Efflux Pump Inhibitors as a Broad-Spectrum Strategy to Combat Multidrug Resistance Acenitobacter Baumanii

Authors

  • Ayat Alaaeldin Abdulazeez Department of Basic Sciences, College of Dentistry, University of Kerbala, Kerbala, Iraq
  • Zainab Salim Jaafar Department of Bioinformatics, College of Biomedical Informatics, University of Information Technology and Communications, Baghdad, Iraq.

DOI:

https://doi.org/10.47577/biochemmed.v10i.11738

Keywords:

Efflux pump inhibitors, Multidrug resistance, Acenitobacter baumanii, synthetic EPIs, natural EPIs, nanoparticles, bacteriophage, antimicrobial peptides

Abstract

The World Health Organization (WHO) identifies A. baumannii as one of the most resistant pathogens. Over the past few years, there has been a significant rise in its resistance to a wide array of antibiotics. Multidrug resistance is attributed to several mechanisms, with efflux pumps being the most notable. Recently, the development of new treatment strategies to tackle A. baumannii infections has shown great promise. This review focuses on the various families of efflux pumps in A. baumannii and explores innovative therapeutic options that have emerged over the past four years. Specifically, we emphasize synthetic and natural efflux pump inhibitors (EPIs), nanoparticles, bacteriophage therapy, and antimicrobial peptides (AMPs) as part of these novel strategies.

References

Pardo-Freire, M., & Domingo-Calap, P. (2023). Phages and nanotechnology: New insights against multidrug-resistant bacteria. BioDesign Research, 5, 0004.

Moradi, F., Ghaedi, A., Fooladfar, Z., & Bazrgar, A. (2023). Recent advance on nanoparticles or nanomaterials with anti-Multidrug resistant Bacteria and anti-bacterial biofilm properties; A systematic review. Heliyon.

Hetta, H. F., Ramadan, Y. N., Al-Harbi, A. I., A. Ahmed, E., Battah, B., Abd Ellah, N. H., ... & Donadu, M. G. (2023). Nanotechnology as a promising approach to combat multidrug resistant bacteria: a comprehensive review and future perspectives. Biomedicines, 11(2), 413.

Saliba, R., Zahar, J. R., Dabar, G., Riachy, M., Karam-Sarkis, D., & Husni, R. (2023). Limiting the spread of Multidrug-resistant Bacteria in Low-to-Middle-Income countries: one size does not fit all. Pathogens, 12(1), 144.

Jiang, W., Li, B., Zheng, X., Liu, X., Pan, X., Qing, R., ... & Zhou, H. (2013). Artesunate has its enhancement on antibacterial activity of β-lactams via increasing the antibiotic accumulation within methicillin-resistant Staphylococcus aureus (MRSA). The Journal of antibiotics, 66(6), 339-345.

AlMatar, M., Albarri, O., Makky, E. A., & Köksal, F. (2021). Efflux pump inhibitors: new updates. Pharmacological Reports, 73, 1-16.

Compagne, N., Vieira Da Cruz, A., Müller, R. T., Hartkoorn, R. C., Flipo, M., & Pos, K. M. (2023). Update on the discovery of efflux pump inhibitors against critical priority Gram-negative bacteria. Antibiotics, 12(1), 180.

Gaurav, A., Bakht, P., Saini, M., Pandey, S., & Pathania, R. (2023). Role of bacterial efflux pumps in antibiotic resistance, virulence, and strategies to discover novel efflux pump inhibitors. Microbiology, 169(5), 001333.

Pérez-Varela, M., Corral, J., Aranda, J., & Barbé, J. (2019). Roles of efflux pumps from different superfamilies in the surface-associated motility and virulence of Acinetobacter baumannii ATCC 17978. Antimicrobial Agents and Chemotherapy, 63(3), 10-1128.

Du, D., Wang-Kan, X., Neuberger, A., Van Veen, H. W., Pos, K. M., Piddock, L. J., & Luisi, B. F. (2018). Multidrug efflux pumps: structure, function and regulation. Nature Reviews Microbiology, 16(9), 523-539.

Alenazy, R. (2022). Drug efflux pump inhibitors: a promising approach to counter multidrug resistance in Gram-negative pathogens by targeting AcrB protein from AcrAB-TolC multidrug efflux pump from Escherichia coli. Biology, 11(9), 1328.

Du, D., Wang-Kan, X., Neuberger, A., Van Veen, H. W., Pos, K. M., Piddock, L. J., & Luisi, B. F. (2018). Multidrug efflux pumps: structure, function and regulation. Nature Reviews Microbiology, 16(9), 523-539.

Ghosh, A., Roymahapatra, G., Paul, D., & Mandal, S. M. (2020). Theoretical analysis of bacterial efflux pumps inhibitors: Strategies in-search of competent molecules and develop next. Computational Biology and Chemistry, 87, 107275.

Kumar, S., Lekshmi, M., Parvathi, A., Ojha, M., Wenzel, N., & Varela, M. F. (2020). Functional and structural roles of the major facilitator superfamily bacterial multidrug efflux pumps. Microorganisms, 8(2), 266.

Kornelsen, V., & Kumar, A. (2021). Update on multidrug resistance efflux pumps in Acinetobacter spp. Antimicrobial agents and chemotherapy, 65(7), 10-1128.

Nogbou, N. D., Nkawane, G. M., Ntshane, K., Wairuri, C. K., Phofa, D. T., Mokgokong, K. K., ... & Musyoki, A. M. (2021). Efflux pump activity and mutations driving multidrug resistance in Acinetobacter baumannii at a Tertiary Hospital in Pretoria, South Africa. International Journal of Microbiology, 2021(1), 9923816.

Leus, I. V., Weeks, J. W., Bonifay, V., Smith, L., Richardson, S., & Zgurskaya, H. I. (2018). Substrate specificities and efflux efficiencies of RND efflux pumps of Acinetobacter baumannii. Journal of bacteriology, 200(13), 10-1128.

Wieczorek, P., Sacha, P., Hauschild, T., Zórawski, M., Krawczyk, M., & Tryniszewska, E. (2008). Multidrug resistant Acinetobacter baumannii--the role of AdeABC (RND family) efflux pump in resistance to antibiotics. Folia histochemica et cytobiologica, 46(3), 257-267.

Vila, J., Martí, S., & Sanchez-Céspedes, J. (2007). Porins, efflux pumps and multidrug resistance in Acinetobacter baumannii. Journal of antimicrobial chemotherapy, 59(6), 1210-1215.

Srinivasan, V. B., Rajamohan, G., & Gebreyes, W. A. (2009). Role of AbeS, a novel efflux pump of the SMR family of transporters, in resistance to antimicrobial agents in Acinetobacter baumannii. Antimicrobial agents and chemotherapy, 53(12), 5312-5316.

Nasr, P. (2020). Genetics, epidemiology, and clinical manifestations of multidrug-resistant Acinetobacter baumannii. Journal of Hospital Infection, 104(1), 4-11.

Kyriakidis, I., Vasileiou, E., Pana, Z. D., & Tragiannidis, A. (2021). Acinetobacter baumannii antibiotic resistance mechanisms. Pathogens, 10(3), 373.

Zack, K. M., Sorenson, T., & 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(3), 197.

Hernández-Durán, M., Colín-Castro, C. A., Fernández-Rodríguez, D., Delgado, G., Morales-Espinosa, R., Martínez-Zavaleta, M. G., ... & López-Jácome, L. E. (2024). Inside-out, antimicrobial resistance mediated by efflux pumps in clinical strains of Acinetobacter baumannii isolated from burn wound infections. Brazilian Journal of Microbiology, 1-13.

Neshani, A., Sedighian, H., Mirhosseini, S. A., Ghazvini, K., Zare, H., & Jahangiri, A. (2020). Antimicrobial peptides as a promising treatment option against Acinetobacter baumannii infections. Microbial pathogenesis, 146, 104238.

Lekshmi, M., Ortiz-Alegria, A., Kumar, S., & Varela, M. F. (2024). Major facilitator superfamily efflux pumps in human pathogens: Role in multidrug resistance and beyond. Current Research in Microbial Sciences, 100248.

Foong, W. E. (2021). Molecular determinants of bacterial antimicrobial efflux by the major facilitator superfamily members CraA and TetA from Acinetobacter baumannii (Doctoral dissertation, Universitätsbibliothek Johann Christian Senckenberg).

Lin, M. F., Lin, Y. Y., Tu, C. C., & Lan, C. Y. (2017). Distribution of different efflux pump genes in clinical isolates of multidrug-resistant Acinetobacter baumannii and their correlation with antimicrobial resistance. Journal of Microbiology, Immunology and Infection, 50(2), 224-231.

Temgoua, F. T. D., & Wu, L. (2018). Mechanisms efflux pumps of Acinetobacter baumannii (MDR): increasing resistance to antibiotics. Journal of Biosciences and Medicines, 7(1), 48-70.

Kumar, S. U. N. I. L., Singhal, L. I. P. I. K. A., Ray, P. A. L. L. A. B., & Gautam, V. I. K. A. S. (2020). Over-expression of RND and MATE efflux pumps contribute to decreased susceptibility in clinical isolates of carbapenem resistant Acinetobacter baumannii. Int. J. Pharm. Res, 12, 342-349.

Siasat, P. A., & Blair, J. M. (2023). Microbial Primer: Multidrug efflux pumps. Microbiology, 169(10), 001370.

Lee, N. Y., Ko, W. C., & Hsueh, P. R. (2019). Nanoparticles in the treatment of infections caused by multidrug-resistant organisms. Frontiers in pharmacology, 10, 1153.

Madhi, M., Hasani, A., Mojarrad, J. S., Rezaee, M. A., Zarrini, G., Davaran, S., ... & Sheikhalizadeh, V. (2020). Impact of chitosan and silver nanoparticles laden with antibiotics on multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Archives of Clinical Infectious Diseases, 15(4).

Behdad, R., Pargol, M., Mirzaie, A., Karizi, S. Z., Noorbazargan, H., & Akbarzadeh, I. (2020). Efflux pump inhibitory activity of biologically synthesized silver nanoparticles against multidrug‐resistant Acinetobacter baumannii clinical isolates. Journal of basic microbiology, 60(6), 494-507.

Shakib, P., Saki, R., Zolfaghari, M. R., & Goudarzi, G. (2023). Efflux Pump and Biofilm Inhibitory Activity of Nanoparticles in Acinetobacter Baumannii: a Systematic Review. Clinical Laboratory, 69(10).

Verma, P., Tiwari, M., & Tiwari, V. (2022). Potentiate the activity of current antibiotics by naringin dihydrochalcone targeting the AdeABC efflux pump of multidrug-resistant Acinetobacter baumannii. International Journal of Biological Macromolecules, 217, 592-605.

Verma, P., Tiwari, M., & Tiwari, V. (2021). Efflux pumps in multidrug-resistant Acinetobacter baumannii: Current status and challenges in the discovery of efflux pumps inhibitors. Microbial pathogenesis, 152, 104766.

Al-Kadmy, I. M., Aziz, S. N., Rheima, A. M., Abid, S. A., Suhail, A., Hamzah, I. H., ... & Hetta, H. F. (2023). Anti-capsular activity of CuO nanoparticles against Acinetobacter baumannii produce efflux pump. Microbial Pathogenesis, 181, 106184.

Saleh, F., Kheirandish, F., Hosseini, F., & Yazdian, F. (2021). Evaluation the effect of ZnO nanoparticle derived Bacillus subtilis on the expression of efflux pump genes (AdeB AdeRS) in Acinetobacter baumannii. Journal of Environmental Health Science and Engineering, 19(1), 1133-1141.

Husain, F. M., Qais, F. A., Ahmad, I., Hakeem, M. J., Baig, M. H., Masood Khan, J., & Al-Shabib, N. A. (2022). Biosynthesized zinc oxide nanoparticles disrupt established biofilms of pathogenic bacteria. Applied Sciences, 12(2), 710.

Okkeh, M., Bloise, N., Restivo, E., De Vita, L., Pallavicini, P., & Visai, L. (2021). Gold nanoparticles: can they be the next magic bullet for multidrug-resistant bacteria?. Nanomaterials, 11(2), 312.

Rabiee, N., Ahmadi, S., Akhavan, O., & Luque, R. (2022). Silver and gold nanoparticles for antimicrobial purposes against multi-drug resistance bacteria. Materials, 15(5), 1799.

Jiménez-Castellanos, J. C., Pradel, E., Compagne, N., Vieira Da Cruz, A., Flipo, M., & Hartkoorn, R. C. (2023). Characterization of pyridylpiperazine-based efflux pump inhibitors for Acinetobacter baumannii. JAC-Antimicrobial Resistance, 5(5), dlad112.

Tambat, R., Kinthada, R. K., Saral Sariyer, A., Leus, I. V., Sariyer, E., D’Cunha, N., ... & Zgurskaya, H. I. (2024). AdeIJK Pump-Specific Inhibitors Effective against Multidrug Resistant Acinetobacter baumannii. ACS Infectious Diseases.

Saini, M., Gaurav, A., Hussain, A., & Pathania, R. (2024). Small Molecule IITR08367 Potentiates Antibacterial Efficacy of Fosfomycin against Acinetobacter baumannii by Efflux Pump Inhibition. ACS Infectious Diseases, 10(5), 1711-1724.

Bankan, N., Koka, F., Vijayaraghavan, R., Basireddy, S. R., & Jayaraman, S. (2021). Overexpression of the adeB efflux pump gene in tigecycline-resistant Acinetobacter baumannii clinical isolates and its inhibition by (+) usnic acid as an adjuvant. Antibiotics, 10(9), 1037.

Migliaccio, A., Esposito, E. P., Bagattini, M., Berisio, R., Triassi, M., De Gregorio, E., & Zarrilli, R. (2022). Inhibition of AdeB, AceI, and AmvA efflux pumps restores chlorhexidine and benzalkonium susceptibility in Acinetobacter baumannii ATCC 19606. Frontiers in Microbiology, 12, 790263.

Singkham-In, U., Higgins, P. G., Wannigama, D. L., Hongsing, P., & Chatsuwan, T. (2020). Rescued chlorhexidine activity by resveratrol against carbapenem-resistant Acinetobacter baumannii via down-regulation of AdeB efflux pump. PLoS One, 15(12), e0243082.

Seukep, A. J., Kuete, V., Nahar, L., Sarker, S. D., & Guo, M. (2020). Plant-derived secondary metabolites as the main source of efflux pump inhibitors and methods for identification. Journal of pharmaceutical analysis, 10(4), 277-290.

Al-ammery, R. K. A., & Chabuck, Z. A. G. (2024). Naturally derived efflux pump inhibitor among tetracycline-resistant Acinetobacter baumannii isolates. Medical Journal of Babylon, 21(1), 57-64.

Saleh, N. M., Ezzat, H., El-Sayyad, G. S., & Zedan, H. (2024). Regulation of overexpressed efflux pump encoding genes by cinnamon oil and trimethoprim to abolish carbapenem-resistant Acinetobacter baumannii clinical strains. BMC microbiology, 24(1), 52.

Ahmadi, F., Khalvati, B., Eslami, S., Mirzaii, M., Roustaei, N., Mazloomirad, F., & Khoramrooz, S. S. (2022). The inhibitory effect of thioridazine on adeb efflux pump gene expression in multidrug-resistant Acinetobacter baumannii isolates using real time PCR. Avicenna Journal of Medical Biotechnology, 14(2), 132.

Ebrahimi, S., Sisakhtpour, B., Mirzaei, A., Karbasizadeh, V., & Moghim, S. (2021). Efficacy of isolated bacteriophage against biofilm embedded colistin-resistant Acinetobacter baumannii. Gene Reports, 22, 100984.

Tu, Q., Pu, M., Li, Y., Wang, Y., Li, M., Song, L., ... & Tong, Y. (2023). Acinetobacter baumannii phages: past, present and future. Viruses, 15(3), 673.

Wintachai, P., & Voravuthikunchai, S. P. (2022). Characterization of novel lytic Myoviridae phage infecting multidrug-resistant Acinetobacter baumannii and synergistic antimicrobial efficacy between phage and Sacha Inchi oil. Pharmaceuticals, 15(3), 291.

Wintachai, P., Phaonakrop, N., Roytrakul, S., Naknaen, A., Pomwised, R., Voravuthikunchai, S. P., ... & Smith, D. R. (2022). Enhanced antibacterial effect of a novel Friunavirus phage vWU2001 in combination with colistin against carbapenem-resistant Acinetobacter baumannii. Scientific Reports, 12(1), 2633.

Wang, X., Loh, B., Gordillo Altamirano, F., Yu, Y., Hua, X., & Leptihn, S. (2021). Colistin-phage combinations decrease antibiotic resistance in Acinetobacter baumannii via changes in envelope architecture. Emerging microbes & infections, 10(1), 2205-2219.

Jayathilaka, E. T., Rajapaksha, D. C., Nikapitiya, C., Lee, J., De Zoysa, M., & Whang, I. (2022). Novel antimicrobial peptide “Octoprohibitin” against multidrug resistant Acinetobacter baumannii. Pharmaceuticals, 15(8), 928.

Peng, J., Wang, Y., Wu, Z., Mao, C., Li, L., Cao, H., ... & Shen, F. (2023). Antimicrobial peptide Cec4 eradicates multidrug-resistant Acinetobacter baumannii in vitro and in vivo. Drug Design, Development and Therapy, 977-992.

Sacco, F., Bitossi, C., Casciaro, B., Loffredo, M. R., Fabiano, G., Torrini, L., ... & Mangoni, M. L. (2022). The antimicrobial peptide Esc (1-21) synergizes with colistin in inhibiting the growth and in killing multidrug resistant Acinetobacter baumannii strains. Antibiotics, 11(2), 234.

Neshani, A., Sedighian, H., Mirhosseini, S. A., Ghazvini, K., Zare, H., & Jahangiri, A. (2020). Antimicrobial peptides as a promising treatment option against Acinetobacter baumannii infections. Microbial pathogenesis, 146, 104238.

Ahmad, I., Ali, M., Ali, R., Nawaz, N., & Patching, S. G. Multidrug Efflux Protein Families in Bacteria: ABC, RND, MFS, SMR, MATE, PACE, AbgT (An Update).

Natsheh, I. Y., Elkhader, M. T., Al-Bakheit, A. A. A., Alsaleh, M. M., El-Eswed, B. I., Hosein, N. F., & Albadawi, D. K. (2023). Inhibition of Acinetobacter baumannii biofilm formation using different treatments of silica nanoparticles. Antibiotics, 12(9), 1365.

Jawad, K. H., Marzoog, T. R., Hasoon, B. A., Sulaiman, G. M., Jabir, M. S., Ahmed, E. M., & Khalil, K. A. (2022). Antibacterial activity of bismuth oxide nanoparticles compared to amikacin against acinetobacter baumannii and Staphylococcus aureus. Journal of Nanomaterials, 2022(1), 8511601.

Wienhold, S. M., Brack, M. C., Nouailles, G., Krishnamoorthy, G., Korf, I. H., Seitz, C., ... & Witzenrath, M. (2021). Preclinical assessment of bacteriophage therapy against experimental Acinetobacter baumannii lung infection. Viruses, 14(1), 33.

Jayathilaka, E. T., Rajapaksha, D. C., Nikapitiya, C., De Zoysa, M., & Whang, I. (2021). Antimicrobial and anti-biofilm peptide octominin for controlling multidrug-resistant Acinetobacter baumannii. International Journal of Molecular Sciences, 22(10), 5353.

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Published

2024-10-27

How to Cite

Abdulazeez, A. A., & Jaafar, Z. S. (2024). Efflux Pump Inhibitors as a Broad-Spectrum Strategy to Combat Multidrug Resistance Acenitobacter Baumanii . Technium BioChemMed, 10, 11–23. https://doi.org/10.47577/biochemmed.v10i.11738