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Escherichia Coli R ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 1983, p. 689-695 Vol. 24, No. 5 0066-4804/83/110689-07$02.00/0 Copyright C 1983, American Society for Microbiology Genetic and Enzymatic Basis of Hygromycin B Resistance in Escherichia coli R. N. RAO, N. E. ALLEN,* J. N. HOBBS, JR., W. E. ALBORN, JR., H. A. KIRST, AND J. W. PASCHAL Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285 Received 11 April 1983/Accepted 23 August 1983 A plasmid conferring resistance to the aminocyclitol antibiotic hygromycin B was isolated from Escherichia coli. The gene conferring resistance to this drug was cloned in pBR322, and the gene was localized to a fragment of ca. 1,510 base pairs. Resistance to hygromycin B is determined by an aminocyclitol phospho- transferase that modifies hygromycin B and structurally related antibiotics. The specific modification of hygromycin B is a phosphorylation of the hydroxyl on the 4 position of the cyclitol ring (hyosamine). The presence of the phosphotransfer- ase in E. coli correlates with reduced accumulation of [14C]hygromycin B. Hygromycin B (Hm) is an aminocyclitol anti- data), BE827 (C600 Hsr- Hsm+ RecA-), and DH1 biotic with broad-spectrum activity against both (provided by D. Hanahan [23]), BE1065, BE1092, and procaryotic and eucaryotic cells (1, 25, 27, 31). BE1098 are described in Table 1. Plasmid pKC7 and (resistant to ampicillin [Ap] and neomycin) has been Like other aminoglycoside aminocyclitol described (29). antibiotics, Hm appears to interfere with amino- Media and culture conditions. Bacteriological media acyl tRNA recognition and cause misreading in and growth conditions were as described (24, 28). bacterial cell-free polypeptide synthesizing sys- Drug-resistant bacteria were selected on plates con- tems (9). A more detailed examination of the taining the appropriate antibiotic at the following con- mechanism of action has suggested that Hm also centrations: Ap, 100 ,ug/ml; tetracycline, 10 ,ug/ml; interferes with the translocation step in cell-free neomycin, 25 ,ug/ml; apramycin (Am), 200 ,g/ml; systems from both bacteria (7) and yeasts (14). G418, 200 ,ug/ml; and Hm, 200 ,ug/ml. Most of the aminocyclitol antibiotics can be Plasmid preparation. Plasmid DNAs were prepared inactivated at least one three by several methods. Rapid preparations were made by by of enzymatic an alkaline lysis procedure (4) or by the sodium mechanisms: (i) acetylation, (ii) adenylylation, dodecyl sulfate lysis procedure (13). Pure DNA prepa- or (iii) phosphorylation (12). Enzymes carrying rations were made by the cleared lysate-cesium chlo- out these reactions and the genes that code for ride-ethidium bromide gradient procedure (5). them have been isolated from bacteria resistant Restriction endonuclease digestion and ligation of to aminocyclitols (12) and from Streptomyces DNA. Restriction enzyme digests and ligation were species that produce these antibiotics (3, 22, 33, done under the conditions specified by the manufac- 34). The presence of these enzymes in bacteria turers (New England Biolabs, Bethesda Research usually makes the bacteria resistant to the ap- Laboratories, and Boehringer Mannheim Corp.). propriate antibiotic (15). Transformations. Transformations were done using published procedures (23). Transformed cells were Although resistance to Hm has been found in grown overnight before selections were done. All the Hm-producing organism Streptomyces hy- recombinant DNA experiments were done under the groscopicus (22), there has been no previous appropriate containment conditions according to Na- report of plasmid-encoded resistance to this tional Institutes of Health guidelines. antibiotic in enterobacteria. Moreover, none of Agarose gel electrophoresis. DNA cut with a restric- the numerous aminoglycoside-modifying en- tion enzyme was analyzed by electrophoresis on a 1% zymes reported to date has been shown to use agarose horizontal slab gel, using Tris-acetate buffer Hm as a substrate. In this paper, we describe the (23). Electrophoresis was carried out at 5 V/cm for ca. isolation of a gene from Escherichia coli that 16 h. Preparation and assay of aminocyclitol-modifying en- codes for Hm phosphotransferase activity and zymes. Bacteria were grown and osmotic lysates were confers resistance to Hm. prepared by the methods of Haas and Dowding (16). Enzyme activities were assayed by the phosphocellu- MATERIALS AND METHODS lose disk method (16) in 50-,ul reactions. The composi- Bacterial strains and plasmids. All strains used were tion of specific reaction mixtures is given below. E. coli K-12 derivatives: W677, W677(JR225) (provid- Reactions were incubated for 15 (adenylyltransferase ed by Julian Davies [11]), BE783 (N. Rao, unpublished and phosphotransferase) or 30 (acetyltransferase) min 689 690 RAO ET AL. ANTIMICROB. AGENTS CHEMOTHER. at 30°C. Samples (25 RI) were removed and applied to mid DNA preparation contained two major plas- phosphocellulose filter-paper disks (Whatman P81). mid species (14.1 and 25 kilobases [kb]). Hm- Filters were washed and counted as previously de- resistant transformants fell into two groups. One scribed (16). (i) Acetyltransferase. Acetyltransferase was assayed group resembled strain W677(JR225) in that it using 50 mM Tris-hydrochloride (pH 7.5), 10 mM had two major plasmids and was resistant to Ap, magnesium chloride, 20 mM ammonium chloride, 1 tetracycline, Hm, and Am. The other group had mM dithiothreitol, 0.2 mM [acetyl-1-'4Cjacetyl-coen- only one plasmid (pKC203; 14.1 kb) and was zyme A (6.7 ,Ci/mol), 0.2 mM aminocyclitol, and 40 resistant to Hm and Am but was susceptible to Lg of lysate protein. Ap and tetracycline. Strain BE827 carrying (ii) Adenylyltraferase. Adenylyltransferase was as- pKC203 was grown in the presence of Hm, and sayed as described previously (2), using 0.4 mM the plasmid DNA was isolated in high yields. [14C]ATP (10 ,uCi/,mol), 0.8 mM aminocyclitol, and This plasmid DNA was used in the structural 40 ,ug of lysate protein. characterization described below. The Hm (fll) p trerase. Phosphotransferase was as- sayed using buffer- (13 mM Tris, 8.4 mM magnesium resistance determinant was shown to reside on chloride, 80 mM ammonium chloride, and 2 mM this plasmid by subsequent plasmid transfer to dithiothreitol; pH adjusted to 8.0 with 1 M maleic another Hm-susceptible E. coli K-12 strain, acid), 2 mM [y-32PJATP (adjusted to 10 p.Ci4.mol), 1 DH1, and by cloning experiments described mM aminocyclitol, and 40 Ig of lysate protein. below. Radiochromatography of phosphorylated lim. Hm Genetic characterization of the Hm resitance was phosphorylated as described above; 25 SLl was gene. Initial characterization of pKC203 showed applied to Whatman no. 1 paper and developed in that it was not cut by HindIII or BamHI and was methanol-chloroform-concentrated ammonium hy- cut once by EcoRI, twice by Sall or XhoI, and droxide (3:1.5:2) by descending chromatography. Ra- dioactivity was determined by scanning on a Packard model 7201 Radiochromatogram Scanner. Uptake of ['4CIHm. Bacteria were grown at 37°C with shaking in Trypticase soy broth (BBL Microbiol- ogy Systems, Cockeysville, Md.) to an optical density at 600 nm of0.2 (1.0-cm cuvette). Cells were collected by centrifugation and suspended in Tryptone-peptone broth (2). The culture was divided into 10-ml volumes with nonradioactive aminocyclitol being added in ex- periments requiring preexposure. Incubation was con- tinued for 20 min, after which cells were harvested by centrifugation and resuspended in an equivalent vol- ume of tryptone-peptone broth. [14C]Hm (0.2-gLCi/ml, 1.0 RCi4Lmol; prepared by K. Koch, Lilly Research Laboratories) was added, and flasks were incubated at 37°C with shaking. At various time intervals, 0.5-mI samples were removed and pipetted onto 0.45-Am membrane filters (Millipore Corp.) that had been pre- soaked in 0.1 M lithium chloride (17). Sampls were washed three times with 0.1 M lithium chloride, dried, and counted in a scintillation counter. RESULTS Plasmlddeternnwd resistanc to Hmi li E. coli. E. coli W67(R22S) harbors a plasmid-coded aminocyclitol-3-N-acetyltransferase that confers resistance to Am and other deoxystreptamine- containing antibiotics (11). This strain is also FIG. 1. Plasmid DNAs cut with restriction en- resistant to Ap and tetracycline. Examination of zymes and analyzed on a 1% agarose gel. Lanes c and this strain for its susceptibility to Hm indicated g, DNAD cut with Hindlll, used as a size marker; that it could grow in the presence of 200 F.g of lanes a and b, pKC203 cut with Bgall (7.4 + 5.6 + 1.2 this drug per ml (minimal inhibitory concentra- kb) and BgIII and Sail (5.6 + 4.6 + 2.8 + 0.56 kb; the tion, 512 Strain W677 lacking the plas- smallest fragment is not visible on this gel), respective- pg/ml). ly; lane d, pKC7 cut with BgIII and Sall (4.2 + 1.1 + mid was inhibited by this concentration of Hm 0.6 kb); the smallest fragment is barety visible on this (minimal inhibitory concentration, 64 ,ug/ml). gel; lanes e and f, pKC222 cut with Bglll and SaII (4.2 Plasmid DNA was isolated from E. coli + 2.6 kb) and EcoRI (5.4 + 1.4 kb), respectively; lane W677(JR225) and used to transform the E. coli h, pKC237 cut with EcoRI (5.4 kb); lane i, pKC222 cut K-12 strain BE827 from a Hm-susceptible phe- with SacI (6.2 + 0.7 kb); lane j, pKC241 cut with SacI notype to a Hm-resistant phenotype. The plas- (6.2 kb). 0 VOL. 24, 1983 HYGROMYCIN B PHOSPHOTRANSFERASE 691 U20 Bgl II Hind III ,-Sal I ,, Bgl II -Sal I ,SalI - Bgl II Eco RI -- - Eco RI pK4 6.~ Sac I RI Sac I deletion deletion EcoRI ,Hind III ~Bg II Sac I pKC237 5.4kb Sac I Sal I Sac I FIG.
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