Activity of the aminoglycoside phosphotransferase APH(3′)-Ia leads to resistance to aminoglycoside antibiotics in pathogenic Gram-negative bacteria, and contributes to the clinical obsolescence of this class of antibiotics. One strategy to rescue compromised antibiotics such as aminoglycosides is targeting the enzymes that confer resistance with small molecules. We demonstrated previously that ePK (eukaryotic protein kinase) inhibitors could inhibit APH enzymes, owing to the structural similarity between these two enzyme families. However, limited structural information of enzyme–inhibitor complexes hindered interpretation of the results. In addition, cross-reactivity of compounds between APHs and ePKs represents an obstacle to their use as aminoglycoside adjuvants to rescue aminoglycoside antibiotic activity. In the present study, we structurally and functionally characterize inhibition of APH(3′)-Ia by three diverse chemical scaffolds, anthrapyrazolone, 4-anilinoquinazoline and PP (pyrazolopyrimidine), and reveal distinctions in the binding mode of anthrapyrazolone and PP compounds to APH(3′)-Ia compared with ePKs. Using this observation, we identify PP derivatives that select against ePKs, attenuate APH(3′)-Ia activity and rescue aminoglycoside antibiotic activity against a resistant Escherichia coli strain. The structures described in the present paper and the inhibition studies provide an important opportunity for structure-based design of compounds to target aminoglycoside phosphotransferases for inhibition, potentially overcoming this form of antibiotic resistance.
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September 2013
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Research Article|
August 09 2013
Structure-guided optimization of protein kinase inhibitors reverses aminoglycoside antibiotic resistance
Peter J. Stogios;
Peter J. Stogios
*Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada, M5G 1L6
†Center for Structural Genomics of Infectious Diseases (CSGID)
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Peter Spanogiannopoulos;
Peter Spanogiannopoulos
‡Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, L8N 3Z5, Canada
∥Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada, L8S 3Z5
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Elena Evdokimova;
Elena Evdokimova
*Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada, M5G 1L6
†Center for Structural Genomics of Infectious Diseases (CSGID)
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Olga Egorova;
Olga Egorova
*Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada, M5G 1L6
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Tushar Shakya;
Tushar Shakya
‡Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, L8N 3Z5, Canada
∥Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada, L8S 3Z5
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Nick Todorovic;
Nick Todorovic
§Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada, L8S 4M1
∥Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada, L8S 3Z5
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Alfredo Capretta;
Alfredo Capretta
§Department of Chemistry and Chemical Biology, McMaster University, Hamilton, Ontario, Canada, L8S 4M1
∥Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada, L8S 3Z5
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Gerard D. Wright;
Gerard D. Wright
‡Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, L8N 3Z5, Canada
∥Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada, L8S 3Z5
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Alexei Savchenko
Alexei Savchenko
1
*Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada, M5G 1L6
†Center for Structural Genomics of Infectious Diseases (CSGID)
1To whom correspondence should be addressed (email alexei.savchenko@utoronto.ca).
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Biochem J (2013) 454 (2): 191–200.
Article history
Received:
March 01 2013
Revision Received:
May 09 2013
Accepted:
June 12 2013
Accepted Manuscript online:
June 12 2013
Citation
Peter J. Stogios, Peter Spanogiannopoulos, Elena Evdokimova, Olga Egorova, Tushar Shakya, Nick Todorovic, Alfredo Capretta, Gerard D. Wright, Alexei Savchenko; Structure-guided optimization of protein kinase inhibitors reverses aminoglycoside antibiotic resistance. Biochem J 1 September 2013; 454 (2): 191–200. doi: https://doi.org/10.1042/BJ20130317
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