Mechanism of Action-based Classification of Antibiotics Using High-content Bacterial Image Analysis

Overview

Journal Mol Biosyst

Publisher Royal Society of Chemistry

Specialties Biochemistry
Molecular Biology

Date 2013 Apr 24

PMID 23609915

Citations 19

Authors

Kelly C Peach

Walter M Bray

Dustin Winslow

Peter F Linington

Roger G Linington

Affiliations

Soon will be listed here.

Abstract

Image-based screening has become a mature field over the past decade, largely due to the detailed information that can be obtained about compound mode of action by considering the phenotypic effects of test compounds on cellular morphology. However, very few examples exist of extensions of this approach to bacterial targets. We now report the first high-throughput, high-content platform for the prediction of antibiotic modes of action using image-based screening. This approach employs a unique feature segmentation and extraction protocol to quantify key size and shape metrics of bacterial cells over a range of compound concentrations, and matches the trajectories of these metrics to those of training set compounds of known molecular target to predict the test compound's mode of action. This approach has been used to successfully predict the modes of action of a panel of known antibiotics, and has been extended to the evaluation of natural products libraries for the de novo prediction of compound function directly from primary screening data.

Citing Articles

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References

Konno H, Matsuya H, Okamoto M, Sato T, Tanaka Y, Yokoyama K . Prodigiosins uncouple mitochondrial and bacterial F-ATPases: evidence for their H+/Cl- symport activity. J Biochem. 1998; 124(3):547-56. DOI: 10.1093/oxfordjournals.jbchem.a022147. View

Diver J, Wise R . Morphological and biochemical changes in Escherichia coli after exposure to ciprofloxacin. J Antimicrob Chemother. 1986; 18 Suppl D:31-41. DOI: 10.1093/jac/18.supplement_d.31. View

Xu J, Kiel M, Golshani A, Chosay J, Aoki H, Ganoza M . Molecular localization of a ribosome-dependent ATPase on Escherichia coli ribosomes. Nucleic Acids Res. 2006; 34(4):1158-65. PMC: 1383619. DOI: 10.1093/nar/gkj508. View

Preller M, Chinthalapudi K, Martin R, Knolker H, Manstein D . Inhibition of Myosin ATPase activity by halogenated pseudilins: a structure-activity study. J Med Chem. 2011; 54(11):3675-85. DOI: 10.1021/jm200259f. View

Klainer A, Perkins R . Surface manifestations of antibiotic-induced alterations in protein synthesis in bacterial cells. Antimicrob Agents Chemother. 1972; 1(2):164-70. PMC: 444186. DOI: 10.1128/AAC.1.2.164. View

Christophe T, Jackson M, Jeon H, Fenistein D, Contreras-Dominguez M, Kim J . High content screening identifies decaprenyl-phosphoribose 2' epimerase as a target for intracellular antimycobacterial inhibitors. PLoS Pathog. 2009; 5(10):e1000645. PMC: 2763345. DOI: 10.1371/journal.ppat.1000645. View

Robson R, BADDILEY J . Morphological changes associated with novobiocin resistance in Bacillus licheniformis. J Bacteriol. 1977; 129(2):1045-50. PMC: 235044. DOI: 10.1128/jb.129.2.1045-1050.1977. View

Cook T, Brown K, Boyle J, Goss W . Bactericidal action of nalidixic acid on Bacillus subtilis. J Bacteriol. 1966; 92(5):1510-4. PMC: 276451. DOI: 10.1128/jb.92.5.1510-1514.1966. View

Falconer S, Czarny T, Brown E . Antibiotics as probes of biological complexity. Nat Chem Biol. 2011; 7(7):415-23. DOI: 10.1038/nchembio.590. View

10.

Watanakunakorn C, Hamburger M . Induction of spheroplasts of Pseudomonas aeruginosa by carbenicillin. Appl Microbiol. 1969; 17(6):935-7. PMC: 377849. DOI: 10.1128/am.17.6.935-937.1969. View

11.

Wright G . Antibiotics: a new hope. Chem Biol. 2012; 19(1):3-10. DOI: 10.1016/j.chembiol.2011.10.019. View

12.

Kiel M, Aoki H, Ganoza M . Identification of a ribosomal ATPase in Escherichia coli cells. Biochimie. 1999; 81(12):1097-108. DOI: 10.1016/s0300-9084(99)00352-1. View

13.

Schulze C, Bray W, Woerhmann M, Stuart J, Lokey R, Linington R . "Function-first" lead discovery: mode of action profiling of natural product libraries using image-based screening. Chem Biol. 2013; 20(2):285-95. PMC: 3584419. DOI: 10.1016/j.chembiol.2012.12.007. View

14.

Silver L . Challenges of antibacterial discovery. Clin Microbiol Rev. 2011; 24(1):71-109. PMC: 3021209. DOI: 10.1128/CMR.00030-10. View

15.

Kohanski M, Dwyer D, Collins J . How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol. 2010; 8(6):423-35. PMC: 2896384. DOI: 10.1038/nrmicro2333. View

16.

Martin R, Jager A, Bohl M, Richter S, Fedorov R, Manstein D . Total synthesis of pentabromo- and pentachloropseudilin, and synthetic analogues--allosteric inhibitors of myosin ATPase. Angew Chem Int Ed Engl. 2009; 48(43):8042-6. DOI: 10.1002/anie.200903743. View

17.

Rodgers F, Tzianabos A, Elliott T . The effect of antibiotics that inhibit cell-wall, protein, and DNA synthesis on the growth and morphology of Legionella pneumophila. J Med Microbiol. 1990; 31(1):37-44. DOI: 10.1099/00222615-31-1-37. View

18.

Peach K, Bray W, Shikuma N, Gassner N, Lokey R, Yildiz F . An image-based 384-well high-throughput screening method for the discovery of biofilm inhibitors in Vibrio cholerae. Mol Biosyst. 2011; 7(4):1176-84. PMC: 8216101. DOI: 10.1039/c0mb00276c. View

19.

Walsh C, Fischbach M . New ways to squash superbugs. Sci Am. 2009; 301(1):44-51. DOI: 10.1038/scientificamerican0709-44. View

20.

Mason D, Power E, Talsania H, Phillips I, Gant V . Antibacterial action of ciprofloxacin. Antimicrob Agents Chemother. 1995; 39(12):2752-8. PMC: 163024. DOI: 10.1128/AAC.39.12.2752. View