EmbB and EmbC regulate the sensitivity of Mycobacterium abscessus to echinomycin
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
Affiliations
Jing He
Institute of Physical Science and Information Technology Anhui University Hefei China
Yamin Gao
State Key Laboratory of Respiratory Disease Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences Guangzhou China
Jingyun Wang
School of Pharmacy, Institute of Marine Drug Guangxi University of Traditional Chinese Medicine Nanning China
H. M. Adnan Hameed
State Key Laboratory of Respiratory Disease Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences Guangzhou China
Shuai Wang
State Key Laboratory of Respiratory Disease Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences Guangzhou China
Cuiting Fang
State Key Laboratory of Respiratory Disease Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences Guangzhou China
Xirong Tian
State Key Laboratory of Respiratory Disease Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences Guangzhou China
Jingran Zhang
State Key Laboratory of Respiratory Disease Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences Guangzhou China
Xingli Han
State Key Laboratory of Respiratory Disease Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences Guangzhou China
Yanan Ju
State Key Laboratory of Respiratory Disease Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences Guangzhou China
Yaoju Tan
State Key Laboratory of Respiratory Disease Guangzhou Chest Hospital Guangzhou China
Junying Ma
CAS Key Laboratory of Tropical Marine Bio‐Resources and Ecology RNAM Center for Marine Microbiology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences Guangzhou China
Jianhua Ju
CAS Key Laboratory of Tropical Marine Bio‐Resources and Ecology RNAM Center for Marine Microbiology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences Guangzhou China
Jinxing Hu
State Key Laboratory of Respiratory Disease Guangzhou Chest Hospital Guangzhou China
Jianxiong Liu
State Key Laboratory of Respiratory Disease Guangzhou Chest Hospital Guangzhou China
Tianyu Zhang
Institute of Physical Science and Information Technology Anhui University Hefei China
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.
