Compounds That Select Against the Tetracycline-resistance Efflux Pump

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2016 Sep 20

PMID 27642863

Citations 25

Authors

Laura K Stone

Michael Baym

Tami D Lieberman

Remy Chait

Jon Clardy

Roy Kishony

Affiliations

Soon will be listed here.

Abstract

We developed a competition-based screening strategy to identify compounds that invert the selective advantage of antibiotic resistance. Using our assay, we screened over 19,000 compounds for the ability to select against the TetA tetracycline-resistance efflux pump in Escherichia coli and identified two hits, β-thujaplicin and disulfiram. Treating a tetracycline-resistant population with β-thujaplicin selects for loss of the resistance gene, enabling an effective second-phase treatment with doxycycline.

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References

Alekshun M, Levy S . Molecular mechanisms of antibacterial multidrug resistance. Cell. 2007; 128(6):1037-50. DOI: 10.1016/j.cell.2007.03.004. View

Wright G . Molecular mechanisms of antibiotic resistance. Chem Commun (Camb). 2011; 47(14):4055-61. DOI: 10.1039/c0cc05111j. View

Palmer A, Angelino E, Kishony R . Chemical decay of an antibiotic inverts selection for resistance. Nat Chem Biol. 2010; 6(2):105-7. PMC: 2811317. DOI: 10.1038/nchembio.289. View

Keane T, Wong K, Adams D . RetroSeq: transposable element discovery from next-generation sequencing data. Bioinformatics. 2012; 29(3):389-90. PMC: 3562067. DOI: 10.1093/bioinformatics/bts697. View

Lazar V, Pal Singh G, Spohn R, Nagy I, Horvath B, Hrtyan M . Bacterial evolution of antibiotic hypersensitivity. Mol Syst Biol. 2013; 9:700. PMC: 3817406. DOI: 10.1038/msb.2013.57. View

Langmead B, Salzberg S . Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012; 9(4):357-9. PMC: 3322381. DOI: 10.1038/nmeth.1923. View

Chait R, Shrestha S, Shah A, Michel J, Kishony R . A differential drug screen for compounds that select against antibiotic resistance. PLoS One. 2011; 5(12):e15179. PMC: 2999542. DOI: 10.1371/journal.pone.0015179. View

Merlin T, Davis G, Anderson W, Moyzis R, Griffith J . Aminoglycoside uptake increased by tet gene expression. Antimicrob Agents Chemother. 1989; 33(9):1549-52. PMC: 172700. DOI: 10.1128/AAC.33.9.1549. View

Bochner B, Huang H, Schieven G, Ames B . Positive selection for loss of tetracycline resistance. J Bacteriol. 1980; 143(2):926-33. PMC: 294396. DOI: 10.1128/jb.143.2.926-933.1980. View

10.

Stone G, Zhang Q, Castillo R, Doppalapudi V, Bueno A, Lee J . Mechanism of action of NB2001 and NB2030, novel antibacterial agents activated by beta-lactamases. Antimicrob Agents Chemother. 2004; 48(2):477-83. PMC: 321519. DOI: 10.1128/AAC.48.2.477-483.2004. View

11.

Ejim L, Farha M, Falconer S, Wildenhain J, Coombes B, Tyers M . Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol. 2011; 7(6):348-50. DOI: 10.1038/nchembio.559. View

12.

Hiramatsu K, Igarashi M, Morimoto Y, Baba T, Umekita M, Akamatsu Y . Curing bacteria of antibiotic resistance: reverse antibiotics, a novel class of antibiotics in nature. Int J Antimicrob Agents. 2012; 39(6):478-85. DOI: 10.1016/j.ijantimicag.2012.02.007. View

13.

Phillips M, Malloy G, Nedunchezian D, Lukrec A, HOWARD R . Disulfiram inhibits the in vitro growth of methicillin-resistant staphylococcus aureus. Antimicrob Agents Chemother. 1991; 35(4):785-7. PMC: 245102. DOI: 10.1128/AAC.35.4.785. View

14.

Lutz R, Bujard H . Independent and tight regulation of transcriptional units in Escherichia coli via the LacR/O, the TetR/O and AraC/I1-I2 regulatory elements. Nucleic Acids Res. 1997; 25(6):1203-10. PMC: 146584. DOI: 10.1093/nar/25.6.1203. View

15.

Chopra I, Roberts M . Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev. 2001; 65(2):232-60 ; second page, table of contents. PMC: 99026. DOI: 10.1128/MMBR.65.2.232-260.2001. View

16.

Chait R, Craney A, Kishony R . Antibiotic interactions that select against resistance. Nature. 2007; 446(7136):668-71. DOI: 10.1038/nature05685. View

17.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

18.

Katayama Y, Ito T, Hiramatsu K . A new class of genetic element, staphylococcus cassette chromosome mec, encodes methicillin resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 2000; 44(6):1549-55. PMC: 89911. DOI: 10.1128/AAC.44.6.1549-1555.2000. View

19.

Lenski R, Simpson S, Nguyen T . Genetic analysis of a plasmid-encoded, host genotype-specific enhancement of bacterial fitness. J Bacteriol. 1994; 176(11):3140-7. PMC: 205481. DOI: 10.1128/jb.176.11.3140-3147.1994. View

20.

Imamovic L, Sommer M . Use of collateral sensitivity networks to design drug cycling protocols that avoid resistance development. Sci Transl Med. 2013; 5(204):204ra132. DOI: 10.1126/scitranslmed.3006609. View