Steven M. Johnson, PhD
Associate Professor of Biochemistry & Molecular Biology
- Phone
- (317) 274-2458
- Address
-
635 Barnhill Drive
Medical Science, Room MS0013D
Indianapolis, IN 46202 - PubMed:
Bio
Dr. Johnson has received industrial and academic training in research throughout the preclinical drug discovery and development process, from target identification, validation, and high-throughput screening, to in vitro and in vivo hit-to-lead optimization. Dr. Johnson received his B.Sc. in Chemistry at the University of Victoria. During his undergraduate studies, Dr. Johnson conducted industrial research internships at Boehringer Ingelheim, where he synthesized new drug candidates to target HIV reverse transcriptase and HCV NS3 protease. These early studies sparked his enthusiasm for pursuing a career in medicinal chemistry and biomedical research. Towards this goal, Dr. Johnson then ventured into the protein misfolding and neurodegeneration fields during his Ph.D. graduate studies with Prof. Jeffery Kelly at The Scripps Research Institute, where he synthesized molecules to study and selectively inhibit transthyretin amyloidogenesis. Dr. Johnson continued with protein folding research during his postdoctoral studies with Prof. Arthur Horwich at Scripps/Yale, where he discovered inhibitors of the bacterial HSP60/10 chaperonin system (a.k.a. GroEL/ES) via high-throughput screening of a 700,000 compound library. Afterwards, while at the University of Washington, Dr. Johnson developed inhibitors of calcium-dependent protein kinases from Toxoplasma gondii and Cryptosporidium parvum as part of a multi-institute collaboration focusing on the pharmacological optimization of antibiotics for toxoplasmosis and cryptosporidiosis. Current research in Dr. Johnson’s independent lab expands on his interests and experiences in protein folding and misfolding to investigate targeting protein homeostasis (proteostasis) pathways to develop new infectious disease, neurodegeneration, and anti-cancer therapeutics.
Key Publications
Sivinski, J.; Ngo, D.; Zerio, C.J.; Ambrose, A.J.; Watson, E.R.; Kaneko, L.K.; Kostelic, M.M.; Stevens, M.; Ray, A.M.; Park, Y.; Wu. C.; Hoang, Q.Q.; Zhang, D.D.; Lander, G.C..; Johnson, S.M.; Chapman, E. Allosteric differences dictate GroEL complementation of E. coli. FASEB Journal 2022, 36 (3), e22198. Link to article
Ray, A.M.; Salim, N.; Stevens M.; Chitre, S.; Abdeen, S.; Washburn, A.; Sivinski, J.; O’Hagan, H.M.; Chapman, E.; Johnson, S.M. Exploiting the human HSP60/10 chaperonin system as a chemotherapeutic target for colorectal cancer. Bioorg. Med. Chem. 2021, Jun 15, 40:116129. Link to article.
Stevens, M.; Howe, C.; Ray, A.M.; Washburn, A.; Chitre, S.; Sivinski, J.; Park, Y.; Hoang, Q.Q.; Chapman, E.; Johnson, S. Analogs of nitrofuran antibiotics are potent GroEL/ES inhibitor pro-drugs. Bioorg. Med. Chem. 2020, 28 (22). Link to article
Ambrose, A.J.; Zerio, C.J.; Sivinski, J.; Schmidlin, C.J.; Shi, T.; Ross, A.B.; Widrick, K.J.; Johnson, S.M.; Zhang, D.D.; Chapman, E. A high throughput substrate binding assay reveals hexachlorophene as an inhibitor of the ER-resident HSP70 chaperone GRP78. Bioorg. Med. Chem. Lett. 2019, 29 (14), 1689-1693. Link to Article in PubMed
Washburn, A.; Abdeen, S.; Ovechkina, Y.; Ray, A.M.; Stevens, M.; Chitre, S.; Sivinski, J.; Park, Y.; Johnson, J.; Hoang, Q.Q.; Chapman, E.; Parish, T.; Johnson, S.M. Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB) inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections. Bioorg. Med. Chem. Lett. 2019, 29 (13), 1665-1672. Link to Article in PubMed
Stevens, M.; Abdeen, S.; Salim, N.; Ray, A.M.; Washburn, A.; Chitre, S.; Sivinski, J.; Park, Y.; Hoang, Q.Q.; Chapman, E.; Johnson, S.M. HSP60/10 chaperonin systems are inhibited by a variety of approved drugs, natural products, and known bioactive molecules. Bioorg. Med. Chem. Lett. 2019, 29 (9), 1106-1112. Link to Article in PubMed
Kunkle, T.; Abdeen, S.; Salim, N.; Ray, A.M.; Stevens, M.; Ambrose, A.J.; Victorino, J.; Park, Y.; Hoang, Q.Q.; Chapman, E.; Johnson, S.M. Hydroxybiphenylamide GroEL/ES inhibitors are potent antibacterials against planktonic and biofilm forms of Staphylococcus aureus. J. Med. Chem. 2018, 61 (23), 10651-10664. Link to Article in PubMed
Abdeen, S.; Kunkle, T.; Salim, N.; Ray, A.M.; Mammadova, N.; Summers, C.M.; Stevens, M.; Ambrose, A.J.; Park, Y.; Schultz, P.G.; Horwich, A.L.; Hoang, Q.; Chapman, E.; Johnson, S.M. Sulfonamido-2-arylbenzoxazole GroEL/ES Inhibitors as Potent Antibacterials against Methicillin-Resistant Staphylococcus aureus (MRSA). J. Med. Chem. 2018, 61 (16), 7345-7357. Link to Article in PubMed
Connelly, S.; Mortenson, D.E.; Choi, S.; Wilson, I.A.; Powers, E.T.; Kelly, J.W.; Johnson, S.M. Semi-quantitative models for identifying potent and selective transthyretin amyloidogenesis inhibitors. Bioorg. Med. Chem. Lett. 2017, 27 (15), 3441-3449. Link to Article in PubMed
Abdeen, S.; Salim, N.; Mammadova, N.; Summers, C.M.; Goldsmith-Pestana, K.; McMahon-Pratt, D.; Schultz, P.G.; Horwich, A.L.; Chapman, E.; Johnson, S.M. Targeting the HSP60/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness. Bioorg. Med. Chem. Lett. 2016, 26 (21), 5247-5253. Link to Article in PubMed
Abdeen, S.; Salim, N.; Mammadova, N.; Summers, C.; Frankson, R.; Ambrose, A.J.; Anderson, G.G.; Schultz, P.G.; Horwich, A.L.; Chapman, E.; Johnson, S.M. GroEL/ES inhibitors as potential antibiotics. Bioorg. Med. Chem. Lett. 2016, 26 (13), 3127-3134. Link to Article in PubMed
Johnson, S.M.; Sharif, O.; Mak, P.A.; Wang, H.T.; Engels, I.H.; Brinker, A.; Schultz, P.; Horwich, A.L.; Chapman, E. A biochemical screen for GroEL/GroES inhibitors. Bioorg. Med. Chem. Lett. 2014, 24 (3), 786-789. Link to Article in PubMed
For a complete list of publications, visit PubMed
| Year | Degree | Institution |
|---|---|---|
| 2006 | PhD | Scripps Research Institute |
| 2001 | BSC | University of Victoria |
Exploiting the GroEL/ES chaperonin system as a mechanistically novel antimicrobial target.
The GroEL/ES chaperonin system is a remarkable example of a diverse class of specialized proteins, called molecular chaperones, which help other proteins fold to their native states. As GroEL/ES is ubiquitous, essential, and highly conserved across bacteria, targeting of this chaperonin system represents an exciting strategy for developing mechanistically unique antibacterials. Preliminary studies have indicated that many of our GroEL/ES chaperonin inhibitors also halt the growth of medically-relevant Gram-positive bacteria such as Staphylococcus aureus. Investigations are focused on developing cell-based models to validate the GroEL/ES system as the primary target for antibacterial activity; investigating the selectivity of these molecules for bacterial GroEL relative to the human HSP60 homologue to gauge potential host cell toxicity concerns; and evaluating lead antimicrobials that are well tolerated by mammalian cell lines for their in vivo efficacy in mouse infection models. We are also investigating the applicability of this strategy for targeting pathogens other than bacteria and have found that Trypanosoma brucei parasites are susceptible to many of these inhibitors.
Modulation of molecular chaperones and protein homeostasis for the development of oncology therapeutics.
It is reasonable to believe that subsets of the recently identified GroEL/ES inhibitors might also have modulatory effects on the human homologue, HSP60/10. This poses an exciting possibility for developing chemical probes to study the function of the mammalian chaperonin system in a variety of cancers where the abnormally propagating cells have hijacked HSP60/10 regulation to help circumvent apoptosis (e.g. breast, cervical, ovarian, colon, and prostate). An increasing array of biological processes are being associated with HSP60/10 function, including apoptotic, pro-survival, and metastatic pathways. The role of HSP60/10 in oncogenesis is not clear and may result from cells accumulating HSP60 in the cytosol either with or without mitochondrial release, the latter of which would be naïve, still bearing its N-terminal mitochondrial import sequence. We are developing inhibitors against both naïve and mitochondrial HSP60 to elucidate possible biochemical differences and to help understand the role of each in pathogenesis. As the HSP60/10 chaperonin system is structurally and functionally distinct from the HSP90 and HSP70 chaperones, it represents a mechanistically unique target for pharmacologic exploitation with the potential to synergize with other chemotherapeutic strategies (in particular with HSP90, HSP70, and proteasome inhibitors).
Personnel in the Johnson lab have expertise in chemical, molecular, and cell biology; biochemistry; synthetic/medicinal chemistry; assay development and high-throughput screening; and pharmacological drug development. Researchers in the lab routinely synthesize and characterize small molecule inhibitors and molecular probes; clone, express, purify, and characterize proteins from/in both prokaryotic and eukaryotic organisms; and evaluate compounds in biochemical/biophysical assays and bacterial, parasite, and mammalian cell culture. Dr. Johnson accepts applications on an ongoing basis from prospective technician, graduate (M.Sc. and Ph.D.), and postdoctoral researchers interested in gaining experience in these techniques. The Johnson lab has close collaborations with Dr. Quyen Hoang (an X-ray crystallographer at the IUSM) and Dr. Eli Chapman (a molecular biologist at the University of Arizona, College of Pharmacy) to investigate the structural/functional mechanisms of action of HSP60 (GroEL) inhibitors. The Johnson lab has developed several hundred inhibitors of the bacterial GroEL/ES and human HSP60/10 chaperonin systems, many of which have antibiotic effects against a range of bacteria and parasites, chemotherapeutic effects against colon and breast cancer cells, and low to no toxicity against normal, non-cancerous cells. As there appear to be no labs actively investigating small molecule chaperonin inhibitors for antibiotic, anti-cancer, or other applications, the Johnson lab brings a unique research program and skill sets that will help diversify these fields. Exploiting mechanistically unique therapeutic targets, such as GroEL/ES and HSP60/10 chaperonin systems, will be integral to developing new strategies to combat hard to treat infectious diseases and cancers.