[NMR paper] NMR Structure-Based Optimization of Staphylococcus aureus Sortase A Pyridazinone Inhibitors.

[nmrlearner]

NMR Structure-Based Optimization of Staphylococcus aureus Sortase A Pyridazinone Inhibitors.

Related Articles NMR Structure-Based Optimization of Staphylococcus aureus Sortase A Pyridazinone Inhibitors.

Chem Biol Drug Des. 2017 Feb 03;:

Authors: Chan AH, Yi SW, Weiner EM, Amer BR, Sue CK, Wereszczynski J, Dillen CA, Senese S, Torres JZ, Andrew McCammon J, Miller LS, Jung ME, Clubb RT

Abstract
Staphylococcus aureus is a leading cause of hospital-acquired infections in the United States and is a major health concern as methicillin-resistant S. aureus (MRSA) 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 analogs 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 analogs 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. This article is protected by copyright. All rights reserved.


PMID: 28160417 [PubMed - as supplied by publisher]



More...