title: Resolution of gene regulatory conflicts caused by combinations of antibiotics.
abstract: Regulatory conflicts occur when two signals that individually trigger opposite cellular responses are present simultaneously. Here, we investigate regulatory conflicts in the bacterial response to antibiotic combinations. We use an Escherichia coli promoter-GFP library to study the transcriptional response of many promoters to either additive or antagonistic drug pairs at fine two-dimensional (2D) resolution of drug concentration. Surprisingly, we find that this data set can be characterized as a linear sum of only two principal components. Component one, accounting for over 70% of the response, represents the response to growth inhibition by the drugs. Component two describes how regulatory conflicts are resolved. For the additive drug pair, conflicts are resolved by linearly interpolating the single drug responses, while for the antagonistic drug pair, the growth-limiting drug dominates the response. Importantly, for a given drug pair, the same conflict resolution strategy applies to almost all genes. These results provide a recipe for predicting gene expression responses to antibiotic combinations.
authors: Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors: Tobias
authors: T
authors: Bollenbach
authors: Roy
authors: R
authors: Kishony
references: Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19484-9
references: 17148599
references: Science. 2008 Dec 5;322(5907):1511-6
references: 19023046
references: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17025-30
references: 12482953
references: Curr Opin Microbiol. 2008 Apr;11(2):161-7
references: 18373943
references: FEMS Microbiol Rev. 2009 Jul;33(4):704-17
references: 19207742
references: Mol Biol Cell. 2008 Jan;19(1):352-67
references: 17959824
references: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7702-7
references: 12805558
references: BMC Genomics. 2008 Jul 18;9:341
references: 18638364
references: Mol Cell Proteomics. 2005 Oct;4(10):1569-90
references: 16030008
references: Appl Environ Microbiol. 2004 Apr;70(4):2354-66
references: 15066832
references: Arzneimittelforschung. 1953 Jun;3(6):285-90
references: 13081480
references: Cell. 2006 Mar 24;124(6):1225-39
references: 16564013
references: BMC Microbiol. 2006 Apr 28;6:39
references: 16646962
references: Cell. 2009 Aug 21;138(4):774-86
references: 19703402
references: Nature. 2010 Sep 9;467(7312):167-73
references: 20829787
references: Nature. 2010 Sep 2;467(7311):82-5
references: 20811456
references: Nat Rev Microbiol. 2010 Jun;8(6):423-35
references: 20440275
references: Cell. 2007 Sep 7;130(5):797-810
references: 17803904
references: Nature. 2003 Oct 16;425(6959):686-91
references: 14562095
references: Mol Cell. 2008 Mar 28;29(6):786-92
references: 18374652
references: Antimicrob Agents Chemother. 2008 Sep;52(9):3394-7
references: 18591271
references: Cell. 2010 Mar 5;140(5):643-51
references: 20211134
references: Nature. 2007 Apr 5;446(7136):668-71
references: 17410176
references: Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12541-6
references: 20616060
references: Proc Natl Acad Sci U S A. 2008 Apr 22;105(16):6145-9
references: 18427112
references: Mol Cell. 2009 Dec 11;36(5):845-60
references: 20005847
references: PLoS One. 2008 Jul 23;3(7):e2774
references: 18648612
references: PLoS Comput Biol. 2009 Oct;5(10):e1000545
references: 19851443
references: Curr Opin Microbiol. 2006 Oct;9(5):445-53
references: 16942902
references: Cell. 2009 Nov 13;139(4):707-18
references: 19914165
references: Mol Cell. 2010 Jun 11;38(5):758-67
references: 20434381
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D464-70
references: 18974181
references: J Antibiot (Tokyo). 2010 Aug;63(8):492-8
references: 20606700
references: Mol Syst Biol. 2007;3:85
references: 17332759
references: PLoS Biol. 2008 Dec 16;6(12):e319
references: 19090622
references: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):6043-8
references: 17376875
references: Science. 2005 Dec 9;310(5754):1646-53
references: 16339439
references: Drug Discov Today. 2005 Sep 15;10(18):1245-52
references: 16213417
references: PLoS Genet. 2008 Dec;4(12):e1000307
references: 19096504
references: Science. 2006 Feb 24;311(5764):1113-6
references: 16497924
references: Cell. 2008 Nov 14;135(4):679-90
references: 19013277
references: Mol Syst Biol. 2007;3:91
references: 17353933
references: Science. 2002 Aug 16;297(5584):1183-6
references: 12183631
references: Nat Genet. 2006 Apr;38(4):489-94
references: 16550172
references: Biotechnol Prog. 2002 Jan-Feb;18(1):6-20
references: 11822894
references: Cell. 2000 Jul 7;102(1):109-26
references: 10929718
references: FEBS Lett. 2009 Dec 17;583(24):3974-8
references: 19878679
references: Science. 2010 Nov 19;330(6007):1099-102
references: 21097934
references: Philos Trans R Soc Lond B Biol Sci. 2007 Jul 29;362(1483):1195-200
references: 17360275
references: J Mol Microbiol Biotechnol. 2003;5(2):105-22
references: 12736533
references: Chem Biol. 2004 Sep;11(9):1307-16
references: 15380191
references: Nat Methods. 2006 Aug;3(8):623-8
references: 16862137
references: Nat Rev Genet. 2008 Aug;9(8):583-93
references: 18591982