A novel antimicrobial polymer efficiently treats multidrug-resistant MRSA-induced bloodstream infection.

Xu Chen,Weiyang Lou,Bisha Ding,Weimin Fan,Jun Hong,Jingxing Liu

doi:10.1042/bsr20192354

Xu Chen, Weiyang Lou + Show 4 more

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https://doi.org/10.1042/bsr20192354

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Abstract

The present study aimed to ascertain if polymer 2a, a novel synthesized antimicrobial polyionene, could treat methicillin-resistant Staphylococcus aureus (MRSA)-induced bloodstream infection. The minimum inhibitory concentration (MIC) of polymer 2a against MRSA was detected. A time-kill assay was employed to determine the killing kinetic of polymer 2a. Potential antimicrobial mechanisms of polymer 2a, including membrane disruption and programmed cell death (PCD), were explored. A resistance development assay was introduced to determine the propensity of polymer 2a toward resistance against MRSA. A mouse model of MRSA bacteremia was established to assess in vivo efficacy of polymer 2a. Furthermore, in vivo toxicity of polymer 2a was also evaluated through injection by tail vein. Polymer 2a exhibited more superior antimicrobial activity and faster killing kinetic than the control antibiotics against clinically isolated MRSA strains. Polymer 2a resulted in an obvious leakage of cellular components (concentration more than 1× MIC). mRNA expression of PCD pathway-related gene (recA) was significantly up-regulated in the presence of polymer 2a with low concentration (concentration less than 1× MIC). Repeated use of polymer 2a did not lead to drug resistance. In a MRSA-induced bloodstream infection mouse model, polymer 2a displayed superior therapeutic efficacy with negligible systemic toxicity. Moreover, polymer 2a treatment by tail vein could evidently reduce MRSA counts in blood and major organs and markedly improve living conditions. In conclusion, all these findings presented in this work convincingly suggested that polymer 2a may be a promising therapeutic alternative for treating MRSA-induced infections, especially bloodstream infection.

Highlights

Over the past decades, antimicrobial resistance has posed a serious threat to global health [1,2,3]
Previous results demonstrated that the minimum inhibitory concentration (MIC) value of polymer 2a against methicillin-resistant Staphylococcus aureus (MRSA) 25312 was only 8 μg/ml [13]
We aimed to investigate if polymer 2a could effectively treat bacteremia or systemic infection caused by MRSA

Summary

Introduction

Antimicrobial resistance has posed a serious threat to global health [1,2,3]. A group of pathogens, namely ESKAPE bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species), are responsible for the majority of antibiotic resistance and hospital-acquired infections [4,5]. Among these pathogens, Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) can cause numerous infectious diseases, such as pneumonia, pleuritis, tympanitis, purulent meningitis as well as bloodstream infection [6]. MRSA-induced bacteremia has been one of the most urgent global issues because of its high rate of treatment failure, leading to an overall mortality of 10–30% [7] Such high rates of treatment failure and death may be attributed to the lack of effective therapeutic agents against MRSA-induced bloodstream infection. Patients with MRSA infections are responsive to vancomycin in general, License 4.0 (CC BY)

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