A novel STK1-targeted small-molecule as an “antibiotic resistance breaker” against multidrug-resistant Staphylococcus aureus

Abstract Ser/Thr protein kinase (STK1) plays a critical role in cell wall biosynthesis of and drug resistance in methicillin-resistant Staphylococcus aureus (MRSA). MRSA strains lacking STK1 become susceptible to failing cephalosporins, such as Ceftriaxone and Cefotaxime. STK1, despite being nonesse...

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Autores principales:	Sashi Kant, Shailendra Asthana, Dominique Missiakas, Vijay Pancholi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f30a240abc5a443889f913e743611aae
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spelling	oai:doaj.org-article:f30a240abc5a443889f913e743611aae2021-12-02T11:40:13ZA novel STK1-targeted small-molecule as an “antibiotic resistance breaker” against multidrug-resistant Staphylococcus aureus10.1038/s41598-017-05314-z2045-2322https://doaj.org/article/f30a240abc5a443889f913e743611aae2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05314-zhttps://doaj.org/toc/2045-2322Abstract Ser/Thr protein kinase (STK1) plays a critical role in cell wall biosynthesis of and drug resistance in methicillin-resistant Staphylococcus aureus (MRSA). MRSA strains lacking STK1 become susceptible to failing cephalosporins, such as Ceftriaxone and Cefotaxime. STK1, despite being nonessential protein for MRSA survival, it can serve as an important therapeutic agent for combination therapy. Here, we report a novel small molecule quinazoline compound, Inh2-B1, which specifically inhibits STK1 activity by directly binding to its ATP-binding catalytic domain. Functional analyses encompassing in vitro growth inhibition of MRSA, and in vivo protection studies in mice against the lethal MRSA challenge indicated that at high concentration neither Inh2-B1 nor Ceftriaxone or Cefotaxime alone was able to inhibit the growth of bacteria or protect the challenged mice. However, the growth of MRSA was inhibited, and a significant protection in mice against the bacterial challenge was observed at a micromolar concentration of Ceftriaxone or Cefotaxime in the presence of Inh2-B1. Cell-dependent minimal to no toxicity of Inh2-B1, and its abilities to down-regulate cell wall hydrolase genes and disrupt the biofilm formation of MRSA clearly indicated that Inh2-B1 serves as a therapeutically important “antibiotic-resistance-breaker,” which enhances the bactericidal activity of Ceftriaxone/Cefotaxime against highly pathogenic MRSA infection.Sashi KantShailendra AsthanaDominique MissiakasVijay PancholiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-19 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sashi Kant Shailendra Asthana Dominique Missiakas Vijay Pancholi A novel STK1-targeted small-molecule as an “antibiotic resistance breaker” against multidrug-resistant Staphylococcus aureus
description	Abstract Ser/Thr protein kinase (STK1) plays a critical role in cell wall biosynthesis of and drug resistance in methicillin-resistant Staphylococcus aureus (MRSA). MRSA strains lacking STK1 become susceptible to failing cephalosporins, such as Ceftriaxone and Cefotaxime. STK1, despite being nonessential protein for MRSA survival, it can serve as an important therapeutic agent for combination therapy. Here, we report a novel small molecule quinazoline compound, Inh2-B1, which specifically inhibits STK1 activity by directly binding to its ATP-binding catalytic domain. Functional analyses encompassing in vitro growth inhibition of MRSA, and in vivo protection studies in mice against the lethal MRSA challenge indicated that at high concentration neither Inh2-B1 nor Ceftriaxone or Cefotaxime alone was able to inhibit the growth of bacteria or protect the challenged mice. However, the growth of MRSA was inhibited, and a significant protection in mice against the bacterial challenge was observed at a micromolar concentration of Ceftriaxone or Cefotaxime in the presence of Inh2-B1. Cell-dependent minimal to no toxicity of Inh2-B1, and its abilities to down-regulate cell wall hydrolase genes and disrupt the biofilm formation of MRSA clearly indicated that Inh2-B1 serves as a therapeutically important “antibiotic-resistance-breaker,” which enhances the bactericidal activity of Ceftriaxone/Cefotaxime against highly pathogenic MRSA infection.
format	article
author	Sashi Kant Shailendra Asthana Dominique Missiakas Vijay Pancholi
author_facet	Sashi Kant Shailendra Asthana Dominique Missiakas Vijay Pancholi
author_sort	Sashi Kant
title	A novel STK1-targeted small-molecule as an “antibiotic resistance breaker” against multidrug-resistant Staphylococcus aureus
title_short	A novel STK1-targeted small-molecule as an “antibiotic resistance breaker” against multidrug-resistant Staphylococcus aureus
title_full	A novel STK1-targeted small-molecule as an “antibiotic resistance breaker” against multidrug-resistant Staphylococcus aureus
title_fullStr	A novel STK1-targeted small-molecule as an “antibiotic resistance breaker” against multidrug-resistant Staphylococcus aureus
title_full_unstemmed	A novel STK1-targeted small-molecule as an “antibiotic resistance breaker” against multidrug-resistant Staphylococcus aureus
title_sort	novel stk1-targeted small-molecule as an “antibiotic resistance breaker” against multidrug-resistant staphylococcus aureus
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f30a240abc5a443889f913e743611aae
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A novel STK1-targeted small-molecule as an “antibiotic resistance breaker” against multidrug-resistant Staphylococcus aureus

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