Large-scale identification and analysis of suppressive drug interactions.
One drug may suppress the effects of another. Although knowledge of drug suppression is vital to avoid efficacy-reducing drug interactions or discover countermeasures for chemical toxins, drug-drug suppression relationships have not been systematically mapped. Here, we analyze the growth response of Saccharomyces cerevisiae to anti-fungal compound ("drug") pairs. Among 440 ordered drug pairs, we identified 94 suppressive drug interactions. Using only pairs not selected on the basis of their suppression behavior, we provide an estimate of the prevalence of suppressive interactions between anti-fungal compounds as 17%. Analysis of the drug suppression network suggested that Bromopyruvate is a frequently suppressive drug and Staurosporine is a frequently suppressed drug. We investigated potential explanations for suppressive drug interactions, including chemogenomic analysis, coaggregation, and pH effects, allowing us to explain the interaction tendencies of Bromopyruvate.
Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul 34956, Turkey; Nanotechnology Research and Application Center, Sabanci University, Istanbul 34956, Turkey. Electronic address: cokol@sabanciuniv.edu.
Murat
M
Cokol
Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul 34956, Turkey; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
Zohar B
ZB
Weinstein
Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul 34956, Turkey; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
Kaan
K
Yilancioglu
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
Murat
M
Tasan
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Allison
A
Doak
Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul 34956, Turkey; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
Dilay
D
Cansever
Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul 34956, Turkey; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
Beste
B
Mutlu
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
Siyang
S
Li
Department of Computational Biology, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT 06877, USA.
Raul
R
Rodriguez-Esteban
Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul 34956, Turkey.
Murodzhon
M
Akhmedov
Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul 34956, Turkey.
Aysegul
A
Guvenek
Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul 34956, Turkey.
Melike
M
Cokol
Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul 34956, Turkey.
Selim
S
Cetiner
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
Guri
G
Giaever
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Ivan
I
Iossifov
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Pharmaceutical Sciences, University of British Columbia, 2405 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
Corey
C
Nislow
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Brian
B
Shoichet
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Center for Cancer Systems Biology, Dana-Farber Cancer Institute, One Jimmy Fund Way, Boston, MA 02215, USA; Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, ON M5G 1X5, Canada; Departments of Molecular Genetics and Computer Science, University of Toronto, Toronto, ON M5S 3E1, Canada. Electronic address: fritz.roth@utoronto.ca.
Frederick P
FP
Roth
D000935:Antifungal Agents / Q000494:pharmacology*; D001681:Biological Assay; D004347:Drug Interactions; D006863:Hydrogen-Ion Concentration; D008826:Microbial Sensitivity Tests; D011773:Pyruvates / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development*; D019311:Staurosporine / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D011773:Pyruvates; C017092:bromopyruvate; D019311:Staurosporine