NMR structure-based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors

Albert H. Chan, Sung Wook Yi, Ethan M. Weiner, Brendan R. Amer, Christopher K. Sue, Jeff Wereszczynski, Carly A. Dillen, Silvia Senese, Jorge Z. Torres, J. Andrew Mccammon, Lloyd S Miller, Michael E. Jung, Robert T. Clubb

Research output: Contribution to journalArticle

Abstract

Staphylococcus aureus is a leading cause of hospital-acquired infections in the USA and is a major health concern as methicillin-resistant S. aureus and other antibiotic-resistant strains are common. Compounds that inhibit the S. aureus sortase (SrtA) cysteine transpeptidase may function as potent anti-infective agents as this enzyme attaches virulence factors to the bacterial cell wall. While a variety of SrtA inhibitors have been discovered, the vast majority of these small molecules have not been optimized using structure-based approaches. Here we have used NMR spectroscopy to determine the molecular basis through which pyridazinone-based small molecules inhibit SrtA. These inhibitors covalently modify the active cysteine thiol and partially mimic the natural substrate of SrtA by inducing the closure of an active site loop. Computational and synthetic chemistry methods led to second-generation analogues that are ~70-fold more potent than the lead molecule. These optimized molecules exhibit broad-spectrum activity against other types of class A sortases, have reduced cytotoxicity, and impair SrtA-mediated protein display on S. aureus cell surface. Our work shows that pyridazinone analogues are attractive candidates for further development into anti-infective agents, and highlights the utility of employing NMR spectroscopy and solubility-optimized small molecules in structure-based drug discovery.

Original languageEnglish (US)
JournalChemical Biology and Drug Design
DOIs
StateAccepted/In press - 2017

Fingerprint

Staphylococcus aureus
Nuclear magnetic resonance
Anti-Infective Agents
Molecules
Cysteine
Magnetic Resonance Spectroscopy
Peptidyl Transferases
Nuclear magnetic resonance spectroscopy
Virulence Factors
Drug Discovery
Methicillin-Resistant Staphylococcus aureus
Cross Infection
Sulfhydryl Compounds
Solubility
Cell Wall
Catalytic Domain
Methicillin
Anti-Bacterial Agents
Cytotoxicity
Health

Keywords

  • Molecular docking
  • Molecular dynamics
  • NMR
  • Protein structure
  • Protein-inhibitor complex
  • Sortase
  • SrtA
  • Staphylococcus aureus
  • Transpeptidase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Chan, A. H., Yi, S. W., Weiner, E. M., Amer, B. R., Sue, C. K., Wereszczynski, J., ... Clubb, R. T. (Accepted/In press). NMR structure-based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors. Chemical Biology and Drug Design. https://doi.org/10.1111/cbdd.12962

NMR structure-based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors. / Chan, Albert H.; Yi, Sung Wook; Weiner, Ethan M.; Amer, Brendan R.; Sue, Christopher K.; Wereszczynski, Jeff; Dillen, Carly A.; Senese, Silvia; Torres, Jorge Z.; Mccammon, J. Andrew; Miller, Lloyd S; Jung, Michael E.; Clubb, Robert T.

In: Chemical Biology and Drug Design, 2017.

Research output: Contribution to journalArticle

Chan, AH, Yi, SW, Weiner, EM, Amer, BR, Sue, CK, Wereszczynski, J, Dillen, CA, Senese, S, Torres, JZ, Mccammon, JA, Miller, LS, Jung, ME & Clubb, RT 2017, 'NMR structure-based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors', Chemical Biology and Drug Design. https://doi.org/10.1111/cbdd.12962
Chan, Albert H. ; Yi, Sung Wook ; Weiner, Ethan M. ; Amer, Brendan R. ; Sue, Christopher K. ; Wereszczynski, Jeff ; Dillen, Carly A. ; Senese, Silvia ; Torres, Jorge Z. ; Mccammon, J. Andrew ; Miller, Lloyd S ; Jung, Michael E. ; Clubb, Robert T. / NMR structure-based optimization of Staphylococcus aureus sortase A pyridazinone inhibitors. In: Chemical Biology and Drug Design. 2017.
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