Cell membrane components of Brucella melitensis play important roles in the resistance of low-level rifampicin.

Xiaowen Yang,Dongri Piao,Qingmin Wu,Hai Jiang,Tonglei Wu,Guozhong Tian,Wenxiao Liu,Hongyan Zhao,Yuanzhi Wang

doi:10.1371/journal.pntd.0008888

Abstract

Brucella spp. are facultative intracellular pathogens that can persistently colonize host cells and cause the zoonosis- brucellosis. The WHO recommended a treatment for brucellosis that involves a combination of doxycycline, rifampicin, or streptomycin. The aim of this study was to screen rifampicin-resistance related genes by transcriptomic analysis and gene recombination method at low rifampicin concentrations and to predict the major rifampicin- resistance pathways in Brucella spp. The results showed that the MIC value of rifampicin for B. melitensis bv.3 Ether was 0.5 μg / mL. Meanwhile, B. melitensis had an adaptive response to the resistance of low rifampicin in the early stages of growth, while the SNPs changed in the rpoB gene in the late stages of growth when incubated at 37°C with shaking. The transcriptome results of rifampicin induction showed that the functions of significant differentially expressed genes were focused on metabolic process, catalytic activity and membrane and membrane part. The VirB operon, β-resistance genes, ABC transporters, quorum-sensing genes, DNA repair- and replication -related genes were associated with rifampicin resistance when no variations of the in rpoB were detected. Among the VirB operons, VirB7-11 may play a central role in rifampicin resistance. This study provided new insights for screening rifampicin resistance-related genes and also provided basic data for the prevention and control of rifampicin-resistant Brucella isolates.

Highlights

Brucella spp. are facultative intracellular pathogens that can persistently colonize animal host cells and cause the zoonosis- brucellosis
The World Health Organization (WHO) recommended a treatment for brucellosis that involves a combination of doxycycline, rifampicin, or streptomycin
Science Foundation of China were provided by the National Natural Science Foundation of China (NSFC), the receivers were XWY (No 81902105) and QMW (No 31372446)

Summary

Introduction

Brucella spp. are facultative intracellular pathogens that can persistently colonize animal host cells and cause the zoonosis- brucellosis. The main symptoms of brucellosis are fever, sweating, weakness, and joint pain. Severe symptoms will make patients with brucellosis incapacitated. Most diagnosed human brucellosis cases to date have been caused by B. melitensis, B. abortus, B. canis and B. suis. If brucellosis patients are not diagnosed and treated in time, the infection might cause various complications, such as spondylitis, endocarditis, or encephalitis [7]. The number of human brucellosis cases exceeds 500,000 per year worldwide, and the incidence of human brucellosis in some endemic countries exceeds 100 per million [8]. In China, the number of human brucellosis cases in 2018 was 39,296, which was slightly less than that in 2017 (40042 cases). The primary Brucella epidemic strains belonged to B. melitensis biovars 1 and 3 [10], while the main isolates in recent years belonged to B. melitensis biovar 3 [11]

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