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ACS Infect Dis. 2018 Oct 12;4(10):1508-1518. doi: 10.1021/acsinfecdis.8b00136. Epub 2018 Aug 15.

GW779439X and Its Pyrazolopyridazine Derivatives Inhibit the Serine/Threonine Kinase Stk1 and Act As Antibiotic Adjuvants against β-Lactam-Resistant Staphylococcus aureus.

Author information

1
Department of Medical Microbiology and Immunology , University of Wisconsin-Madison , 1550 Linden Drive , Madison , Wisconsin 53706 , United States.
2
Department of Medicine , University of Wisconsin-Madison , 1685 Highland Avenue , Madison , Wisconsin 53706 , United States.
3
UNC Eshelman School of Pharmacy, SGC Center for Chemical Biology , University of North Carolina at Chapel Hill , 120 Mason Farm Road , Chapel Hill , North Carolina 27599 , United States.
4
School of Pharmacy , University of Wisconsin-Madison , 777 Highland Avenue , Madison , Wisconsin 53705 , United States.
5
Department of Medicine , W. S. Middleton Memorial Veteran's Hospital , 2500 Overlook Terrace , Madison , Wisconsin 53705 , United States.

Abstract

As antibiotic resistance rises, there is a need for strategies such as antibiotic adjuvants to conserve already-established antibiotics. A family of bacterial kinases known as the penicillin-binding-protein and serine/threonine kinase-associated (PASTA) kinases has attracted attention as targets for antibiotic adjuvants for β-lactams. Here, we report that the pyrazolopyridazine GW779439X sensitizes methicillin-resistant Staphylococcus aureus (MRSA) to various β-lactams through inhibition of the PASTA kinase Stk1. GW779439X potentiates β-lactam activity against multiple MRSA and MSSA isolates, including the sensitization of a ceftaroline-resistant isolate to ceftaroline. In silico modeling was used to guide the synthesis of GW779439X derivatives. The presence and orientation of GW779439X's methylpiperazine moiety was crucial for robust biochemical and microbiologic activity. Taken together, our data provide a proof of concept for developing the pyrazolopyridazines as selective Stk1 inhibitors which act across S. aureus isolates.

KEYWORDS:

MRSA; PASTA kinase; antibiotic; drug discovery; pyrazolopyridazine; β-lactam

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