et al (2014) First emergence of acrAB and oqxAB mediated tigecycline resistance in clinical isolates of Klebsiella pneumoniae pre-dating the use of tigecycline in a Chinese Hospital. PLoS ONE. https://doi.org/10.1371/journal.pone
Funding
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Author information
Authors and Affiliations
Contributions
All authors contributed to the study conception and design. The first draft of the manuscript was written by SNB and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors have no relevant financial or non-financial interests to disclose. The authors declare no competing interests.
Additional information
Communicated by Yusuf Akhter.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The original online version of this article was revised due to update in author affiliation.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Başaran, S.N., Öksüz, L. The Role of Efflux Pumps in Antibiotic Resistance of Gram Negative Rods. Arch Microbiol 205, 192 (2023). https://doi.org/10.1007/s00203-023-03539-3
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00203-023-03539-3