title: Potential roles for DNA replication and repair functions in cell killing by streptomycin.
abstract: The aminoglycoside streptomycin binds to ribosomes to promote mistranslation and eventual inhibition of translation. Streptomycin kills bacteria, whereas many other non-aminoglycoside inhibitors of translation do not. Because mistranslation is now known to affect DNA replication, we asked if hydroxyurea, a specific inhibitor of DNA synthesis, affects killing, and find that hydroxyurea significantly attenuates killing by streptomycin. We find that the hydroxyl radical scavengers d-mannitol and thiourea have either no effect or only a modest protective effect. The iron chelator 2,2'-dipyridyl eliminated killing by streptomycin, but further investigation revealed that it blocks streptomycin uptake. Prior treatment of cells with low-levels of methyl methanesulfonate to induce the adaptive response to alkylation leads to a significant attenuation of killing, which, together with the hydroxyurea effect, suggests roles for DNA replication and repair functions in cell killing by streptomycin.
authors: Department of Microbiology and Molecular Genetics, Rutgers New Jersey Medical School, 225 Warren Street, Newark, NJ 07107, United States. Electronic address: humayun@rutgers.edu.
authors: M Zafri
authors: MZ
authors: Humayun
authors: Vasudevan
authors: V
authors: Ayyappan
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004256:DNA Polymerase I / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects / Q000235:genetics; D030781:Organisms, Genetically Modified; D013307:Streptomycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D004256:DNA Polymerase I; D013307:Streptomycin
keywords: Antibiotic uptake; DNA alkylation damage; DNA replication and repair; Dipyridyl; Hydroxyl radicals; Mistranslation; alkB
references: J Biol Chem. 2002 Nov 29;277(48):46319-27
references: 12324458
references: Mutat Res. 2004 Apr 14;548(1-2):9-18
references: 15063131
references: Science. 2013 Mar 8;339(6124):1210-3
references: 23471409
references: J Biochem Mol Biol. 2002 May 31;35(3):297-301
references: 12297013
references: Mol Cell. 2009 Dec 11;36(5):845-60
references: 20005847
references: Mol Microbiol. 1999 May;32(3):607-15
references: 10320582
references: Science. 1988 Apr 29;240(4852):640-2
references: 2834821
references: BMC Microbiol. 2009 Sep 03;9:186
references: 19728878
references: J Phys Chem A. 2007 May 10;111(18):3465-79
references: 17439193
references: Mol Microbiol. 1999 Aug;33(4):732-40
references: 10447883
references: Cell. 2007 Sep 7;130(5):797-810
references: 17803904
references: J Bacteriol. 1961 Jun;81:918-23
references: 13725528
references: Nature. 1960 Jan 2;185:22-3
references: 13793255
references: Mutat Res. 2001 Jan 25;490(1):21-6
references: 11152968
references: J Bacteriol. 2000 Mar;182(5):1427-31
references: 10671469
references: Science. 2013 Mar 8;339(6124):1213-6
references: 23471410
references: J Bacteriol. 1996 Sep;178(17):5105-11
references: 8752326
references: Nature. 1959 Feb 28;183(4661):618-9
references: 13632818
references: Jpn J Cancer Res. 2001 Nov;92(11):1166-74
references: 11714440
references: Science. 1988 Jun 3;240(4857):1302-9
references: 3287616
references: Carcinogenesis. 1997 Aug;18(8):1561-7
references: 9276631
references: J Mol Biol. 2009 Jul 31;390(5):845-62
references: 19467244
references: J Bacteriol. 2002 Mar;184(5):1407-16
references: 11844771
references: Nature. 2002 Sep 12;419(6903):174-8
references: 12226667
references: Br Med J. 1948 Feb 28;1(4547):382-6
references: 18905256
references: PLoS Biol. 2008 Dec 16;6(12):e319
references: 19090622
references: Mol Gen Genet. 1977 Nov 29;157(1):1-9
references: 414071
references: Genes Dev. 2000 Aug 15;14(16):2097-105
references: 10950872
references: J Bacteriol. 1999 Feb;181(3):1043-4
references: 9922274
references: Antimicrob Agents Chemother. 2012 Jun;56(6):3216-23
references: 22391551
references: J Bacteriol. 1997 Dec;179(23):7507-14
references: 9393717
references: J Bacteriol. 1986 May;166(2):519-27
references: 3516975
references: Cell. 2008 Nov 14;135(4):679-90
references: 19013277
references: Microbiol Rev. 1987 Sep;51(3):341-50
references: 3312985
references: Mutat Res. 2012 Jul 1;735(1-2):46-50
references: 22677460
references: J Mol Biol. 2002 Jan 25;315(4):513-27
references: 11812126
references: DNA Repair (Amst). 2007 Apr 1;6(4):429-42
references: 17112791
references: Biometals. 2007 Jun;20(3-4):485-99
references: 17216355
references: J Bacteriol. 1993 Nov;175(22):7363-72
references: 8226684
references: J Bacteriol. 1972 Dec;112(3):1321-4
references: 4565541
references: J Bacteriol. 1945 Dec;50(6):651-4
references: 16561041
references: Annu Rev Biochem. 1988;57:133-57
references: 3052269
references: Ren Fail. 1999 May-Jul;21(3-4):433-42
references: 10416224
references: Biochim Biophys Acta. 1965 Jan 11;95:181-3
references: 14289027
references: DNA Repair (Amst). 2013 Mar 1;12(3):188-95
references: 23276627
references: Proc Natl Acad Sci U S A. 1964 Apr;51:703-9
references: 14166778
references: J Bacteriol. 2003 Aug;185(16):5015-8
references: 12897024
references: Clin Orthop Relat Res. 2005 Aug;(437):3-6
references: 16056018
references: J Antimicrob Chemother. 2010 Mar;65(3):520-4
references: 20067982
references: Mol Microbiol. 2006 Dec;62(6):1752-63
references: 17427291
references: Antimicrob Agents Chemother. 1976 Jun;9(6):928-38
references: 820248
references: Carcinogenesis. 1996 Oct;17(10):2105-11
references: 8895475
references: Mol Microbiol. 2002 Apr;44(1):131-41
references: 11967074
references: Nature. 1977 May 19;267(5608):281-3
references: 325420
references: Antimicrob Agents Chemother. 2007 Mar;51(3):1119-22
references: 17210778
references: J Biol Chem. 1986 Sep 25;261(27):12472-6
references: 3017976