Abstract
Multidrug resistance (MDR) systems are ubiquitously present in prokaryotes and eukaryotes and defend both types of organisms against toxic compounds in the environment. Four families of MDR systems have been described, each family removing a broad spectrum of compounds by a specific membrane-bound active efflux pump. In the present study, at least four MDR systems were identified genetically in the soil bacterium Streptomyces lividans. The resistance genes of three of these systems were cloned and sequenced. Two of them are accompanied by a repressor gene. These MDR gene sequences are found in most other Streptomyces species investigated. Unlike the constitutively expressed MDR genes in Escherichia coli and other gram-negative bacteria, all of the Streptomyces genes were repressed under laboratory conditions, and resistance arose by mutations in the repressor genes.
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Abbreviations
- MDR :
-
Multidrug resistance
References
Ahmed M, Borsch CM, Taylor SS, Vazquez-Laslop N, Neyfakh AA (1994) A protein that activates expression of a multidrug efflux transporter upon binding the transporter substrates. J Biol Chem 269:28506–28513
Alekshun MN, Levy SB, Mealy TR, Seaton BA, Head JF (2001) The crystal structure of MarR, a regulator of multiple antibiotic resistance, at 2.3 A resolution. Nat Struct Biol 8:710–714
August PR, Tang L, Yoon YJ, Ning S, Muller R, Yu TW, Taylor M, Hoffmann D, Kim CG, Zhang X, Hutchinson CR, Floss HG (1998) Biosynthesis of the ansamycin antibiotic rifamycin: deductions from the molecular analysis of the rif biosynthetic gene cluster of Amycolatopsis mediterranei S699. Chem Biol 5:69–79
Bechthold A, Sohng JK, Smith TM, Chu X, Floss HG (1995) Identification of Streptomyces violaceoruber Tü22 genes involved in the biosynthesis of granaticin. Mol Gen Genet 248:610–620
Bibb MJ, Findlay PR, Johnson MW (1984) The relationship between base composition and codon usage in bacterial genes and its use for the simple and reliable identification of protein-coding sequences. Gene 30:157–166
Blanc V, Salah-Bey K, Flocher M, Thompson CJ (1995) Molecular characterization and transcriptional analysis of a multidrug resistance gene cloned from the pristinamycin-producing organism, Streptomyces pristinaespiralis. Mol Microbiol 17:989–999
Cundliffe E (1989) How antibiotic-producing organisms avoid suicide. Annu Rev Microbiol 43:207–233
Cundliffe E (1992) Self-protection mechanisms in antibiotic producers. Ciba Foundation Symposium 171:199–214
Dairi T, Aisaka K, Katsumata R, Hasegawa M (1995) A self-defense gene homologous to tetracycline effluxing gene essential for antibiotic production in Streptomyces aureofaciens. Biosci Biotechnol Biochem 59:1835–1841
Davies J (1994) Inactivation of antibiotics and the dissemination of resistance genes. Science 264:375–382
Faust B, Hoffmeister D, Weitnauer G, Westrich L, Haag S, Schneider P, Decker H, Kunzel E, Rohr J, Bechthold A (2000) Two new tailoring enzymes, a glycosyltransferase and an oxygenase, involved in biosynthesis of the angucycline antibiotic urdamycin A in Streptomyces fradiae Tü2717. Microbiology 146:147–154
Fernandez-Moreno MA, Carbo L, Cuesta T, Vallin C, Malpartida F (1998) A silent ABC transporter isolated from Streptomyces rochei F20 induces multidrug resistance. J Bacteriol 180:4017–4023
Gottesman MM, Pastan I (1993) Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 62:385–427
Grinius L, Dreguniene, Goldberg EB, Liao C-H, Projan SJ (1992) A Staphylococcal multidrug resistance gene product is a membrane of a new protein family. Plasmid 27:119–129
Grkovic S, Brown MH, Roberts NJ, Paulsen IT, Skurray RA (1998) QacR is a repressor protein that regulates expression of the Staphylococcus aureus multidrug efflux pump QacA. J Biol Chem 273:18665–18673
Grkovic S, Brown MH, Skurray RA (2002) Regulation of Bacterial Drug Export Systems. Microbiol Mol Biol Rev 66:671–701
Hancock RE (1998) Resistance mechanisms in Pseudomonas aeruginosa and other nonfermentative gram-negative bacteria. Clin Infect Dis 27 Suppl 1:S93–99
Hopwood DA, Kieser T, Wright HM, Bibb MJ (1983) Plasmids, recombination, and chromosomal mapping in Streptomyces lividans 66. J Gen Microbiol 129:2257–2269
Hopwood DA, Bibb MJ, Chater KF, Kieser T, Bruton CJ, Kieser HM, Lydiate DJ, Smith CP, Ward JM, Schrempf H (1985) Genetic manipulation of Streptomyces: a laboratory manual. The John Innes Foundation, Norwich, UK
Jack DL, Storms ML, Tchieu JH, Paulsen IT, Saier MHJ (2000) A broad-specificity multidrug efflux pump requiring a pair of homologous SMR-type proteins. J Bacteriol 182:2311–2313
Katz E, Thompson CJ, Hopwood DA (1983) Cloning and expression of the tyrosinase gene from Streptomyces antibioticus in Streptomyces lividans. J Gen Microbiol 129:2703–2714
Kieser HM, Kieser T, Hopwood DA (1992) A combined genetic and physical map of the Streptomyces coelicolor A3(2) chromosome. J Bacteriol 174:5496–5507
Kohler T, Pechere JC, Plesiat P (1999) Bacterial antibiotic efflux systems of medical importance. Cell Mol Life Sci 56:771–778
Lee L-F, Chen CW (1998) Multidrug resistant genes in Streptomyces. Actinomycetology 12:148–152
Lee L-F, Huang Y-J, Chen CW (1996) Two classes of ethidium-bromide-resistant mutants of Streptomyces lividans 66. Microbiology 142:1041-1047
Lee CK, Kamitani Y, Nihira T, Yamada Y (1999) Identification and in vivo functional analysis of a virginiamycin S resistance gene ( varS) from Streptomyces virginiae. J Bacteriol 181:3293–3297
Lewis K (1994) Multidrug resistance pumps in bacteria: variations on a theme. Trends Biochem Sci 19:119–123
Lewis K (2001) In search of natural substrates and inhibitors of MDR pumps. J Mol Microbiol Biotechnol 3:247–254
Liu W, Shen B (2000) Genes for production of the enediyne antitumor antibiotic C-1027 in Streptomyces globisporus are clustered with the cagA gene that encodes the C-1027 apoprotein. Antimicrob Agents Chemother 44:382–392
Masaoka Y, Ueno Y, Morita Y, Kuroda T, Mizushima T, Tsuchiya T (2000) A two-component multidrug efflux pump, EbrAB, in Bacillus subtilis. J Bacteriol 182:2307–2310
Mazzariol A, Cornaglia G, Nikaido H (2000) Contributions of the AmpC beta-lactamase and the AcrAB multidrug efflux system in intrinsic resistance of Escherichia coli K-12 to beta-lactams. Antimicrob Agents Chemother 44:1387–1390
McMurry L, Levy S (1998) Revised sequence of OtrB (tet347) tetracycline efflux protein from Streptomyces rimosus. Antimicrob Agents Chemother 42:3050
Miller PF, Sulavik MC (1996) Overlaps and parallels in the regulation of intrinsic multiple-antibiotic resistance in Escherichia coli. Mol Microbiol 21:441–448
Neyfakh AA (1997) Natural functions of bacterial multidrug transporters. Trends Microbiol 5:309–313
Neyfakh AA, Bidnenko VE, Chen LB (1991) Efflux-mediated multidrug resistance in Bacillus subtilis: similarities and dissimilarities with the mammalian system. Proc Natl Acad Sci USA 88:4781–4785
Nikaido H (1994) Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science 264:382–388
Nikaido H (1998) Antibiotic resistance caused by gram-negative multidrug efflux pumps. Clin Infect Dis 27 Suppl 1:S32–41
Ohki R, Murata M (1997) bmr3, a third multidrug transporter gene of Bacillus subtilis. J Bacteriol 179:1423–1427
Paulsen IT, Brown MH, Dunstan SJ, Skurray RA (1995) Molecular characterization of the staphylococcal multidrug resistance export protein QacC. J Bacteriol 177:2827–2833
Paulsen IT, Brown MH, Skurray RA (1996) Proton-dependent multidrug efflux systems. Microbiol Rev 60:575–608
Redenbach M, Kieser HM, Denapaite D, Eichner A, Cullum J, Kinashi H, Hopwood DA (1996) A set of ordered cosmids and a detailed genetic and physical map for the 8 Mb Streptomyces coelicolor A3(2) chromosome. Molec Microbiol 21:77–96
Saier J, M. H., Paulsen IT, Sliwinski MK, Pao SS, Skurray RA, Nikaido H (1998) Evolutionary origins of multidrug and drug-specific efflux pumps in bacteria. FASEB J 12:265–274
Salah-Bey K, Blanc B, Thompson CJ (1995) Stress-activated expression of a Streptomyces pristinaespiralis multidrug resistance gene ( ptr) in various Streptomyces spp. and Escherichia coli. Mol. Microbiol. 17:1001–1012
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning. Cold Spring Harbor Laboratory , Cold Spring Harbor, New York
Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467
Schumacher MA, Miller MC, Grkovic S, Brown MH, Skurray RA, Brennan RG (2001) Structural mechanisms of QacR induction and multidrug recognition. Science 294:2158–2163
Takiff HE, Cimino M, Musso MC, Weisbrod T, Martinez R, Delgado MB, Salazar L, Bloom BR, Jacobs J, W. R. (1996) Efflux pump of the proton antiporter family confers low-level fluoroquinolone resistance in Mycobacterium smegmatis. Proc Natl Acad Sci USA 93:362–366
Tegos G, Stermitz FR, Lomovskaya O, Lewis K (2002) Multidrug pump inhibitors uncover remarkable activity of plant antimicrobials. Antimicrob Agents Chemother 46:3133–3141
Tercero JA, Lacalle RA, Jimenez A (1993) The pur8 gene from the pur cluster of Streptomyces alboniger encodes a highly hydrophobic polypeptide which confers resistance to puromycin. Eur J Biochem 218:963–971
van Veen HW, Konings WN (1998) The ABC family of multidrug transporters in microorganisms. Biochim Biophys Acta 1365:31–36
Westrich L, Domann S, Faust B, Bedford D, Hopwood DA, Bechthold A (1999) Cloning and characterization of a gene cluster from Streptomyces cyanogenus S136 probably involved in landomycin biosynthesis. FEMS Microbiol Lett 170:381–387
Williams ST, Goodfellow M, Alderson G, Wellington EMH, Sneath PHA, Sackin MJ (1983) Numerical classification of Streptomyces and related genera. J Gen Microbiol 129:1743–1813
Yerushalmi H, Lebendiker M, Schuldiner S (1995) EmrE, an Escherichia coli 12-kDa multidrug transporter, exchanges toxic cations and H+ and is soluble in organic solvents. J Biol Chem 270:6856–6863
Acknowledgements
This research was supported by research grants from National Science Council (NSC90-2312-B010-002) and Ministry of Education (89-B-FA22–2-4), Taiwan (R.O.C).
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Lee, LF., Huang, YJ. & Chen, C.W. Repressed multidrug resistance genes in Streptomyces lividans . Arch Microbiol 180, 176–184 (2003). https://doi.org/10.1007/s00203-003-0574-z
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DOI: https://doi.org/10.1007/s00203-003-0574-z