MAB_2355c Confers Macrolide Resistance in Mycobacterium abscessus by Ribosome Protection

Guo, Qi; Zhang, Yongjie; Fan, Junsheng; Zhang, Haonan; Zhang, Zhemin; Li, Bing; Chu, Haiqing

doi:10.1128/aac.00330-21

Cited by 11 publications

(8 citation statements)

References 33 publications

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“…Among the genes regulated by Lsr2 in both Mabs-S and Mabs-R, we have identified four genes ( eis2, MAB_1409c, MAB_2355 c, and erm41 ) encoding proteins modifying the activity of aminoglycoside and macrolide antibiotic families, both widely used in the clinical treatment of M. abscessus ( 9 , 48 – 53 ). Our RNA-seq data show that Lsr2 activates these antimicrobial resistance genes, exhibiting higher expression in wild-type strains ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Lsr2, a pleiotropic regulator at the core of the infectious strategy of Mycobacterium abscessus

Gerges,

Rodríguez-Ordoñez,

Durand

et al. 2024

Microbiol Spectr

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Mycobacterium abscessus is a non-tuberculous mycobacterium, causing lung infections in cystic fibrosis patients. During pulmonary infection, M. abscessus switches from smooth (Mabs-S) to rough (Mabs-R) morphotypes, the latter being hyper-virulent. Previously, we isolated the lsr2 gene as differentially expressed during S-to-R transition. lsr2 encodes a pleiotropic transcription factor that falls under the superfamily of nucleoid-associated proteins. Here, we used two functional genomic methods, RNA-seq and chromatin immunoprecipitation-sequencing (ChIP-seq), to elucidate the molecular role of Lsr2 in the pathobiology of M. abscessus . Transcriptomic analysis shows that Lsr2 differentially regulates gene expression across both morphotypes, most of which are involved in several key cellular processes of M. abscessus , including host adaptation and antibiotic resistance. These results were confirmed through quantitative real-time PCR, as well as by minimum inhibitory concentration tests and infection tests on macrophages in the presence of antibiotics. ChIP-seq analysis revealed that Lsr2 extensively binds the M. abscessus genome at AT-rich sequences and appears to form long domains that participate in the repression of its target genes. Unexpectedly, the genomic distribution of Lsr2 revealed no distinctions between Mabs-S and Mabs-R, implying more intricate mechanisms at play for achieving target selectivity. IMPORTANCE Lsr2 is a crucial transcription factor and chromosome organizer involved in intracellular growth and virulence in the smooth and rough morphotypes of Mycobacterium abscessus . Using RNA-seq and chromatin immunoprecipitation-sequencing (ChIP-seq), we investigated the molecular role of Lsr2 in gene expression regulation along with its distribution on M. abscessus genome. Our study demonstrates the pleiotropic regulatory role of Lsr2, regulating the expression of many genes coordinating essential cellular and molecular processes in both morphotypes. In addition, we have elucidated the role of Lsr2 in antibiotic resistance both in vitro and in vivo , where lsr2 mutant strains display heightened sensitivity to antibiotics. Through ChIP-seq, we reported the widespread distribution of Lsr2 on M. abscessus genome, revealing a direct repressive effect due to its extensive binding on promoters or coding sequences of its targets. This study unveils the significant regulatory role of Lsr2, intricately intertwined with its function in shaping the organization of the M. abscessus genome.

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Section: Resultsmentioning

confidence: 99%

Lsr2, a pleiotropic regulator at the core of the infectious strategy of Mycobacterium abscessus

Gerges,

Rodríguez-Ordoñez,

Durand

et al. 2024

Microbiol Spectr

View full text Add to dashboard Cite

show abstract

“…Among the genes regulated by Lsr2 in both Mabs-S and Mabs-R, we have identified four genes ( eis2, MAB_1409c, MAB_2355c and erm41 ) encoding proteins modifying the activity of aminoglycosides and macrolides antibiotics families, both widely used in the clinical treatment of M. abscessus (9, 48–53). Our RNA-seq data shows that Lsr2 activates these antimicrobial resistance genes, exhibiting higher expression in wild-type strains ( Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

Lsr2, a pleiotropic regulator at the core of the infectious strategy ofMycobacterium abscessus

Gerges,

del Pilar Rodríguez-Ordoñez,

Durand

et al. 2023

Preprint

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Mycobacterium abscessusis a non-tuberculous mycobacterium, causing lung infections in cystic fibrosis patients. During pulmonary infection,M. abscessusswitches from smooth (Mabs-S) to rough (Mabs-R) morphotypes, the latter being hyper-virulent. Previously, we isolated thelsr2gene as differentially expressed during S-to-R transition.lsr2encodes a pleiotropic transcription factor that falls under the superfamily of nucleoid-associated proteins (NAPs). Here, we used two functional genomics methods, RNA-seq and ChIP-seq, to elucidate the molecular role of Lsr2 in the pathobiology ofM. abscessus. Transcriptomic analysis shows that Lsr2 differentially regulates gene expression across both morphotypes, most of which are involved in several key cellular processes ofM. abscessus, including host adaptation and antibiotic resistance. These results were confirmed through RT-qPCR, as well as by minimum inhibitory concentration (MIC) tests and infection tests on macrophages in the presence of antibiotics. ChIP-seq analysis revealed that Lsr2 extensively binds theM. abscessusgenome at AT-rich sequences and appears to form long domains that participate in the repression of its target genes. Unexpectedly, the genomic distribution of Lsr2 revealed no distinctions between Mabs-S and Mabs-R, implying more intricate mechanisms at play for achieving target selectivity.IMPORTANCELsr2 is a crucial transcription factor and chromosome organizer involved in intracellular growth and virulence in the smooth and rough morphotypes ofMycobacterium abscessus(Mabs). Using RNA-seq and ChIP-seq, we investigated the molecular role of Lsr2 in gene expression regulation along with its distribution on Mabs genome. Our study demonstrates the pleiotropic regulatory role of Lsr2, regulating the expression of many genes coordinating essential cellular and molecular processes in both morphotypes. In addition, we have elucidated the role of Lsr2 in antibiotic resistance bothin vitroandin vivo, wherelsr2mutant strains display heightened sensitivity to antibiotics. Through ChIP-seq, we reported the widespread distribution of Lsr2 on Mabs genome, revealing a direct repressive effect due to its extensive binding on promoters or coding sequences of its targets. This study unveils the significant regulatory role of Lsr2, intricately intertwined with its function in shaping the organization of the Mabs genome.

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“…Their mode of action involves binding to the 50S ribosomal subunit in bacteria, which results in the inhibition of protein synthesis ( Dinos, 2017 ). Macrolides remain the core drugs for treating Mab infections ( Guo et al, 2021 ). In certain NTMs, exposure to macrolides triggers the production of specific enzymes that modify the drug’s target binding site.…”

Section: Mechanisms Of Mab Resistance To Current A...mentioning

confidence: 99%

“…More recently, Guo et al identified another macrolide-resistant gene in Mab . The gene MAB_2355c exhibits ATP hydrolysis activity and contributes to macrolide resistance by protecting ribosomes ( Guo et al, 2021 ). Expression of MAB_2355c mRNA is significantly upregulated after exposure to macrolides compared to other ribosome-targeting antibiotics.…”

Section: Mechanisms Of Mab Resistance To Current A...mentioning

confidence: 99%

Exploring antibiotic resistance mechanisms in Mycobacterium abscessus for enhanced therapeutic approaches

Nguyen,

Heo,

Jeon

et al. 2024

Front. Microbiol.

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Mycobacterium abscessus, a leading cause of severe lung infections in immunocompromised individuals, poses significant challenges for current therapeutic strategies due to resistance mechanisms. Therefore, understanding the intrinsic and acquired antibiotic resistance of M. abscessus is crucial for effective treatment. This review highlights the mechanisms employed by M. abscessus to sustain antibiotic resistance, encompassing not only conventional drugs but also newly discovered drug candidates. This comprehensive analysis aims to identify novel entities capable of overcoming the notorious resistance exhibited by M. abscessus, providing insights for the development of more effective therapeutic interventions.

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MAB_2355c Confers Macrolide Resistance in Mycobacterium abscessus by Ribosome Protection

Cited by 11 publications

References 33 publications

Lsr2, a pleiotropic regulator at the core of the infectious strategy of Mycobacterium abscessus

Lsr2, a pleiotropic regulator at the core of the infectious strategy of Mycobacterium abscessus

Lsr2, a pleiotropic regulator at the core of the infectious strategy ofMycobacterium abscessus

Exploring antibiotic resistance mechanisms in Mycobacterium abscessus for enhanced therapeutic approaches

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