Deciphering the possible role of MmpL7 efflux pump in SQ109 resistance in Mycobacterium tuberculosis.

IF 4.6 2区 医学 Q1 MICROBIOLOGY
Wei Jing, Fuzhen Zhang, Yuanyuan Shang, Wenhui Shi, Cong Yao, Xuxia Zhang, Naihui Chu, Jie Lu, Jinfeng Yuan
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引用次数: 0

Abstract

Background: SQ109 is a promising candidate drug for the treatment of patients with drug-resistant tuberculosis (DR-TB). The purpose of this study was to investigate the activity of SQ109 against clinical isolates of Mycobacterium tuberculosis (MTB) from patients with multidrug-resistant TB (MDR-TB) and pre-extensively drug-resistant TB (pre-XDR-TB), and to explore new drug-resistant mechanisms of SQ109.

Methods: We evaluated the in vitro activity of SQ109 against clinical isolates from patients with MDR-TB and pre-XDR-TB using minimal inhibitory concentration (MIC) assay. The drug-resistant gene, mmpL3 of SQ109-resistant strains was sequenced, and a quantitative real-time PCR assay was used to analyze 28 efflux pump genes in SQ109-resistant strains without mmpL3 mutations. The role of candidate efflux pumps mmpL5 and mmpL7 on the MIC of SQ109 was evaluated using recombinantly cloned MmpL5 and MmpL7 expressed in Mycobacterium smegmatis.

Results: The MIC90, MIC95 and MIC99 values of SQ109 for 225 clinical isolates of MTB were 0.25 mg/L, 0.5 mg/L and 1.0 mg/L, respectively. Among the pre-XDR strains, six showed resistance to SQ109 despite the absence of gene mutations in mmpL3. In six resistant pre-XDR strains, the MIC of SQ109 decreased with the use of an efflux pump inhibitor, and there was significant upregulation of mmpL5 and mmpL7 in two strains after exposure to SQ109. The presence of MmpL7 in Mycobacterium smegmatis resulted in decreased susceptibility to SQ109, with the MIC increasing from 16 mg/L to 32 mg/L.

Conclusions: Our data demonstrated that SQ109 exhibited excellent levels of in vitro activity against MTB. MmpL7 may be a potential gene for MTB resistance to SQ109, providing a useful target for detecting SQ109 resistance in MTB.

解密 MmpL7 外排泵在结核分枝杆菌 SQ109 抗药性中可能扮演的角色
背景:SQ109是治疗耐药结核病(DR-TB)患者的一种前景看好的候选药物。本研究旨在探讨 SQ109 对耐多药结核病(MDR-TB)和广泛耐药结核病(Pre-XDR-TB)患者临床分离的结核分枝杆菌(MTB)的活性,并探索 SQ109 新的耐药机制:我们使用最小抑菌浓度(MIC)测定法评估了SQ109对MDR-TB和前XDR-TB患者临床分离株的体外活性。对 SQ109 耐药菌株的耐药基因 mmpL3 进行了测序,并使用定量实时 PCR 法分析了无 mmpL3 突变的 SQ109 耐药菌株中的 28 个外排泵基因。利用重组克隆的MmpL5和MmpL7在分枝杆菌中的表达,评估了候选外排泵mmpL5和mmpL7对SQ109 MIC的作用:结果:SQ109对225株临床分离的MTB的MIC90、MIC95和MIC99值分别为0.25 mg/L、0.5 mg/L和1.0 mg/L。在前 XDR 菌株中,尽管 mmpL3 基因没有发生突变,但仍有 6 株对 SQ109 产生耐药性。在六株耐药的前 XDR 菌株中,使用外排泵抑制剂后 SQ109 的 MIC 下降,两株暴露于 SQ109 后 mmpL5 和 mmpL7 显著上调。烟曲霉分枝杆菌中 MmpL7 的存在导致其对 SQ109 的敏感性降低,MIC 从 16 mg/L 升至 32 mg/L:我们的数据表明,SQ109 对 MTB 具有出色的体外活性。MmpL7可能是MTB对SQ109产生耐药性的潜在基因,为检测MTB对SQ109的耐药性提供了一个有用的靶标。
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来源期刊
CiteScore
8.60
自引率
0.00%
发文量
49
审稿时长
>12 weeks
期刊介绍: Annals of Clinical Microbiology and Antimicrobials considers good quality, novel and international research of more than regional relevance. Research must include epidemiological and/or clinical information about isolates, and the journal covers the clinical microbiology of bacteria, viruses and fungi, as well as antimicrobial treatment of infectious diseases. Annals of Clinical Microbiology and Antimicrobials is an open access, peer-reviewed journal focusing on information concerning clinical microbiology, infectious diseases and antimicrobials. The management of infectious disease is dependent on correct diagnosis and appropriate antimicrobial treatment, and with this in mind, the journal aims to improve the communication between laboratory and clinical science in the field of clinical microbiology and antimicrobial treatment. Furthermore, the journal has no restrictions on space or access; this ensures that the journal can reach the widest possible audience.
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