Kinase Inhibitors that Increase the Sensitivity of Methicillin Resistant Staphylococcus aureus to β-Lactam Antibiotics

Pathogens

Jay Vornhagen¹  Kellie Burnside¹  Christopher Whidbey¹  Jessica Berry²  Xuan Qin²  Lakshmi Rajagopal¹ 

[1] Department of Pediatric Infectious Diseases, University of Washington School of Medicine, Seattle, WA 98195, USA; E-Mails:;Seattle Children’s Research Institute, 1900 Ninth Avenue, Seattle, WA 98101, USA; E-Mails:

关键词: serine/threonine kinase;    sulfonamides;    antibiotics;    inhibition;    mouse;   

DOI  :  10.3390/pathogens4040708

来源: mdpi

【 摘 要 】

Staphylococcus aureus are Gram-positive bacteria that are the leading cause of recurrent infections in humans that include pneumonia, bacteremia, osteomyelitis, arthritis, endocarditis, and toxic shock syndrome. The emergence of methicillin resistant S. aureus strains (MRSA) has imposed a significant concern in sustained measures of treatment against these infections. Recently, MRSA strains deficient in expression of a serine/threonine kinase (Stk1 or PknB) were described to exhibit increased sensitivity to β-lactam antibiotics. In this study, we screened a library consisting of 280 drug-like, low-molecular-weight compounds with the ability to inhibit protein kinases for those that increased the sensitivity of wild-type MRSA to β-lactams and then evaluated their toxicity in mice. We report the identification of four kinase inhibitors, the sulfonamides ST085384, ST085404, ST085405, and ST085399 that increased sensitivity of WT MRSA to sub-lethal concentrations of β-lactams. Furthermore, these inhibitors lacked alerting structures commonly associated with toxic effects, and toxicity was not observed with ST085384 or ST085405 in vivo in a murine model. These results suggest that kinase inhibitors may be useful in therapeutic strategies against MRSA infections.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.