A novel nitro-dexamethasone inhibits agr system activity and improves therapeutic effects in MRSA sepsis models without antibiotics.

Yun Yang,Ling Guo,Zhen Song,Yun Shi,Haibo Li,Hao Zeng,Changzhi Cai,Chao Wei,Liuyang Yang,Hao Gu,Li Gong,Hongwu Sun,Yanan Tong,Quanming Zou

doi:10.1038/srep20307

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) sepsis is a life-threatening medical condition that involves systemic inflammation throughout the body. Glucocorticoids are widely used in combination with antibiotics in the treatment of MRSA sepsis to fight the overwhelming inflammation. Here, we describe the improved anti-inflammatory properties of a nitric oxide (NO)-releasing derivative of dexamethasone, ND8008. ND8008 affected MRSA biofilm formation, caused biofilm cell death, and reduced the effects of virulence factors, such as α-toxin, by inhibiting the activity of the Staphylococcus aureus accessory gene regulator (agr) system. Dosing of mice with ND8008 (127.4 nmol/kg, i.p.) alone greatly reduced the inflammatory response caused by MRSA blood stream infection and considerably increased the survival rate of septic mice. These findings suggest that this novel NO-releasing derivative of dexamethasone ND8008 could be helpful in the treatment of MRSA sepsis.

Highlights

Methicillin-resistant staphylococcus aureus (MRSA) sepsis is a blood infection with staphylococcus bacteria that are resistant to treatment with beta-lactam antibiotics
The structure of ND8008 was confirmed by 1H NMR, 13C NMR, HMBC and NOESY spectra, which are provided in the Supplementary material
The results showed that the release rate of nitric oxide (NO) from ND8008 was much slower than that from isosorbide mononitrate (ISMN) (Fig. 1b)

Summary

Introduction

Methicillin-resistant staphylococcus aureus (MRSA) sepsis is a blood infection with staphylococcus bacteria that are resistant to treatment with beta-lactam antibiotics. Diagnosis and rapid treatment increase the chances of patient survival, the death rate from MRSA sepsis remains greater than 20% due to uncontrolled inflammation and drug resistance. These challenges necessitate investigations of new therapeutic approaches for MRSA sepsis. NO-releasing glucocorticoid derivatives have shown an improved profile of pharmacological activity in terms of either enhanced anti-inflammatory efficacy or reduced side effects[12,13]. A novel NO-releasing derivative of dexamethasone (ND8008) was synthesized in this study, and the protective effect of ND8008 in a model of MRSA sepsis was assessed without the use of antibiotics. In addition to evaluating anti-inflammatory and antibacterial activity, the underlying mechanisms of ND8008 on MRSA sepsis were investigated

Methods

Results

Conclusion