Understanding multidrug resistance in Staphylococcus aureus: The role of efflux pumps and key protein structures
DOI:
https://doi.org/10.56511/JIPBS.2024.11403Abstract
A rising health concern is the occurrence of illnesses brought on by multidrug-resistant bacteria in healthcare facilities or in public spaces. The growth of microbial biofilms and efflux pumps are the main causes of S. aureus's antibiotic resistance. Multidrug EPs cells utilizing proteins to detoxify from toxic substances, appear to be essential in the development of this drug-resistant bacteria. Through the extrusion of numerous unrelated chemicals, experimental data have demonstrated their role in reduced antibacterial resistance in bacteria as well as the possible significance in the emergence of resistant phenotypes. Efflux systems plays an important role in MDR resistance in addition to helping to transport molecules that are important for cell signaling, and because they are common, there is a real danger that we could soon return to a time before antibiotics. According to recent research, cells may use the efflux systems as the initial step of defence to prevent drugs from reaching deadly concentrations while waiting for a stable, more effective modification to occur. The primary facilitator superfamily-belonging S. aureus efflux pump NorA imparts resistance to various substrates. Even though many EPI i.e inhibitors of the efflux pump have been found, from them, no one has received clinical approval because of unfavourable toxicity. In this review article, we will discuss the current understanding of the MDR efflux pump and its clinical importance, concentrating on current discoveries on the efflux system of S. aureus, and the regulation of efflux pump based on protein/gene expression, and emphasize significant genes and proteins along with their PDB IDs.
Keywords:
Antibiotics resistance, Efflux pumps, MDR, S. aureus, PDB IDs, Clinical SignificanceDownloads
References
Nguyen THT, Nguyen HD, Le MH, Nguyen TTH, Nguyen TD, Nguyen DL, Pham HN. Efflux pump inhibitors in controlling antibiotic resistance: outlook under a heavy metal contamination context. Molecules. 2023; 28(7): 2912.
Kumar G, Tudu AK. Tackling multidrug - resistant Staphylococcus aureus by natural products and their analogues acting as NorA efflux pump inhibitors. Bioorg. Med. Chem. 2023; 80: 117187.
Abd El - Rahman OA, Rasslan F, Hassan SS, Ashour HM, Wasfi R. The RND efflux pump gene expression in the biofilm formation of Acinetobacter baumannii. Antibiotics. 2023; 12(2): 419.
Seukep AJ, Mbuntcha HG, Kuete V, Chu Y, Fan E, Guo MQ. What approaches to thwart bacterial efflux pumps - mediated resistance?. Antibiotics. 2022; 11(10): 1287.
Huang L, Wu C, Gao H, Xu C, Dai M, Huang L, Cheng G. Bacterial multidrug efflux pumps at the frontline of antimicrobial resistance: an overview. Antibiotics. 2022; 11(4): 520.
Zwama M, Nishino K. Ever - adapting RND efflux pumps in gram - negative multidrug - resistant pathogens: a race against time. Antibiotics. 2021; 10(7): 774.
Nishino K, Yamasaki S, Nakashima R, Zwama M, Hayashi - Nishino M. Function and inhibitory mechanisms of multidrug efflux pumps. Front. Microbiol. 2021; 12: 737288.
Howden, B. P., McEvoy, C. R., Allen, D. L., Chua, K., Gao, W., Harrison, P. F., ... & Stinear, T. P. (2011). Evolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two - component regulator WalKR. PLoS Pathogens, 7(11), e1002359.
Mwangi, M. M., Wu, S. W., Zhou, Y., Sieradzki, K., de Lencastre, H., Richardson, P., ... & Tomasz, A. (2007). Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole - genome sequencing. Proceedings of the National Academy of Sciences, 104(22), 9451 - 9456.
Ghosh A, Roymahapatra G, Paul D, Mandal SM. Theoretical analysis of bacterial efflux pumps inhibitors: strategies in - search of competent molecules and develop next. Comput. Biol. Chem. 2020; 87: 107275.
Ni RT, Onishi M, Mizusawa M, Kitagawa R, Kishino T, Matsubara F, Ogawa W. The role of RND - type efflux pumps in multidrug - resistant mutants of Klebsiella pneumoniae. Sci. Rep. 2020; 10(1): 10876.
Rao M, Padyana S, Dipin KM, Kumar S, Nayak B, Varela MF. Antimicrobial compounds of plant origin as efflux pump inhibitors: new avenues for controlling multidrug resistant pathogens. J. Antimicrob. Agents. 2018; 4(1000159): 2472 - 1212.
Hassan KA, Liu Q, Elbourne LD, Ahmad I, Sharples D, Naidu V, Paulsen IT. Pacing across the membrane: the novel PACE family of efflux pumps is widespread in Gram - negative pathogens. Res. Microbiol. 2018; 169(7 - 8): 450 - 454.
Krishnamoorthy G, Weeks JW, Zhang Z, Chandler CE, Xue H, Schweizer HP, Zgurskaya HI. Efflux pumps of Burkholderia thailandensis control the permeability barrier of the outer membrane. Antimicrob. Agents Chemother. 2019; 63(10): 10 - 1128.
Kumar S, Lekshmi M, Parvathi A, Ojha M, Wenzel N, Varela MF. Functional and structural roles of the major facilitator superfamily bacterial multidrug efflux pumps. Microorganisms. 2020; 8(2): 266.
Colclough AL, Alav I, Whittle EE, Pugh HL, Darby EM, Legood SW, Blair JM. RND efflux pumps in Gram - negative bacteria; regulation, structure and role in antibiotic resistance. Future Microbiol. 2020; 15(2): 143 - 157.
Alcalde - Rico M, Hernando - Amado S, Blanco P, Martínez JL. Multidrug efflux pumps at the crossroad between antibiotic resistance and bacterial virulence. Front. Microbiol. 2016; 7: 1483.
Thanassi DG, Cheng LW, Nikaido H. Active efflux of bile salts by Escherichia coli. J. Bacteriol. 1997; 179(8): 2512 - 2518.
Soto SM. Role of efflux pumps in the antibiotic resistance of bacteria embedded in a biofilm. Virulence. 2013; 4(3): 223 - 229.
Ubukata K, Itoh - Yamashita N, Konno M. Cloning and expression of the norA gene for fluoroquinolone resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 1989; 33(9): 1535 - 1539.
Schmitz FJ, Hertel B, Hofmann B, Scheuring S, Verhoef J, Fluit AC, Jones ME. Relationship between mutations in the coding and promoter regions of the norA genes in 42 unrelated clinical isolates of Staphylococcus aureus and the MICs of norfloxacin for these strains. J. Antimicrob. Chemother. 1998; 42(4): 561 - 563.
Sierra JM, Ruiz J, Jimenez De Anta MT, Vila J. Prevalence of two different genes encoding NorA in 23 clinical strains of Staphylococcus aureus. J. Antimicrob. Chemother. 2000; 46(1): 145 - 146.
Noguchi N, Okada H, Narui K, Sasatsu M. Comparison of the nucleotide sequence and expression of norA genes and microbial susceptibility in 21 strains of Staphylococcus aureus. Microb. Drug Resist. 2004; 10(3): 197 - 203.
Yoshida HMSKM, Bogaki M, Nakamura S, Ubukata K, Konno M. Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones. J. Bacteriol. 1990; 172(12): 6942 - 6949.
Neyfakh AA. The multidrug efflux transporter of Bacillus subtilis is a structural and functional homolog of the Staphylococcus NorA protein. Antimicrob. Agents Chemother. 1992; 36(2): 484 - 485.
Neyfakh, A. A., Borsch, C. M., & Kaatz, G. W. (1993). Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter. Antimicrobial Agents and Chemotherapy, 37(1), 128 - 129.
Kaatz, G. W., Seo, S. M., & Ruble, C. A. (1993). Efflux - mediated fluoroquinolone resistance in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 37(5), 1086 - 1094.
Kaatz, G. W., & Seo, S. M. (1995). Inducible NorA - mediated multidrug resistance in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 39(12), 2650 - 2655.
Ng, E. Y., Trucksis, M., & Hooper, D. C. (1994). Quinolone resistance mediated by norA: Physiologic characterization and relationship to flqB, a quinolone resistance locus on the Staphylococcus aureus chromosome. Antimicrobial Agents and Chemotherapy, 38(6), 1345 - 1355.
Couto, I., Costa, S. S., Viveiros, M., Martins, M., & Amaral, L. (2008). Efflux - mediated response of Staphylococcus aureus exposed to ethidium bromide. Journal of Antimicrobial Chemotherapy, 62(3), 504 - 513.
Kaatz, G. W., Seo, S. M., O'Brien, L., Wahiduzzaman, M., & Foster, T. J. (2000). Evidence for the existence of a multidrug efflux transporter distinct from NorA in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 44(5), 1404 - 1406.
Kaatz, G. W., Moudgal, V. V., Seo, S. M. (2002). Identification and characterization of a novel efflux - related multidrug resistance phenotype in Staphylococcus aureus. Journal of Antimicrobial Chemotherapy, 50, 833 - 838.
Truong - Bolduc, Q. C., Dunman, P. M., Strahilevitz, J., Projan, S. J., & Hooper, D. C. (2005). MgrA is a multiple regulator of two new efflux pumps in Staphylococcus aureus. Journal of Bacteriology, 187(7), 2395 - 2405.
Ding, Y., Onodera, Y., Lee, J. C., & Hooper, D. C. (2008). NorB, an efflux pump in Staphylococcus aureus strain MW2, contributes to bacterial fitness in abscesses. Journal of Bacteriology, 190(21), 7123 - 7129.
Truong - Bolduc, Q. C., Bolduc, G. R., Okumura, R., Celino, B., Bevis, J., Liao, C. H., & Hooper, D. C. (2011). Implication of the NorB efflux pump in the adaptation of Staphylococcus aureus to growth at acid pH and in resistance to moxifloxacin. Antimicrobial Agents and Chemotherapy, 55(7), 3214 - 3219.
Truong - Bolduc, Q. C., Hsing, L. C., Villet, R., Bolduc, G. R., Estabrooks, Z., Taguezem, G. F., & Hooper, D. C. (2012). Reduced aeration affects the expression of the NorB efflux pump of Staphylococcus aureus by posttranslational modification of MgrA. Journal of Bacteriology, 194(7), 1823 - 1834.
Truong - Bolduc, Q. C., Strahilevitz, J., & Hooper, D. C. (2006). NorC, a new efflux pump regulated by MgrA of Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 50(3), 1104 - 1107.
Truong - Bolduc, Q. C., Dunman, P. M., Eidem, T., & Hooper, D. C. (2011). Transcriptional profiling analysis of the global regulator NorG, a GntR - like protein of Staphylococcus aureus. Journal of Bacteriology, 193(22), 6207 - 6214.
Kaatz, G. W., McAleese, F., & Seo, S. M. (2005). Multidrug resistance in Staphylococcus aureus due to overexpression of a novel multidrug and toxin extrusion (MATE) transport protein. Antimicrobial Agents and Chemotherapy, 49(5), 1857 - 1864.
McAleese, F., Petersen, P., Ruzin, A., Dunman, P. M., Murphy, E., Projan, S. J., & Bradford, P. A. (2005). A novel MATE family efflux pump contributes to the reduced susceptibility of laboratory - derived Staphylococcus aureus mutants to tigecycline. Antimicrobial Agents and Chemotherapy, 49(5), 1865 - 1871.
Huang, J., O'Toole, P. W., Shen, W., Amrine - Madsen, H., Jiang, X., Lobo, N., & McDevitt, D. (2004). Novel chromosomally encoded multidrug efflux transporter MdeA in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 48(3), 909 - 917.
Yamada, Y., Shiota, S., Mizushima, T., Kuroda, T., & Tsuchiya, T. (2006). Functional gene cloning and characterization of MdeA, a multidrug efflux pump from Staphylococcus aureus. Biological and Pharmaceutical Bulletin, 29(4), 801 - 804.
Narui, K., Noguchi, N., Wakasugi, K., & Sasatsu, M. (2002). Cloning and characterization of a novel chromosomal drug efflux gene in Staphylococcus aureus. Biological and Pharmaceutical Bulletin, 25(12), 1533 - 1536.
Yamada, Y., Hideka, K. I., Shiota, S., Kuroda, T., & Tsuchiya, T. (2006). Gene cloning and characterization of SdrM, a chromosomally - encoded multidrug efflux pump, from Staphylococcus aureus. Biological and Pharmaceutical Bulletin, 29(3), 554 - 556.
Floyd, J. L., Smith, K. P., Kumar, S. H., Floyd, J. T., & Varela, M. F. (2010). LmrS is a multidrug efflux pump of the major facilitator superfamily from Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 54(12), 5406 - 5412.
Tennent, J. M., Lyon, B. R., Gillespie, M. T., May, J. W., & Skurray, R. A. (1985). Cloning and expression of Staphylococcus aureus plasmid - mediated quaternary ammonium resistance in Escherichia coli. Antimicrobial Agents and Chemotherapy, 27(1), 79 - 83.
do Vale, B. C. M., Nogueira, A. G., Cidral, T. A., Lopes, M. C. S., & de Melo, M. C. N. (2019). Decreased susceptibility to chlorhexidine and distribution of qacA/B genes among coagulase - negative Staphylococcus clinical samples. BMC Infectious Diseases, 19, 1 - 5.
Hong, S. I., Lee, Y. M., Park, K. H., Ryu, B. H., Hong, K. W., Kim, S., & Cho, O. H. (2019). Clinical and molecular characteristics of qacA - and qacB - positive methicillin - resistant Staphylococcus aureus causing bloodstream infections. Antimicrobial Agents and Chemotherapy, 63(4), 10 - 1128.
Cho, O. H., Park, K. H., Song, J. Y., Hong, J. M., Kim, T., Hong, S. I., & Bae, I. G. (2018). Prevalence and microbiological characteristics of qacA/B - positive methicillin - resistant Staphylococcus aureus isolates in a surgical intensive care unit. Microbial Drug Resistance, 24(3), 283 - 289.
Majumder, P., Khare, S., Athreya, A., Hussain, N., Gulati, A., & Penmatsa, A. (2019). Dissection of protonation sites for antibacterial recognition and transport in QacA, a multi - drug efflux transporter. Journal of Molecular Biology, 431(11), 2163 - 2179.
Nakaminami, H., Takadama, S., Okita, M., Sasaki, M., & Noguchi, N. (2019). Fast - acting bactericidal activity of olanexidine gluconate against qacA/B - positive methicillin - resistant Staphylococcus aureus. Journal of Medical Microbiology, 68(6), 957 - 960.
Mitchell, B. A., Paulsen, I. T., Brown, M. H., & Skurray, R. A. (1999). Bioenergetics of the staphylococcal multidrug export protein QacA: Identification of distinct binding sites for monovalent and divalent cations. Journal of Biological Chemistry, 274(6), 3541 - 3548.
Lebreton, F., & Cattoir, V. (2019). Resistance to glycopeptide antibiotics. Bacterial Resistance to Antibiotics – From Molecules to Man, 51 - 80.
Tong, C., Hu, H., Chen, G., Li, Z., Li, A., & Zhang, J. (2021). Disinfectant resistance in bacteria: Mechanisms, spread, and resolution strategies. Environmental Research, 195, 110897.
Li, W., Chern, M., Yin, J., Wang, J., & Chen, X. (2019). Recent advances in broad - spectrum resistance to the rice blast disease. Current Opinion in Plant Biology, 50, 114 - 120.
Garcia, Í. R., de Oliveira Garcia, F. A., Pereira, P. S., Coutinho, H. D. M., Siyadatpanah, A., Norouzi, R., ... & Rodrigues, F. F. G. (2022). Microbial resistance: The role of efflux pump superfamilies and their respective substrates. Life Sciences, 295, 120391.
Seukep, A. J., Fokoua - Maxime, C. D., Mbuntcha, H. G., Chen, G., Assob, J. C. N., Tenniswood, M., ... & Ming - Quan, G. (2022). Bacterial drug efflux pump inhibitors from plants. Antimicrobial Resistance: Underlying Mechanisms and Therapeutic Approaches, 487 - 532.
Islam, M. D., Harrison, B. D., Li, J. J., McLoughlin, A. G., & Court, D. A. (2023). Do mitochondria use efflux pumps to protect their ribosomes from antibiotics?. Microbiology, 169(1), 001272.
Bay, D. C., Rommens, K. L., & Turner, R. J. (2008). Small multidrug resistance proteins: A multidrug transporter family that continues to grow. Biochimica et Biophysica Acta (BBA) - Biomembranes, 1778(9), 1814 - 1838.
Brown, D., Demeter, M., & Turner, R. J. (2019). Prevalence of multidrug resistance efflux pumps (MDREPs) in environmental communities. In Microbial Diversity in the Genomic Era (pp. 545 - 557). Academic Press.
Heir, E., Sundheim, G., & Holck, A. L. (1998). The Staphylococcus qacH gene product: A new member of the SMR family encoding multidrug resistance. FEMS Microbiology Letters, 163(1), 49 - 56.
Walker, M. A., Singh, A., Gibson, T. W., Rousseau, J., & Weese, J. S. (2020). Presence of Qac genes in clinical isolates of methicillin ‐ resistant and methicillin ‐ susceptible Staphylococcus pseudintermedius and their impact on chlorhexidine digluconate susceptibility. Veterinary Surgery, 49(5), 971 - 976.
Schindler, B. D., Jacinto, P., & Kaatz, G. W. (2013). Inhibition of drug efflux pumps in Staphylococcus aureus: Current status of potentiating existing antibiotics. Future Microbiology, 8(4), 491 - 507.
Handzlik, J., Matys, A., & Kie ć - Kononowicz, K. (2013). Recent advances in multi - drug resistance (MDR) efflux pump inhibitors of Gram - positive bacteria S. aureus. Antibiotics, 2(1), 28 - 45.
Kaatz, G. W., Moudgal, V. V., Seo, S. M., & Kristiansen, J. E. (2003). Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 47(2), 719 - 726.
Piddock, L. J. (2006). Multidrug - resistance efflux pumps? Not just for resistance. Nature Reviews Microbiology, 4(8), 629 - 636.
Poole, K. (2008). Bacterial multidrug efflux pumps serve other functions. Microbe - American Society for Microbiology, 3(4), 179.
Huang, L., Wu, C., Gao, H., Xu, C., Dai, M., Huang, L., ... & Cheng, G. (2022). Bacterial multidrug efflux pumps at the frontline of antimicrobial resistance: An overview. Antibiotics, 11(4), 520.
Deng, W., Li, C., & Xie, J. (2013). The underlying mechanism of bacterial TetR/AcrR family transcriptional repressors. Cellular Signalling, 25(7), 1608 - 1613.
Guerin, F., Galimand, M., Tuambilangana, F., Courvalin, P., & Cattoir, V. (2014). Overexpression of the novel MATE fluoroquinolone efflux pump FepA in Listeria monocytogenes is driven by inactivation of its local repressor FepR. PLoS One, 9(9), e106340.
Henderson, P. J., Maher, C., Elbourne, L. D., Eijkelkamp, B. A., Paulsen, I. T., & Hassan, K. A. (2021). Physiological functions of bacterial “multidrug” efflux pumps. Chemical Reviews, 121(9), 5417 - 5478.
Melamed, S., Naftaly, S., & Belkin, S. (2014). Improved detection of antibiotic compounds by bacterial reporter strains achieved by manipulations of membrane permeability and efflux capacity. Applied Microbiology and Biotechnology, 98, 2267 - 2277.
Hong, H., & Park, W. (2014). TetR repressor - based bioreporters for the detection of doxycycline using Escherichia coli and Acinetobacter oleivorans. Applied Microbiology and Biotechnology, 98, 5039 - 5050.
Weber, C. C., Link, N., Fux, C., Zisch, A. H., Weber, W., & Fussenegger, M. (2005). Broad ‐ spectrum protein biosensors for class ‐ specific detection of antibiotics. Biotechnology and Bioengineering, 89(1), 9 - 17.
Espinosa - Urgel, M., Serrano, L., Ramos, J. L., & Fernández - Escamilla, A. M. (2015). Engineering biological approaches for detection of toxic compounds: A new microbial biosensor based on the Pseudomonas putida TtgR repressor. Molecular Biotechnology, 57, 558 - 564.
Li, X. Z., Plésiat, P., & Nikaido, H. (2015). The challenge of efflux - mediated antibiotic resistance in Gram - negative bacteria. Clinical Microbiology Reviews, 28(2), 337 - 418.
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.
Goli, H. R., Nahaei, M. R., Rezaee, M. A., Hasani, A., Kafil, H. S., Aghazadeh, M., & Sheikhalizadeh, V. (2016). Contribution of mexAB - oprM and mexXY ( - oprA) efflux operons in antibiotic resistance of clinical Pseudomonas aeruginosa isolates in Tabriz, Iran. Infection, Genetics and Evolution, 45, 75 - 82.
Huang, J. J., Hu, H. Y., Wu, Y. H., Wei, B., & Lu, Y. (2013). Effect of chlorination and ultraviolet disinfection on tetA - mediated tetracycline resistance of Escherichia coli. Chemosphere, 90(8), 2247 - 2253.
Bley, C., van Der Linden, M., & Reinert, R. R. (2011). mef (A) is the predominant macrolide resistance determinant in Streptococcus pneumoniae and Streptococcus pyogenes in Germany. International Journal of Antimicrobial Agents, 37(5), 425 - 431.
Wang, J., Guo, Z. W., Zhi, C. P., Yang, T., Zhao, J. J., Chen, X. J., ... & Liu, J. H. (2017). Impact of plasmid - borne oqxAB on the development of fluoroquinolone resistance and bacterial fitness in Escherichia coli. Journal of Antimicrobial Chemotherapy, 72(5), 1293 - 1302.
Henderson, P. J., Maher, C., Elbourne, L. D., Eijkelkamp, B. A., Paulsen, I. T., & Hassan, K. A. (2021). Physiological functions of bacterial “multidrug” efflux pumps. Chemical Reviews, 121(9), 5417 - 5478.
Kaur, B., Gupta, J., Sharma, S., Sharma, D., & Sharma, S. (2021). Focused review on dual inhibition of quorum sensing and efflux pumps: a potential way to combat multi drug resistant Staphylococcus aureus infections. International Journal of Biological Macromolecules, 190, 33 - 43.
Brawley, D. N., Sauer, D. B., Li, J., Zheng, X., Koide, A., Jedhe, G. S., ... & Traaseth, N. J. (2022). Structural basis for inhibition of the drug efflux pump NorA from Staphylococcus aureus. Nature Chemical Biology, 18(7), 706 - 712.
Li, J., Li, Y., Koide, A., Kuang, H., Torres, V. J., Koide, S., ... & Traaseth, N. J. (2024). Proton - coupled transport mechanism of the efflux pump NorA. Nature Communications, 15(1), 4494.
Kumar, S., Athreya, A., Gulati, A., Nair, R. M., Mahendran, I., Ranjan, R., & Penmatsa, A. (2021). Structural basis of inhibition of a transporter from Staphylococcus aureus, NorC, through a single - domain camelid antibody. Communications Biology, 4(1), 836.
Allister, C., Yuji, M., Hiroyuki, A., & Arthur, O. (2016). Structure of the Membrane - intrinsic Nitric Oxide Reductase from Roseobacter denitrificans.
Agah, S., Poulos, S., Banchs, C., & Faham, S. (2014). Structural characterization of MepB from Staphylococcus aureus reveals homology to endonucleases. Protein Science, 23(5), 594 - 602.
Kumaraswami, M., Schuman, J. T., Seo, S. M., Kaatz, G. W., & Brennan, R. G. (2009). Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA. Nucleic Acids Research, 37(4), 1211 - 1224.
RCSB Protein Data Bank. (n.d.). Structure summary for PDB ID 5FFZ. Retrieved September 4, 2024, from https://www.rcsb.org/structure/5FFZ
RCSB Protein Data Bank. (n.d.). Structure summary for PDB ID 5FFX. Retrieved September 4, 2024, from https://www.rcsb.org/structure/5FFX
Birukou, I., Tonthat, N. K., Seo, S. M., Schindler, B. D., Kaatz, G. W., & Brennan, R. G. (2013). The molecular mechanisms of allosteric mutations impairing MepR repressor function in multidrug - resistant strains of Staphylococcus aureus. MBio, 4(5), 10 - 1128.
Maldonado - Contreras, A., Birtley, J. R., Boll, E., Zhao, Y., Mumy, K. L., Toscano, J., ... & McCormick, B. A. (2017). Shigella depends on SepA to destabilize the intestinal epithelial integrity via cofilin activation. Gut Microbes, 8(6), 544 - 560.
Majumder, P., Ahmed, S., Ahuja, P., Athreya, A., Ranjan, R., & Penmatsa, A. (2023). Cryo ‐ EM structure of antibacterial efflux transporter QacA from Staphylococcus aureus reveals a novel extracellular loop with allosteric role. The EMBO Journal, 42(16), e113418.
Diercks, T., Eiso, A. B., Daniels, M. A., de Jong, R. N., Besseling, R., Kaptein, R., & Folkers, G. E. (2008). Solution Structure and Characterization of the DNA - Binding Activity of the B3BP – Smr Domain. Journal of Molecular Biology, 383(5), 1156 - 1170.
RCSB Protein Data Bank. (n.d.). Structure summary for PDB ID 3NPI. Retrieved September 4, 2024, from https://www.rcsb.org/structure/3NPI
Alguel, Y., Meng, C., Terán, W., Krell, T., Ramos, J. L., Gallegos, M. T., & Zhang, X. (2007). Crystal structures of multidrug binding protein TtgR in complex with antibiotics and plant antimicrobials. Journal of Molecular Biology, 369(3), 829 - 840.
Hiramatsu, K., Katayama, Y., Matsuo, M., Sasaki, T., Morimoto, Y., Sekiguchi, A., & Baba, T. (2014). Multi - drug - resistant Staphylococcus aureus and future chemotherapy. Journal of Infection and Chemotherapy, 20(10), 593 - 601.
Lamut A, Peterlin Maši č L, Kikelj D, Tomaši č T. Efflux pump inhibitors of clinically relevant multidrug resistant bacteria. Med. Res. Rev. 2019; 39(6): 2460 - 2504.
Maurya N, Jangra M, Tambat R, Nandanwar H. Alliance of efflux pumps with β - lactamases in multidrug - resistant Klebsiella pneumoniae isolates. Microb. Drug Resist. 2019; 25(8): 1155 - 1163.
DeMarco CE, Cushing LA, Frempong - Manso E, et al. Efflux - related resistance to norfloxacin, dyes, and biocides in bloodstream isolates of Staphylococcus aureus. Antimicrob Agents Chemother. 2007;51:3235 – 9.
Schmitz F - J, Fluit AC, Lückefahr M, et al. The effect of reserpine, an inhibitor of multidrug efflux pumps, on the in - vitro activities of ciprofloxacin, sparfloxacin, and moxifloxacin against clinical isolates of Staphylococcus aureus. J Antimicrob Chemother. 1998;42:807 – 10.
Marquez B. Bacterial efflux systems and efflux pump inhibitors. Biochimie. 2005;87:1137 – 47.
Frempong - Manso E, Raygada JL, DeMarco CE, et al. Inability of a reserpine - based screen to identify strains overexpressing efflux pump genes in clinical isolates of Staphylococcus aureus. Int J Antimicrob Agents. 2009;33:360 – 3.
Pagès JM, Amaral L. Mechanisms of drug efflux and strategies to combat them challenging the efflux pump of Gram - negative bacteria. Biochim Biophys Acta. 2009;1794:826 – 33.
Couto I, Costa SS, Viveiros M, et al. Efflux - mediated response of Staphylococcus aureus exposed to ethidium bromide. J Antimicrob Chemother. 2008;62:504 – 13.
Kosmidis C, DeMarco C, Frempong - Manso E, et al. In silico correlations of multidrug efflux pump gene expression in Staphylococcus aureus. Int J Antimicrob Agents. 2010;36:222 – 9.
Patel D, Kosmidis C, Seo SM, et al. Ethidium bromide MIC screening for enhanced efflux pump gene expression or efflux activity in Staphylococcus aureus. Antimicrob Agents Chemother. 2010;54:5070 – 3.
Costa SS, Falcão C, Viveiros M, et al. Exploring the contribution of efflux on the resistance to fluoroquinolones in clinical isolates of Staphylococcus aureus. BMC Microbiol. 2011;11
Martins M, Viveiros M, Couto I, et al. Identification of efflux pump - mediated multidrug - resistant bacteria. Ethidium Bromide - Agar Cartwheel Method. In Vivo. 2011;25:171 – 8.
Gillespie SH, McHugh TD, Viveiros M, Rodrigues L, Martins M, et al. In Evaluation of efflux activity of bacteria by a semi - automated fluorometric system. New York: Humana Press; 2010. Antibiotic Resistance Protocols; pp. 159 – 72.
Piddock LJV. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev. 2006;19:382 – 402.
Costa SS, Viveiros M, Amaral L, Couto I. Multidrug efflux pumps in Staphylococcus aureus: an update. The Open Microbiology Journal. 2013;7:59.
Kaatz GW, DeMarco CE, Seo SM. MepR, a repressor of the Staphylococcus aureus MATE family multidrug efflux pump MepA, is a substrate - responsive regulatory protein. Antimicrob Agents Chemother. 2006;50:1276 – 81.
Kumaraswami M, Schuman JT, Seo SM, et al. Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA. Nucleic Acids Res. 2009;37:1211 – 24.
Rouch DA, Cram DS, DiBerardino D, et al. Efflux - mediated antiseptic resistance gene qacA from Staphylococcus aureus common ancestry with tetracycline - and sugar - transport proteins. Mol Microbiol. 1990;4:2051 – 62.
Grkovic S, Brown MH, Roberts NJ, et al. QacR is a repressor protein that regulates expression of the Staphylococcus aureus multidrug efflux pump QacA. J Biol Chem. 1998;273:18665 – 73.
Grkovic S, Brown MH, Schumacher MA, et al. The staphylococcal QacR multidrug regulator binds a correctly spaced operator as a pair of dimers. J Bacteriol. 2001;183:7102 – 9.
Brennan RG. Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA. Nucleic Acids Res. 2009 Mar;37(4):1211 - 24.
Kumaraswami M, Schuman JT, Seo SM, Kaatz GW, Brennan RG. Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA. Nucleic Acids Res. 2009 Mar;37(4):1211 - 24.
Majumder P, Ahmed S, Ahuja P, Athreya A, Ranjan R, Penmatsa A. Cryo - EM structure of antibacterial efflux transporter QacA from Staphylococcus aureus reveals a novel extracellular loop with allosteric role. EMBO J. 2023 Aug 15;42(16)
Eicher, Thomas. Structural and functional studies on AcrB, a bacterial multidrug efflux pump and homologue of Niemann - Pick C1 protein. Diss. University of Zurich, 2009.
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