Efficacy of NEMO-binding domain peptide used to treat experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus: an in-vivo study

Chang-Peng Xu,Yong Qi,Lei Huang,Ya Chen,Fa-Zheng Wang,Hong-Tao Sun,Zhuang Cui,Ya-Jun Yang,Qing-Po Yang,Bin Yu

doi:10.1186/s13756-019-0627-y

Abstract

PurposeTreatment of chronic osteomyelitis (bone infection) remains a clinical challenge. Our previous study had demonstrated that NEMO-binding domain (NBD) peptide effectively ameliorates the inhibition of osteoblast differentiation by TNF-α in vitro. In this work, NBD peptide was evaluated in vivo for treating chronic osteomyelitis induced by methicillin-resistant Staphylococcus aureus (MRSA) in a rabbit model.MethodsTibial osteomyelitis was induced in 50 New Zealand white rabbits by tibial canal inoculation of MRSA strain. After 3 weeks, 45 rabbits with osteomyelitis were randomly divided into four groups that correspondingly received the following interventions: 1) Control group (9 rabbits, no treatment); 2) Van group (12 rabbits, debridement and parenteral treatment with vancomycin); 3) NBD + Van group (12 rabbits, debridement and local NBD peptide injection, plus parenteral treatment with vancomycin); 4) NBD group (12 rabbits, debridement and local NBD peptide injection). Blood samples were collected weekly for the measurement of leucocyte count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels. The rabbits in all four groups were sacrificed 6 weeks after debridement; the anti-infective efficacy was evaluated by radiological, histological, and microbiological examination, and promotion of bone remodeling was quantified by micro-CT using the newly formed bone.ResultsExcept two rabbits in the Control group and one in the NBD group that died from severe infection before the end point, the remaining 42 animals (7, 12, 12, 11 in the Control, Van, NBD + Van, and NBD group respectively) were sacrificed 6 weeks after debridement. In general, there was no significant difference in the leucocyte count, and ESR and CRP levels, although there were fluctuations throughout the follow-up period after debridement. MRSA was still detectable in bone tissue samples of all animals. Interestingly, treatment with NBD peptide plus vancomycin significantly reduced radiological and histological severity scores compared to that in other groups. The best therapeutic efficacy in bone defect repair was observed in the NBD peptide + Van group.ConclusionsIn a model of osteomyelitis induced by MRSA, despite the failure in demonstrating antibacterial effectiveness of NBD peptide in vivo, the results suggest antibiotics in conjunction with NBD peptide to possibly have promising therapeutic potential in osteomyelitis.

Highlights

Chronic osteomyelitis is a bone infection with hallmarks of progressive bone necrosis and sequestrum formation [1]
General conditions The clinical signs of infection varied from mild to severe, following induction, and in the one-week follow-up after debridement, two rabbits in the Control group and one in the NFκB essential modulator (NEMO)-binding domain (NBD) group died from severe infection, as confirmed by autopsy
NBD + Van group showed the highest infection clearance rate, there was no significant difference with the Van (P = 0.667) or NBD group (P = 0.214)

Summary

Introduction

Chronic osteomyelitis is a bone infection with hallmarks of progressive bone necrosis and sequestrum formation [1]. Due to the recurrence and chronicity of osteomyelitis, it is often necessary that the infected bone be debrided, tissues reconstructed, and long-term antibiotic therapy administered [2]. The growing incidence of antibiotic-resistant S. aureus strains can explain the recurrent attacks of osteomyelitis in patients undergoing therapy [4]. The cement may act as a foreign body when antibiotics are no longer being released, requiring additional surgery for its removal. Finding new antibiotic substances for antibiotic resistance is expensive and often involves compromised efficacy within short time periods due to the enormous potential of rapid adaptation in microorganisms. “cellular hysteresis” strategy, using the currently available antibiotics, was harnessed to optimize the antibiotic therapy, in order to achieve both enhanced elimination of bacteria and reduced evolution of resistance [6]

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