Genomic reconnaissance of clinical isolates of emerging human pathogen Mycobacterium abscessus reveals high evolutionary potential

Choo, Siew Woh; Wee, Wei Yee; Ngeow, Yun Fong; Mitchell, Wayne; Tan, Joon Liang; Wong, George T.F.; Zhao, Yongbing; Xiao, Jingfa

doi:10.1038/srep04061

Cited by 60 publications

(51 citation statements)

References 67 publications

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“…The resulting phylogeny supports the three previously recognized M. abscessus subspecies as monophyletic, consistent with population studies utilizing MLST genotyping (19,21), and the NJH isolates grouped into expected clades consistent with subspecies identifications based on rpoB, hsp65, and erm(41) findings. Our phylogeny is also consistent with previously reported, independent, phylogenomic comparisons (8,20,24,25,44).…”

Section: Clinical and Microbiological Attributes Of Patients And Isolsupporting

confidence: 81%

Genome Sequencing of Mycobacterium abscessus Isolates from Patients in the United States and Comparisons to Globally Diverse Clinical Strains

et al. 2014

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f Nontuberculous mycobacterial infections caused by Mycobacterium abscessus are responsible for a range of disease manifestations from pulmonary to skin infections and are notoriously difficult to treat, due to innate resistance to many antibiotics. Previous population studies of clinical M. abscessus isolates utilized multilocus sequence typing or pulsed-field gel electrophoresis, but high-resolution examinations of genetic diversity at the whole-genome level have not been well characterized, particularly among clinical isolates derived in the United States. We performed whole-genome sequencing of 11 clinical M. abscessus isolates derived from eight U.S. patients with pulmonary nontuberculous mycobacterial infections, compared them to 30 globally diverse clinical isolates, and investigated intrapatient genomic diversity and evolution. Phylogenomic analyses revealed a cluster of closely related U.S. and Western European M. abscessus subsp. abscessus isolates that are genetically distinct from other European isolates and all Asian isolates. Large-scale variation analyses suggested genome content differences of 0.3 to 8.3%, relative to the reference strain ATCC 19977 T . Longitudinally sampled isolates showed very few single-nucleotide polymorphisms and correlated genomic deletion patterns, suggesting homogeneous infection populations. Our study explores the genomic diversity of clinical M. abscessus strains from multiple continents and provides insight into the genome plasticity of an opportunistic pathogen. N ontuberculous mycobacteria (NTM) represent a diverse group of environmental and pathogenic bacteria that are increasing in clinical prevalence in the United States (1) and other countries (2, 3). NTM are thought to be acquired primarily through environmental exposure (4), as they reside in water, biofilms, and soil environments (5, 6), although a few recent studies provide evidence of possible person-to person transmission among individuals with cystic fibrosis (CF) (7,8). Mycobacterium abscessus is the second most clinically prevalent NTM species in pulmonary NTM infections (1, 9, 10), with Mycobacterium avium complex (MAC) being the most prevalent. M. abscessus infections are challenging to treat because they are innately resistant to many antimicrobials, including some that are effective against Mycobacterium tuberculosis and other mycobacteria (11-13). Acquired antibiotic resistance has been observed in some M. abscessus strains, with mechanisms of resistance ranging from mutational resistance to aminoglycosides (14) to mutational (15) and inducible (16) resistance to macrolides.The current taxonomy of M. abscessus recognizes two subspecies, M. abscessus subsp. abscessus and M. abscessus subsp. bolletii (17), although recent population and comparative genomic studies support the three previously recognized subspecies, i.e., M. abscessus subsp. abscessus, M. abscessus subsp. massiliense, and M. abscessus subsp. bolletii (18)(19)(20)(21). This delineation is important because clinical studies suggest diff...

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Section: Clinical and Microbiological Attributes Of Patients And Isolsupporting

confidence: 81%

Genome Sequencing of Mycobacterium abscessus Isolates from Patients in the United States and Comparisons to Globally Diverse Clinical Strains

et al. 2014

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“…This is corroborated by recent comparative genomic studies indicating that M. abscessus evolves rapidly and should be monitored closely for the acquisition of more pathogenic traits. Mycobacterium abscessus genomes are very plastic, with many recently introduced insertion sequences such as prophages and novel genes, and have an open pan-genome [75,76], suggesting that they might continue to acquire new genetic material, for the adaptation to divergent environmental conditions.…”

Section: Discussionmentioning

confidence: 99%

The distinct fate of smooth and roughMycobacterium abscessusvariants inside macrophages

et al. 2016

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Mycobacterium abscessus is a pathogenic, rapidly growing mycobacterium responsible for pulmonary and cutaneous infections in immunocompetent patients and in patients with Mendelian disorders, such as cystic fibrosis (CF). Mycobacterium abscessus is known to transition from a smooth (S) morphotype with cell surface-associated glycopeptidolipids (GPL) to a rough (R) morphotype lacking GPL. Herein, we show that M. abscessus S and R variants are able to grow inside macrophages and are present in morphologically distinct phagosomes. The S forms are found mostly as single bacteria within phagosomes characterized by a tightly apposed phagosomal membrane and the presence of an electron translucent zone (ETZ) surrounding the bacilli. By contrast, infection with the R form leads to phagosomes often containing more than two bacilli, surrounded by a loose phagosomal membrane and lacking the ETZ. In contrast to the R variant, the S variant is capable of restricting intraphagosomal acidification and induces less apoptosis and autophagy. Importantly, the membrane of phagosomes enclosing the S forms showed signs of alteration, such as breaks or partial degradation. Although not frequently encountered, these events suggest that the S form is capable of provoking phagosome–cytosol communication. In conclusion, M. abscessus S exhibits traits inside macrophages that are reminiscent of slow-growing mycobacterial species.

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“…An important observation arising from the present analysis is that a higher number of MmpLs is found in the RGM group than in the SGM group, and particularly in the M. abscessus clade. This is corroborated by recent comparative genomic studies indicating that M. abscessus evolves rapidly and continues to acquire new genetic material for the adaptation to divergent environmental conditions (Choo et al ., ; Sapriel et al ., ). The capacity of M. abscessus to transition from a smooth intra‐macrophage‐resistant form to a rough extracellular form is likely to facilitate its capacity to adapt and survive in the changing environments (Roux et al ., ).…”

Section: Introductionmentioning

confidence: 98%

The diverse family of MmpL transporters in mycobacteria: from regulation to antimicrobial developments

Viljoen

Dubois

Girard-Misguich

et al. 2017

Molecular Microbiology

110

119

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SummaryMycobacterial genomes contain large sets of loci encoding membrane proteins that belong to a family of multidrug resistance pumps designated Resistance-Nodulation-Cell Division (RND) permeases. Mycobacterial membrane protein Large (MmpL) transporters represent a subclass of RND transporters known to participate in the export of lipid components across the cell envelope. These surfaceexposed lipids with unusual structures play key roles in the physiology of mycobacteria and/or can act as virulence factors and immunomodulators. Defining the substrate specificity of MmpLs and their mechanisms of regulation helps understanding how mycobacteria elaborate their complex cell wall. This review describes the diversity of MmpL proteins in mycobacteria, emphasising their high abundance in a few opportunistic rapid-growing mycobacteria. It reports the conservation of mmpL loci between Mycobacterium tuberculosis and non-tuberculous mycobacteria, useful in predicting the role of MmpLs with unknown functions. Paradoxically, whereas MmpLs participate in drug resistance mechanisms, they represent also attractive pharmacological targets, opening the way for exciting translational applications. The most recent advances regarding structural/ functional information are also provided to explain the molecular basis underlying the proton-motive force driven lipid transport. Overall, this review emphasises the Janus-face nature of MmpLs at the crossroads between antibiotic resistance mechanisms and exquisite vulnerability to drugs.

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Genomic reconnaissance of clinical isolates of emerging human pathogen Mycobacterium abscessus reveals high evolutionary potential

Cited by 60 publications

References 67 publications

Genome Sequencing of Mycobacterium abscessus Isolates from Patients in the United States and Comparisons to Globally Diverse Clinical Strains

Genome Sequencing of Mycobacterium abscessus Isolates from Patients in the United States and Comparisons to Globally Diverse Clinical Strains

The distinct fate of smooth and roughMycobacterium abscessusvariants inside macrophages

The diverse family of MmpL transporters in mycobacteria: from regulation to antimicrobial developments

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