TY - JOUR
T1 - Kinase inhibitors that increase the sensitivity of methicillin resistant Staphylococcus aureus to β-lactam antibiotics
AU - Vornhagen, Jay
AU - Burnside, Kellie
AU - Whidbey, Christopher
AU - Berry, Jessica
AU - Qin, Xuan
AU - Rajagopal, Lakshmi
N1 - Publisher Copyright:
© 2015 by the authors; licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2015/10/22
Y1 - 2015/10/22
N2 - 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.
AB - 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.
KW - Antibiotics
KW - Inhibition
KW - Mouse
KW - Serine/threonine kinase
KW - Sulfonamides
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U2 - 10.3390/pathogens4040708
DO - 10.3390/pathogens4040708
M3 - Article
AN - SCOPUS:85023186196
VL - 4
SP - 708
EP - 721
JO - Pathogens
JF - Pathogens
SN - 2076-0817
IS - 4
ER -