In Silico Screen and Structural Analysis Identifies Bacterial Kinase Inhibitors which Act with β-Lactams To Inhibit Mycobacterial Growth

Wlodarchak, Nathan; Teachout, Nathan; Beczkiewicz, Jeffrey; Procknow, Rebecca; Schaenzer, Adam J.; Satyshur, Kenneth; Pavelka, Martin; Zuercher, William; Drewry, David; Sauer, John-Demian; Striker, Rob

doi:10.1021/acs.molpharmaceut.8b00905

Title: In Silico Screen and Structural Analysis Identifies Bacterial Kinase Inhibitors which Act with β-Lactams To Inhibit Mycobacterial Growth

Journal Article · 03 October 2018 · Molecular Pharmaceutics

DOI: https://doi.org/10.1021/acs.molpharmaceut.8b00905 · OSTI ID:1544869

^[1]; Teachout, Nathan ^[1]; Beczkiewicz, Jeffrey ^[1]; Procknow, Rebecca ^[1]; Schaenzer, Adam J. ^[1]; Satyshur, Kenneth ^[2]; Pavelka, Martin ^[3];

^[4]; Drewry, David ^[4];

^[1];

^[5]

Univ. of Wisconsin, Madison, WI (United States)
Univ. of Wisconsin, Madison, WI (United States); Carbone Cancer Center, Small Molecule Screening Facility
Univ. of Rochester, NY (United States)
Univ. of North Carolina, Chapel Hill, NC (United States)
Univ. of Wisconsin, Madison, WI (United States); William S. Middleton Memorial Veterans Hospital, Madison, WI (United States)

New tools and concepts are needed to combat antimicrobial resistance. Actinomycetes and firmicutes share several eukaryotic-like Ser/Thr kinases (eSTK) that offer antibiotic development opportunities, including PknB, an essential mycobacterial eSTK. Despite successful development of potent biochemical PknB inhibitors by many groups, clinically useful microbiologic activity has been elusive. Additionally, PknB kinetics are not fully described, nor are structures with specific inhibitors available to inform inhibitor design. We used computational modeling with available structural information to identify human kinase inhibitors predicted to bind PknB, and we selected hits based on drug-like characteristics intended to increase the likelihood of cell entry. The computational model suggested a family of inhibitors, the imidazopyridine aminofurazans (IPAs), bind PknB with high affinity. We performed an in-depth characterization of PknB and found that these inhibitors biochemically inhibit PknB, with potency roughly following the predicted models. A novel X-ray structure confirmed that the inhibitors bound as predicted and made favorable protein contacts with the target. These inhibitors also have antimicrobial activity toward mycobacteria and nocardia. Furthermore, we demonstrated that the inhibitors are uniquely potentiated by β-lactams but not antibiotics traditionally used to treat mycobacteria, consistent with PknB’s role in sensing cell wall stress. This is the first demonstration in the phylum actinobacteria that some β-lactam antibiotics could be more effective if paired with a PknB inhibitor. Collectively, our data show that in silico modeling can be used as a tool to discover promising drug leads, and the inhibitors we discovered can act with clinically relevant antibiotics to restore their efficacy against bacteria with limited treatment options.

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Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: Canada Foundation for Innovation; National Institutes of Health (NIH); USDOE; Wellcome Trust

OSTI ID:: 1544869

Journal Information:: Molecular Pharmaceutics, Journal Name: Molecular Pharmaceutics Journal Issue: 11 Vol. 15; ISSN 1543-8384

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
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Title: In Silico Screen and Structural Analysis Identifies Bacterial Kinase Inhibitors which Act with β-Lactams To Inhibit Mycobacterial Growth

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