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

Abstract

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.

A screen for kinase inhibitors identifies antimicrobial imidazopyridine aminofurazans as specific inhibitors of the Listeria monocytogenes PASTA kinase PrkA

“…S4 ). Consistent with this, three recent papers have identified small molecule inhibitors of Stk1 that are structurally distinct from the IPAs we identified as PrkA inhibitors ( 41 – 43 ). These data suggest that GSK690693 selectively inhibits the kinase activity of PrkA relative to Stk1 and highlight the possibility of designing non-broad spectrum, pathogen-specific inhibitors.…”

Importance of protein Ser/Thr/Tyr phosphorylation for bacterial pathogenesis

“…Intriguingly, and consistent with the known role of PknB in cell wall homeostasis, these inhibitors were able to significantly potentiate the effect of b-lactams in several types of mycobacteria and in the related Nocardia asteroides [236]. This synergistic concept has also been reported for kinase inhibitors of the nonessential L. monocytogenes PrkA and S. aureus Stk1 Hanks kinases [219,223,[237][238][239][240]. In L. monocytogenes, the broad-spectrum kinase inhibitor staurosporine, as well as some more selective repurposed human kinase inhibitors, was seen to inhibit PrkA activity and sensitize cells to b-lactam drugs [219,237].…”

“…In L. monocytogenes, the broad-spectrum kinase inhibitor staurosporine, as well as some more selective repurposed human kinase inhibitors, was seen to inhibit PrkA activity and sensitize cells to b-lactam drugs [219,237]. Similarly, several studies have identified Stk1-inhibiting molecules from small-molecule libraries that sensitize MRSA S. aureus strains to b-lactams [223,[238][239][240]. Notably, Kant et al optimized a quinazoline-based Stk1-inhibiting molecule (Inh2-B1) that potentiates the bactericidal activity of the cephalosporins ceftriaxone and cefotaxime on drug-resistant S. aureus, both in vitro and in an in vivo septicemia mouse model with negligible cytotoxic side effects [240].…”

Repurposed kinase inhibitors and β-lactams as a novel therapy for antibiotic resistant bacteria

“…While combination therapy is traditionally used for mycobacterial infections, the limited microbiologic activity of previously optimized PknB inhibitors in combination with traditional first line drugs such as isoniazid and ethambutol did not show any potentiation of activity (Lougheed et al, 2011). Previous data from our lab and others demonstrated that genetic deletion or pharmacologic inhibition of PASTA kinases in Listeria monocytogenes and S. aureus increases susceptibility to β-lactams(Pensinger et al, 2014, Vornhagen et al, 2015). Despite β-lactams' general ineffectiveness against mycobacteria (Sotgiu et al, 2016) our decision to pair IPAs with β-lactams based on our previous data in firmicutes demonstrated significant benefit (Fig.…”

“…Despite a clear rationale for PknB inhibitors, compounds with biochemical activity thus far have demonstrated poor microbiologic activity (Chapman, Bouloc et al, 2012, Lougheed, Osborne et al, 2011, Naqvi, Malasoni et al, 2014. Pharmacologic inhibition or genetic deletion of PASTA kinases in Listeria monocytogenes and MRSA sensitizes these bacteria to β-lactam antibiotics, suggesting this strategy may be useful in other pathogenic PASTA-kinase containing bacteria (Pensinger, Aliota et al, 2014, Vornhagen, Burnside et al, 2015.…”