From Antihistamine to Anti-infective: Loratadine Inhibition of Regulatory PASTA Kinases in Staphylococci Reduces Biofilm Formation and Potentiates β-Lactam Antibiotics and Vancomycin in Resistant Strains of Staphylococcus aureus.,ACS Infectious Diseases

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From Antihistamine to Anti-infective: Loratadine Inhibition of Regulatory PASTA Kinases in Staphylococci Reduces Biofilm Formation and Potentiates β-Lactam Antibiotics and Vancomycin in Resistant Strains of Staphylococcus aureus.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2019-06-07 , DOI: 10.1021/acsinfecdis.9b00096
Nicholas Cutrona ₁ , Kyra Gillard ₁ , Rebecca Ulrich ₁ , Mikaela Seemann ₁ , Heather B Miller ₁ , Meghan S Blackledge ₁

Affiliation

Staphylococcus epidermidis and Staphylococcus aureus are important human pathogens responsible for two-thirds of all postsurgical infections of indwelling medical devices. Staphylococci form robust biofilms that provide a reservoir for chronic infection, and antibiotic-resistant isolates are increasingly common in both healthcare and community settings. Novel treatments that can simultaneously inhibit biofilm formation and antibiotic-resistance pathways are urgently needed to combat the increasing rates of antibiotic-resistant infections. Herein we report that loratadine, an FDA-approved antihistamine, significantly inhibits biofilm formation in both S. aureus and S. epidermidis. Furthermore, loratadine potentiates β-lactam antibiotics in methicillin-resistant strains of S. aureus and potentiates both β-lactam antibiotics and vancomycin in vancomycin-resistant strains of S. aureus. Additionally, we elucidate loratadine's mechanism of action as a novel inhibitor of the regulatory PASTA kinases Stk and Stk1 in S. epidermidis and S. aureus, respectively. Finally, we describe how Stk1 inhibition affects the expression of genes involved in both biofilm formation and antibiotic resistance in S. epidermidis and S. aureus.

中文翻译：

从抗组胺药到抗感染药：氯雷他定抑制葡萄球菌中的PASTA激酶可减少生物膜形成并增强金黄色葡萄球菌耐药菌株中的β-内酰胺抗生素和万古霉素。

表皮葡萄球菌和金黄色葡萄球菌是重要的人类病原体，占留置医疗器械术后所有感染的三分之二。葡萄球菌形成坚固的生物膜，可为慢性感染提供储存，在医疗保健和社区环境中，耐药菌分离株越来越普遍。迫切需要能够同时抑制生物膜形成和抗生素耐药性途径的新疗法，以对抗抗生素耐药性感染率的上升。在本文中，我们报道氯雷他定是一种FDA批准的抗组胺药，可显着抑制金黄色葡萄球菌和表皮葡萄球菌的生物膜形成。此外，氯雷他定增强耐甲氧西林的S菌株中的β-内酰胺抗生素。金黄色葡萄球菌并在耐万古霉素的金黄色葡萄球菌菌株中增强β-内酰胺抗生素和万古霉素。此外，我们阐明了氯雷他定的作用机理，分别作为表皮葡萄球菌和金黄色葡萄球菌中调节性PASTA激酶Stk和Stk1的新型抑制剂。最后，我们描述了Stk1抑制如何影响表皮葡萄球菌和金黄色葡萄球菌中与生物膜形成和抗生素抗性有关的基因表达。

更新日期：2019-05-27

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