EmbB and EmbC regulate the sensitivity of Mycobacterium abscessus to echinomycin.

IF 4.5 Q1 MICROBIOLOGY mLife Pub Date : 2024-09-30 eCollection Date: 2024-09-01 DOI:10.1002/mlf2.12139
Jing He, Yamin Gao, Jingyun Wang, H M Adnan Hameed, Shuai Wang, Cuiting Fang, Xirong Tian, Jingran Zhang, Xingli Han, Yanan Ju, Yaoju Tan, Junying Ma, Jianhua Ju, Jinxing Hu, Jianxiong Liu, Tianyu Zhang
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Abstract

Treatment of Mycobacterium abscessus (Mab) infections is very challenging due to its intrinsic resistance to most available drugs. Therefore, it is crucial to discover novel anti-Mab drugs. In this study, we explored an intrinsic resistance mechanism through which Mab resists echinomycin (ECH). ECH showed activity against Mab at a minimum inhibitory concentration (MIC) of 2 µg/ml. A ΔembC strain in which the embC gene was knocked out showed hypersensitivity to ECH (MIC: 0.0078-0.0156 µg/ml). The MICs of ECH-resistant strains screened with reference to ΔembC ranged from 0.25 to 1 µg/ml. Mutations in EmbB, including D306A, D306N, R350G, V555I, and G581S, increased the Mab's resistance to ECH when overexpressed in ΔembC individually (MIC: 0.25-0.5 µg/ml). These EmbB mutants, edited using the CRISPR/Cpf1 system, showed heightened resistance to ECH (MIC: 0.25-0.5 µg/ml). The permeability of these Mab strains with edited genes and overexpression was reduced, as evidenced by an ethidium bromide accumulation assay, but it remained significantly higher than that of the parent Mab. In summary, our study demonstrates that ECH exerts potent anti-Mab activity and confirms that EmbB and EmbC are implicated in Mab's sensitivity to ECH. Mutation in EmbB may partially compensate for a loss of EmbC function.

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EmbB 和 EmbC 可调节脓肿分枝杆菌对棘霉素的敏感性。
由于脓肿分枝杆菌(Mab)对大多数现有药物具有内在的抗药性,因此治疗脓肿分枝杆菌(Mab)感染非常具有挑战性。因此,发现新型抗马巴菌药物至关重要。在这项研究中,我们探索了马巴对棘霉素(ECH)产生耐药性的内在机制。在最低抑菌浓度(MIC)为 2 µg/ml 时,ECH 对马巴具有活性。embC基因被敲除的ΔembC菌株对ECH表现出超敏反应(MIC:0.0078-0.0156 µg/ml)。参照 ΔembC 筛选出的耐 ECH 菌株的 MIC 为 0.25 至 1 µg/ml 不等。EmbB中的突变体,包括D306A、D306N、R350G、V555I和G581S,单独在ΔembC中过表达时,会增加Mab对ECH的抗性(MIC:0.25-0.5 µg/ml)。使用 CRISPR/Cpf1 系统编辑的这些 EmbB 突变体对 ECH 的抗性也有所增强(MIC:0.25-0.5 µg/ml)。通过溴化乙锭蓄积试验证明,这些基因经过编辑和过表达的 Mab 株系的渗透性有所降低,但仍明显高于亲本 Mab。总之,我们的研究证明了 ECH 具有强大的抗马巴活性,并证实了 EmbB 和 EmbC 与马巴对 ECH 的敏感性有关。EmbB 的突变可部分弥补 EmbC 功能的缺失。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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