Strynadka, Natalie

Research Interest

Resistance to standard antibiotic therapies to treat disease is a global health concern. Certain infections that are essentially untreatable have been identified in both hospital and community settings. The increasing frequency of drug resistance has been attributed to a combination of antibiotic over-prescription and societal and technologic changes that affect the transmission of drug-resistant organisms.

The ultimate goal of the research in our laboratory is the structure-based design of novel, therapeutically useful antibiotics and inhibitors of antibiotic-resistance mechanisms. To achieve this goal of capturing atomic resolution information, and the functional and mechanistic implications therein, we use a combination of x-ray crystallography, cryo electron microscopy, cryo-electron tomography, molecular modelling, and molecular biology in collaboration with medicinal chemists to design drugs that specifically interact with and disable critical bacterial target proteins. Specific areas of interest include several complex membrane nanomachines that underly bacterial pathogenicity and subsequent disease. Membrane proteins are amongst the most challenging protein class to study at the atomic level, and our multivalent structural biology toolbox allow us to do so in our antimicrobial therapeutic development research aims.

• Blocking antibiotic resistance – We aim to preserve action of the cherished, still most-oft used clinically beta-lactam antibiotics (penicillin/cephalosporin) by characterizing and inhibiting antibiotic resistance mechanisms clinical pathogens have acquired to disarm them. Our laboratory has used state of the art structural biology methods and infrastructure including xray crystallography and single particle cryoEM to acquire first to field atomic resolution information on several of the key widely disseminated antibiotic resistance mechanisms in Staphlococcal aureus superbugs such as MRSA, and highly antibiotic resistant Enterobacteraciae. These structures have provided a blueprint to design and implement potent antibacterials in collaboration with the pharmaceutical industry.
• Novel antibiotics and vaccines – targeting membrane secretion assemblies in pathogenic bacteria. Our state of the art toolbox has allowed us to provide first to field atomic structures of massive membrane assemblies bacteria require to transport disease causing proteins into infected human cells.  This includes the 3 MDa, 24 protein Type III secretion system “injectisome”, a syringe shaped nanomachine essential to downstream disease of many of the most prominent Gram negative bacterial pathogens including those responsible for potentially fatal food and water borne disease, hospital acquired (nosocomial) infections and sexually transmitted disease.
• Novel antibiotics – targeting the bacterial cell wall nanomachine. Perhaps one of the most important drugs in history, beta-lactam antibiotics continue to be widely prescribed due to their economy, effectiveness. However resistance to beta-lactam antibiotics,  as above, makes it essential we also reinforce our antibiotic arsenal to fight future drug resistant infections. Beta-lactams target the biosynthesis of the bacterial cell wall, a protective outer barrier essential to ultimate bacterial survival. However, the target of beta-lactams is only one of the dozens of enzymes that create the cell wall, leaving much space for new antibiotic design. Furthermore, many of these enzymes work together as a dynamic nanomachines to “knit” and reinforce the cell wall, and these interactions have as yet not been well characterized or exploited for drug development. Our laboratory has made significant and ongoing contributions to the structure/function characterization and inhibition of this fascinating cell wall factory, a virtual potential health gold mine of new antibiotic development.

Publications

Comprehensive List

• Google Scholar
• Lab Website
• PubMed

Selected Publications

1. Alexander A, Hu J, Worrall L, Vuckovic M, Sobhanifar S, Chaterjee S, Strynadka NCJ. The CryoEM-derived structural basis for BlaR mediated regulation of broad spectrum β-lactam antibiotic resistance in Staphylococcus aureus Nature, (2023)
2. Caveney, NA; Workman SD; Yan R, Atkinson CE, Yu Z & Strynadka NCJ. CryoEM structure of the antibacterial target PBP1b at 3.3 Å resolution Nature: Communications 12:2775 (2021)
3. Lee J, Worrall L, Vuckovic M, Gentile F, Cherkasov A, Paetzel M,Strynadka NCJ. Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site. Nature: Communications 11:5877 (2020)
4. Zeytuni N, Chou HT, Dickey S, Carlson, ML, Nosella, M, Duong F, Otto M, Yu Z, Strynadka NCJ.Molecular warfare: Structural insight into the ATP-driven exporter of modulating peptides essential to pathogenicity and persistence of drug resistant Staphylococcal aureus. Science Advances 6: eabb8219 (2020)
5. Hu J, Worrall LJ, Hong C, Atkinson CE, Vuckovic M, Yu Z, Strynadka NCJ. Cryo-EM snapshots of T3S injectisome needle complex membrane coupling and assembly. Nature: Microbiology 4: 2010-9 (2019)
6. Caveney NA, Caballero G, Voedts H, Niciforovic A, Worrall LJ, Vuckovic M, Fonvielle M, Hugonnet JE, Arthur M, Strynadka NCJ. Structural insight into YcbB-mediated beta-lactam resistance in Escherichia coli. Nature: Communications 10: 1849 (2019)
7. Majewski DD, Worrall LJ, Hong C, Atkinson CE, Vuckovic M, Zu Z, Strynadka NCJ. Cryo-EM structure of the homohexameric T3SS ATPase-central stalk complex reveals rotary ATPase-like asymmetry. Nature: Communications 10: 626 (2019)
8. Workman SD, Worrall LJ, Strynadka NCJ. Crystal structure of an intramembranal phosphatase central to bacterial cell-wall peptidoglycan biosynthesis and lipid recycling. Nature: Communications 20;9(1):1159 (2018)
9. Worrall LJ, Hong C, Vuckovic M, Deng W, Bergeron JR, Majewski DD, Huang RK, Spreter T, Finlay BB, Yu Z, Strynadka NC. Near-atomic-resolution cryo-EM analysis of the Salmonella T3S injectisome basal body. Nature 540; 597-602 (2016)
10. Volkers, G, Worrall, LJ, Kwan, DH, Ching-Ching, Y., L, Baumann, L, Foster, LJ, Withers, SG, Strynadka, NC Structure of human ST8SiaIII sialyltransferase provides insight into cell surface polysialylation. Nature: Struct. Mol. Biol., 22(8):627-35. (2015) 
11. King DT, Worrall LJ, Gruninger R, Strynadka NC. New Delhi metallobeta-lactamase: structural insights into beta-lactam recognition and inhibition. J Am Chem Soc. 134(28):11362-5 (2012)
12. Lovering, A., Lin, L, Sewell, T., Spreter, T., Brown, E., Strynadka, N.C Structure of the bacterial teichoic acid polymerase TagF provides insights into membrane association and catalysis. Nature: Struct. Mol. Biol., 17:582-9, (2010)
13. Zarivach, R., Deng, W., Zuckovic, M., Finlay, B.B., Strynadka, N.C. Structural nalysis of the essential self-cleaving type III secretion proteins EscU and SpaS. Nature, 453(7191):124-7 (2008).
14. Lovering, A., D’Castro, L., Lim, D.C., Strynadka, N.C. Structural Insight Into the Transglycosylation Step of Bacterial Cell Wall Biosynthesis. Science,  315, 1402-5, (2007).
15. Moraes, T., Baines, M., Hancock, R., Strynadka, N.C. Arginine ladder in OprP mediates phosphate-specific transfer across the outer membrane Nature: Structural and Molecular Biology 14:85-7, (2007)
16. Zarivach, R., Vukovic, M., Deng., W., Finlay, B.B, Strynadka.N.C. Structural and biochemical analysis of a prototypical ATPase from the type III secretion system of pathogenic bacteria. Nature: Structural and Molecular Biology 14:131-137, (2007)
17. Yip CK, Kimbrough TG, Felise HB, Vuckovic M, Thomas NA, Pfuetzner RA, Frey EA, Finlay BB, Miller SI, Strynadka N.C. Structural characterization of the molecular platform for type III secretion system assembly. Nature  435:702-7 (2005)
18. Lim D, Strynadka NC. Structural basis for the beta lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nature: Structural Biology 9:870-6 (2002).
19. Lim D, Park HU, De Castro L, Kang SG, Lee HS, Jensen S, Lee KJ, Strynadka NC. Crystal structure and kinetic analysis of beta-lactamase inhibitor protein-II in complex with TEM-1 beta-lactamase. Nature: Structural Biology 8:848-52 (2001)
20. Luo Y, Pfuetzner RA, Mosimann S, Paetzel M, Frey EA, Cherney M, Kim B, Little JW, Strynadka NC. Crystal structure of LexA: a conformational switch for regulation of self-cleavage. Cell 106:585-94 (2001)
21. Crystal structure of enteropathogenic Escherichia coli intimin-receptor complex. Y. Luo, E.A. Frey, R. Pfuetzner, L. Craigh, D. Knoechel, C. Haynes, B.B. Finlay and N.C. Strynadka Nature 405, 1073-1077 (2000)
22. Crystal structure of a bacterial signal peptidase in complex with a beta-lactam inhibitor. M. Paetzel, R.E. Dalbey and N.C. Strynadka Nature 396, 186-90 (1998)