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Characterization of Saccharomyces Cerevisiae Mutants Supersensitive to Aminoglycoside Antibiotics JOACHIM F

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Characterization of Saccharomyces Cerevisiae Mutants Supersensitive to Aminoglycoside Antibiotics JOACHIM F JOURNAL OF BACTERIOLOGY, JUlY 1985, p. 8-14 Vol. 163, No. 1 0021-9193/85/070008-07$02.00/0 Copyright © 1985, American Society for Microbiology Characterization of Saccharomyces cerevisiae Mutants Supersensitive to Aminoglycoside Antibiotics JOACHIM F. ERNST* AND RUSSELL K. CHAN Department ofMicrobiology, Biogen S. A., CH-1227 Geneva, Switzerland Received 14 January 1985/Accepted 25 March 1985 We describe mutants of Saccharomyces cerevisiae that are more sensitive than the wild type to the aminoglycoside antibiotics G418, hygromycin B, destomycin A, and gentamicin X2. In addition, the mutants are sensitive to apramycin, kanamycin B, lividomycin A, neamine, neomycin, paromomycin, and tobramy- cin-antibiotics which do not inhibit wild-type strains. Mapping studies suggest that supersensitivity is caused by mutations in at least three genes, denoted AGS), AGS2, andAGS3 (for aminoglycoside antibiotic sensitivity). Mutations in all three genes are required for highest antibiotic sensitivity; ags1 ags2 double mutants have intermediate antibiotic sensitivity. AGS1 was mapped 8 centimorgans distal from LEU2 on chromosome III. Analyses of yeast strains transformed with vectors carrying antibiotic resistance genes revealed that G418, gentamicin X2, kanamycin B, lividomycin A, neamine, and paromomycin are inactivated by the Tn903 phosphotransferase and that destomycin A is inactivated by the hygromycin B phosphotransferase. ags strains are improved host strains for vectors carrying the phosphotransferase genes because a wide spectrum of aminoglycoside antibiotics can be used to select for plasmid maintenance. Several approaches have led to the discovery of dominant procedures were used for crosses and scoring of phenotypes selectable transformation markers in the yeast Sac- (26). The Ags- phenotype was routinely scored on 1% yeast charomyces cerevisiae. First, procaryotic antibiotic resis- extract-2% peptone-2% glucose-2% Bacto-agar (Difco Lab- tance genes have been expressed in yeast, and it has been oratories, Detroit, Mich.) (YPD) agar (26) containing 20 jig of demonstrated that certain aminoglycoside antibiotics select G418 per ml or 20 ,ug of hygromycin B per ml; in addition, for the growth of strains expressing the corresponding resis- zones of inhibition surrounding antibiotic-containing filter tance gene. The kanamycin phosphotransferase (APH) en- disks on yeast lawns were determined in some cases. Con- coded by a gene of transposon Tn9O3, which inactivates the centration-dependent inhibition by antibiotics was deter- antibiotic G418 (8, 10, 32), and the gene encoding mined by inoculating 5 ml of liquid YPD containing antibiot- hygromycin B phosphotransferase (HPH) (7, 12) have been ics with 50 ,ul of a saturated yeast culture grown in minimal used in this fashion. Second, certain proteins have been medium (26); starter cultures of transformed strains were overproduced in yeast by inserting the encoding genes on grown selectively (without uracil) in minimal medium. After high-copy-number vectors; yeast strains transformed with incubation at 30'C for 72 h on a rotating wheel, the optical these vectors are resistant to specific metabolic inhibitors of density at 600 nm was recorded. Sensitivity to chlorampheni- the overproduced enzymes. Overproduction of enzymes (15, col (4 mg/ml), cycloheximide (0.5 jig/ml), or tetracycline (2 22), copper chelatin (11), and a ribosomal protein (5) ren- mg/ml) was determined on YP agar (26) containing 4% glyc- dered yeast resistant to the corresponding specific inhibitors. erol, sensitivity to oligomycin (5 jig/ml) was determined on Whereas the overproduction approach usually requires YP agar containing 3% glycerol, and sensitivity to dequali- the use of high-copy-number vectors, the gene encoding nium chloride (5 ,ug/ml) was determined on YPD agar. Plat- APH renders yeast resistant to G418 even at low copy ing efficiencies were determined on YPD agar for whole cells numbers (32). In addition, the genes encoding APH and and on YPD agar containing 1 M sorbitol for spheroplasts. HPH are expressed in S. cerevisiae, as well as in Escherichia The ability of ags mutants to suppress nonsense mutations coli (7, 8, 32), allowing for antibiotic selection in both was assessed by crossing an ags strain with a strain carrying organisms with yeast shuttle vectors (2). However, the nonsense mutations. The resulting diploid was sporulated, relatively high concentrations of G418 and hygromycin B (7, and tetrads were dissected. The presence of ags spores that 32) needed in selective growth media have hampered the use expressed the phenotype of the unsuppressed marker was of phosphotransferase genes as dominant selectable markers taken as evidence that ags did not suppress that mutation. in yeast. We describe here mutants of S. cerevisiae that are Plasmids. Standard procedures were used for the con- particularly sensitive to G418 and hygromycin B. These struction and amplification of plasmids (14). For construc- strains are also sensitive to a series of other aminoglycoside tion of pEX-2, the CYCI terminator region was subcloned antibiotics, many of which are inactivated by the Tn9O3 first. The 270-base-pair HaeIII-to-HindIII fragment contain- phosphotransferase. Thus, in our approach the modification ing the terminator (29, 33) was isolated and inserted between of the yeast host allows optimal use of the existing phospho- the HincII and HindIII sites of bacteriophage M13mp8 (14). transferase genes. The EcoRI-to-HindIII terminator fragment was isolated MATERIALS AND METHODS from double-stranded phage DNA and ligated with the following two fragments to construct pEX-1: (i) the 4.85- Strains and growth conditions. The yeast strains used in kilobase HindIII-to-BamHI fragment of plasmid pAB107 (S. this study are listed in Table 1. Standard yeast genetic Baim and F. Sherman, unpublished results)-pAB107 con- tains the 0.85-kilobase EcoRI-to-HindIII ARSI fragment of * Corresponding author. YRp7 (2) inserted between the EcoRI and HindIII sites of 8 VOL. 163, 1985 S. CEREVISIAE MUTANTS SUPERSENSITIVE TO ANTIBIOTICS 9 TABLE 1. Yeast strains than were other laboratory strains. This phenotype was denoted Ags-, for aminoglycoside antibiotic sensitivity. Strain Genotype Origin Comparisons of wild-type and Ags- strains for antibiotic BJ1991 MATaz pep4-3 prbl-1122 E. Jones, sensitivity demonstrated that Ags- strains are 10- to 20-fold ura3-52 leu2 trpl Carnegie- mnore sensitive to G418 and hygromycin B than are wild-type Mellon strains (Fig. 2). In complex growth medium, 50% inhibition University HR12S-llb MATa leu2-3 leu2-112 G. Sprague, was obtained at 1 to 2 ,ug/ml. Ags- strains were also more trpl ura3-52 his3 his4 University of sensitive to gentamicin X2 and destomycin A-two antibiot- Oregon ics that inhibit growth of wild-type strains (Fig. 3, Fig. 4). MB50OC-T1OC MATa his7 met2 tup7 gall L. F. Bisson (1) To verify that the Ags- strain could be used as host for ags yeast vectors carrying the known phosphotransferase genes RC1678 MATa ura3-52 trpl tup7 HR125-llb x (7, 10), we constructed plasmids that carry either the HPH- ags MB50OC-TlOC encoding gene (pLG89) or the Tn9O3 APH-encoding gene RC1705 MATa ura3-52 trpl leu2 BJ199i x RC1678 (pEX-4) or both (pGH41) (Fig. 1). All constructed plasmids prbl-1122 carry the yeast URA3 gene in addition to the antibiotic RC1707 MATa ura3-52 trpl tup7 Same tetrad as pep4-3 prbl-1122 ags RC1705 resistance marker(s). An Ags+ ura3 strain and an Ags- ura3 strain were transformed with plasmids pEX-2, pLG89, or pGH-1, selecting for uracil prototrophy. Quantitative aniti- biotic sensitivity tests were performed on the untransformed YIp5 (2); (ii) the 1.1-kilobase BamHI-to-EcoRI fragment of and transformed strains (Fig. 3, Fig. 4). As expected, an plasmid pAB63 carrying the cycl-13 promoter (Baim and Ags+ transformant expressing APH (encoded on pEX-4) was Sherman, unpublished results). The cycl-13 mutation is a resistant to G418 at all antibiotic concentrations tested. single nucleotide change altering the ATG translation start Similarly, an Ags- strain expressing APH was more resis- codon to ATA (27). The sequence of the junction cycl-13 tant to G418 than the untransformed Ags- host and the Ags- promoter-M13 sequences-CYCI terminator is given in Fig. host carrying plasmid pLG89. However, at G418 concentra- 1A. pEX-2 was constructed by insertion of the 1.47-kilobase tions greater than 20 ,ug/ml, inhibition by G418 was seen HincII fragment carrying the origin of replication of the even when the Ags- strain contained pEX-4. The presence yeast 2,u circle (8) into the single PvuII site of pEX-1. The of plasmid pLG89 rendered Ags+ and Ags- strains more construction of pLG89 from pEX-2 has been described resistant to hygromycin B (Fig. 3, Fig. 4). As described previously (7). pGH-1 and pEX-4 were constructed by previously (7), hygromycin B resistance was incomnplete at insertion of the 1.7-kilobase PvuII fragment of plasmid pAJ50 (10) carrying the APH-coding gene of Tn9O3 (16) into the filled-in SalI sites of pEX-2 and pLG89, respectively (Fig. 1B). The Sall sites were restored in these construc- A EcoRI SMO I BOmHI tions; in pGH-1, a 0.6-kilobase Sall fragment containing TTAATAIJACTGAATTC CCGGGGATCCGTC CCCCTTTTCC upstream sequences of the cycl-13 promoter and pBR322 cyc/-I3 promoter ------- Ml3mp8----- *-_CYC/ terminator sequences was deleted during the construction. Transforma- tion of yeast strains with plasmids was performed by the spheroplast method (26) or by the salt method (9). B Reagents. G418 sulfate (Geneticin) was obtained from ARSI GIBCO Europe Ltd., Paisley, United Kingdom, and from Schering Corp., Bloomfield, N.J. Hygromycin B was ob- PEX-2 G89 R tained from Eli Lilly & Co., Indianapolis, Ind. Kanamycin A B B I Hyy sulfate (95% kanamnycin A, 5% kanamycin B), neomycin 9.3kb 310.3kb 2,p cyc/- 3 B sulfate (90 to 95% neomycin B), tobramycin, chlorampheni- oni col, cycloheximide, tetracycline, oligomycin (65% oligomycin A, 20% oligomycin B, 15% oligomycin C), ami- URA3 smR S kacin, and dequalinium chloride were obtained from Sigma Chemical Co., St.
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