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PubMed2026

Phylogenetic distribution and longitudinal persistence of plasmids in Mycobacterium abscessus.

Mycobacterium abscessus, a non-tuberculous mycobacterium, is a cause of severe respiratory infections, notably in individuals with underlying lung conditions. Its high levels of intrinsic and acquired antimicrobial resistance make it particularly difficult to treat and horizontally acquired genetic elements may facilitate the spread of resistance. A small number of plasmids have been identified in this species, but their distribution, transmission dynamics across subspecies and clonal lineages remain poorly characterized. We analysed short-read genomic data from 3,060 M. abscessus isolates, including longitudinal samples, to characterize plasmid diversity and dynamics. Using a graph-based pan-genome approach, we identified 28 plasmids, including 15 previously unreported plasmids, mapped their distribution onto the species phylogeny and assessed their functional potential. Overall, 23.1% of isolates carried at least one plasmid, with higher prevalence in dominant circulating clones (DCCs) compared with non-DCCs. Plasmid carriage varied across subspecies and clonal backgrounds, and plasmids encoded numerous genes which may be linked to bacterial adaptation. Several plasmids persisted across multiple time points within individual patients, suggesting they can be highly stable over the course of a chronic infection.

Plasmids↗
PubMed2025

Mutations in the transcriptional regulator MAB_2885 confer tedizolid and linezolid resistance through the MmpS-MmpL efflux pump MAB_2302-MAB_2303 in Mycobacterium abscessus.

Mycobacterium abscessus (MAB) is a clinically significant multidrug-resistant (MDR) pathogen, particularly implicated in pulmonary infections among cystic fibrosis (CF) patients. Tedizolid (TZD), an oxazolidinone-class antibacterial drug, has been recommended as an alternative treatment for MAB-infected patients who are intolerant to or whose isolate is resistant to first-line drugs including linezolid (LZD). To investigate the TZD resistance mechanisms in MAB, we isolated 23 TZD-resistant MAB mutants and performed whole-genome sequencing (WGS) to identify resistance-associated genes. Frequent mutations were identified in MAB_2885, encoding a putative TetR transcriptional regulator, and MAB_2303, encoding a putative mycobacterial membrane protein large (MmpL). Drug susceptibility testing confirmed that MAB_2885 mutations contribute to both TZD and LZD resistance in MAB. RNA-seq analysis revealed that restoring wild-type MAB_2885 in mutants downregulated the MAB_2302-MAB_2303. Electrophoretic mobility shift assay (EMSA) showed the MAB_2885 protein binds to its target sequence upstream of MAB_2302-MAB_2303, further confirming their regulatory relationship. The W91R mutation in the MAB_2885 protein was found to impair its DNA-binding activity compared to the wild-type. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis confirmed that MAB_2302-MAB_2303 functions as a TZD efflux pump. Additionally, overexpression of MAB_2885 in M. abscessus subsp. bolletii and M. abscessus subsp. massiliense also increased their TZD susceptibility and downregulated their respective MmpS-MmpL orthologs. Overall, our study demonstrates that mutations in MAB_ 2885 contribute to TZD and LZD resistance by disrupting the negative regulation of the downstream MAB_2302-MAB_2303, which functions as a direct efflux pump for TZD. These findings provide new insights into oxazolidinone resistance mechanisms in MAB and identify potential biomarkers for detecting drug resistance.

Mycobacterium abscessus↗
PubMed2026

Investigation of Mycobacterium abscessus Cluster in Hospital, Maryland, USA, 2024.

Mycobacterium abscessus infections are frequently drug resistant and can cause severe disease, particularly among vulnerable populations in healthcare settings. In June 2024, a cluster of M. abscessus infection cases was reported at a hospital in Maryland, USA. An investigation involving hospital infection prevention staff, the Maryland Department of Health, the Centers for Disease Control and Prevention, and the Wadsworth Laboratory of the New York State Department of Health included initiation of mitigation efforts such as tap water use restrictions, point-of-use water filters, hospitalwide water flushing, and staff education regarding sink safety. Whole-genome sequencing of patient and environmental isolates, coupled with epidemiologic data, revealed a strong association (0-24 single-nucleotide polymorphism differences) between environmental and patient samples, indicating that infections were likely a result of patient exposure to M. abscessus. Ensuring initiation of mitigation initiatives likely prevented additional patient infections. Although effective in this investigation, not all mitigation strategies are equal or sustainable.

Humans↗
PubMed2026

Intratumoral Mycobacterium abscessus promotes cytidine deaminase mutagenesis in non-small cell lung cancer.

The intratumoral microbiota is increasingly recognized as an active component of the tumor microenvironment, yet whether it directly drives tumor mutagenesis remains unclear. Here, integrated multi-omics analysis of human non-small cell lung cancer (NSCLC) identifies Mycobacterium abscessus as a microbial determinant of APOBEC3A-associated mutagenesis. Mechanistically, the bacterial effector nucleoside diphosphate kinase (NDK) directly targets the host transcription factor IRF3 and installs a non-canonical 1-phosphohistidine modification at H263, thereby amplifying type I interferon signaling and sustaining APOBEC3A expression. This inter-kingdom phosphotransfer event links intratumoral microbial colonization to an endogenous mutational process that promotes genomic diversification. Genetic inactivation of NDK, or pharmacologic elimination using an engineered NDK-PROTAC, suppresses APOBEC3A activation and attenuates microbe driven mutagenesis. Together, these findings establish a direct microbial effector mechanism that promotes APOBEC3A-associated mutagenesis and provide a therapeutic framework to intercept microbiome driven mutagenesis in NSCLC.

Humans↗
PubMed2026

The SigD regulon of Mycobacterium abscessus determines cell envelope composition and antibiotic susceptibility.

A major determinant of the exceptional intrinsic resistance of M. abscessus is the lipid-rich cell envelope, yet the regulatory systems that remodel envelope-associated pathways remain poorly defined. Here, we determine the σD regulon in M. abscessus and establish its role in cell envelope homeostasis and intrinsic resistance to hydrophobic antibiotics. RNA-Seq analysis of a MabΔsigD mutant identified 447 differentially expressed genes, while ChIP-Seq mapped 72 σD binding sites and defined a conserved promoter motif (GTAACA/G-N16-CGAT). Using a combination of σD binding, motif orientation and expression data, we identified a core set of directly regulated genes, distinct from what was previously observed in M. tuberculosis, many of which encode proteins involved in envelope-associated functions. These include loci involved in trehalose polyphleate (TPP) biosynthesis, the antigen 85 complex and peptidoglycan remodeling enzymes. Deletion of sigD resulted in a significant reduction in TPPs in the cell envelope and an increase in ethidium bromide accumulation. Consistent with these changes, loss of σD selectively sensitized M. abscessus to hydrophobic antibiotics, including rifampicin and tigecycline. Deletion of mmpL10, which is required for transport of TPP precursors, recapitulated the drug sensitivity of MabΔsigD, implicating envelope composition as a key effector of the phenotype. Expression of the σD regulon further increased during starvation and in response to SDS, isoniazid, and ethambutol, mediated by degradation of RsdA, consistent with a role in stress-responsive envelope adaptation. Together, these findings demonstrate σD is active during logarithmic growth in rich media where it regulates the expression of envelope-associated genes that influence envelope permeability and basal level susceptibility to hydrophobic antibiotics; its activity further increases in response to cell envelope stress, presumably promoting envelope remodeling to counteract damage.

Regulon↗
PubMed2025

Ultra-high field strength electroporation enables efficient DNA transformation and genome editing in nontuberculous mycobacteria.

Efficient DNA delivery is essential for genetic manipulation of mycobacteria and for dissecting their physiology, pathogenesis, and drug resistance. Although electroporation enables transformation efficiencies exceeding 10⁵ CFU per µg DNA in Mycobacterium smegmatis and Mycobacterium tuberculosis, it remains highly inefficient in many nontuberculous mycobacteria (NTM), including Mycobacterium abscessus. Here, we discovered that NTM such as M. abscessus exhibit exceptional tolerance to ultra-high electric field strengths and that hypertonic preconditioning partially protects cells from electroporation-induced damage. Using ultra-high electric field strength (3 kV/mm) electroporation, we achieved dramatic improvements in plasmid transformation efficiency-up to 106-fold in M. abscessus, 83-fold in Mycobacterium marinum, and 37-fold in Mycobacterium kansasii-compared to standard conditions (1.25  kV/mm). Transformation efficiency was further influenced by the choice of selectable marker. Ultra-high field strength electroporation also markedly enhanced allelic exchange in M. abscessus expressing Che9c RecET recombinases, increasing the recovery of gene deletion mutants by over 1,000-fold relative to conventional electroporation. In parallel, oligonucleotide-mediated recombineering for targeted point mutations produced nearly 10,000-fold more mutants under ultra-high field conditions. Together, these findings establish ultra-high field electroporation as a robust, broadly applicable platform for genetic engineering of NTMs. This method substantially enhances transformation efficiency and enables construction of advanced genetic tools-including expression libraries and CRISPRi knockdown libraries-in species that have historically resisted genetic manipulation.IMPORTANCEInfections caused by nontuberculous mycobacteria (NTM), including Mycobacterium abscessus, are increasing globally, yet genetic manipulation of these pathogens remains technically challenging due to inefficient DNA delivery and low gene editing success. The ultra-high electric field strength electroporation strategy described here overcomes these barriers, enabling dramatic improvements in both transformation and genome editing efficiency. This advance paves the way for high-throughput functional genomics in NTMs, including the construction of genome-wide knockout, CRISPRi knockdown, and expression libraries. Broad adoption of this approach will accelerate discovery of genetic determinants of virulence and drug resistance, facilitating the development of antimicrobials and vaccines.

Electroporation↗
PubMed2026

Phylogenomic and Clinical Perspectives of an East Asia-Specific Cluster of Mycobacterium massiliense.

BACKGROUND: Mycobacterium abscessus subspecies massiliense (MAM) can form genetically related clusters through continuous within-host adaptations. RESEARCH QUESTION: What is the epidemiologic and clinical significance of the sequence type 120 (ST120) strain of MAM, an East Asia-specific cluster? STUDY DESIGN AND METHODS: Isolates were obtained from patients with MAM pulmonary disease at Seoul National University Hospital between October 1, 2019, and December 31, 2023. These isolates were analyzed using multilocus sequence typing and colony morphotyping and were evaluated for glycopeptidolipid biosynthesis-related gene deletions. Whole-genome sequencing was performed for phylogenomic and pangenome analyses, incorporating MAM genome data from public databases. Finally, the clinical course and treatment outcomes of patients infected with ST120 were evaluated. RESULTS: Among the isolates obtained from 136 patients, 50 isolates (36.8%) were classified as ST120. All ST120 isolates exhibited a rough colony morphotype and harbored deletions in glycopeptidolipid biosynthesis-related genes. From 796 global strains, ST120 was identified exclusively in the isolates obtained from South Korea (51/137 isolates [37.1%]), Japan (3/53 [5.7%]), and Taiwan (2/52 [3.8%]). Genomic analysis revealed the stepwise genetic evolution of ST120, suggesting transmission from Taiwan to Japan and from Japan to South Korea. The ST120 strains exhibited genetic mutations associated with virulence and structural alterations within the ESX system. Consequently, patients with ST120 strain infections had a higher prevalence of cavitary disease (23/50 [46%]) than those infected with non-ST120 strains (19/86 [22.1%]; P = .004). Among those who initiated treatment, the proportion of microbiological cure was lower in patients with ST120 infection (6/15 [40.0%]) than in those with non-ST120 infection (24/34 [70.6%]; P = .043). INTERPRETATION: Our results show that ST120, a strain predominantly found in South Korea, is characterized by the extensive loss of glycopeptidolipid biosynthesis-related genes and is associated with increased disease severity and worse treatment outcomes.

Humans↗
PubMed2026

Development of an arabinose-inducible gene expression system for nontuberculous mycobacteria.

Nontuberculous mycobacteria (NTM) are emerging pathogens for which genetic tools remain limited. Here, we developed an arabinose-inducible gene expression system based on a modified pBAD24 vector adapted for mycobacterial hosts. The vector carries replication origins for mycobacteria and Escherichia coli, as well as selectable markers compatible with NTM. In Mycobacterium abscessus (Mycobacteroides abscessus), the system enabled dose-dependent induction of target gene expression by arabinose, as demonstrated by increased antibiotic resistance and quantitative RT-PCR analysis. Although basal expression was observed in the absence of arabinose, expression levels were tunable across arabinose concentrations. The system was also functional in Mycobacterium smegmatis (Mycolicibacterium smegmatis) and Mycobacterium bovis BCG, although the degree of basal expression varied among host species. These results establish a tunable inducible expression system for mycobacteria and provide a useful genetic tool for studies of NTM biology.

Arabinose↗
PubMed2026

Th2 bias and T-cell exhaustion characterize the immunopathology of non-tuberculous mycobacterial pulmonary disease.

Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is an escalating global health concern with poorly defined immunological mechanisms, necessitating comprehensive profiling to guide therapeutic advances. We analyzed peripheral blood from 28 treatment-naïve NTM-PD patients (19 Mycobacterium avium complex, 9 Mycobacterium abscessus) and 27 matched controls using 42-marker mass cytometry (CyTOF) and Luminex multiplex assays. A random forest model identified predictive markers, while an in vitro murine macrophage model evaluated chemokine production. NTM-PD patients displayed significant immune shifts, including increased classical monocytes (CD14+ CD16-), reduced NKT-like cells (CD3+ CD56+), and elevated T-cell exhaustion markers (PD-1, TOX). This coincided with a Th1/Th2 balance shift characterized by heightened IL-13. Elevated IFN-γ-inducible chemokines CXCL9 and CXCL10 coexisted with this Th2-biased signature, indicating a complex, dysregulated inflammatory state. A model integrating immune-cell frequencies and cytokine profiles achieved robust diagnostic accuracy (AUC = 0.922) with prognostic potential. In vitro, NTM-infected macrophages produced substantial CXCL9 and CXCL10 levels relative to the LPS maximal activation benchmark, identifying them as a major cellular source. These findings propose an immunological framework wherein T-cell exhaustion and a Th2-biased microenvironment strongly correlate with NTM-PD pathogenesis. CXCL9, CXCL10, and IL-13 emerge as candidate therapeutic targets, while our predictive model offers a foundational approach for risk stratification.

Humans↗
PubMed2026

Comparison of culture and culture-free methods for comprehensive identification of mycobacteria: a single-center prospective study.

The genus Mycobacterium, including Mycobacterium tuberculosis and over 200 nontuberculous mycobacteria (NTM), shows wide variability in clinical outcomes and drug susceptibility. Although culture-based identification remains the gold standard, slow mycobacterial growth delays diagnosis and treatment. In this study, we evaluated a novel culture-free method for subspecies-level identification directly from sputum. In this single-center prospective cohort study at Osaka Toneyama Medical Center, we analyzed 125 sputum samples from 115 patients with NTM pulmonary disease and 10 with non-NTM respiratory conditions. Samples were decontaminated using N-acetyl-L-cysteine-sodium hydroxide (NALC-NaOH) or succinic acid. We compared the reference culture method (mycobacterial culture plus whole-genome sequencing) and a culture-free direct target capture sequencing method. Core genome multi-locus sequence typing identified subspecies in both workflows, covering 186 mycobacterial species, including M. tuberculosis. The 115 NTM cohort specimens yielded 57 smear-positive and 93 culture-positive results. The identified subspecies included 48 Mycobacterium avium subsp. hominissuis, 22 Mycobacterium intracellulare subsp. intracellulare, 5 subsp. chimaera, 7 Mycobacterium abscessus subsp. abscessus, 5 subsp. massiliense, 1 M. tuberculosis, and 5 other NTM species. The culture-free method showed a high identification rate for smear-positive specimens (75.4%) but a low identification rate for smear-negative specimens (13.9%). NALC-NaOH pretreatment resulted in higher accuracy (90.5%) than did succinic acid pretreatment (66.7%). Thus, our culture-free subspecies-level identification method achieved high accuracy, especially in alkaline-treated smear-positive sputum samples, achieving rates above 90%. This method is recommended in clinical practice for patients who require rapid diagnosis and timely initiation of appropriate treatment, bypassing time-consuming culture steps.IMPORTANCEAccurate identification of Mycobacterium species and subspecies is crucial for effective treatment, as drug susceptibility and clinical outcomes vary significantly among them. However, conventional diagnosis relies on culture-based methods that can take several weeks, critically delaying appropriate therapy. This study validates a novel culture-free method using target capture sequencing for the comprehensive, subspecies-level identification of over 186 mycobacterial species directly from sputum specimens. Our findings revealed the high accuracy of this approach for smear-positive specimens, especially with alkaline pretreatment. This rapid method is applicable in clinical settings and enables timely and precise treatment decisions, greatly benefiting patients who require urgent intervention.

Humans↗
PubMed2026

Comparative evaluation of molecular technologies for the identification of prevalent non-tuberculous mycobacteria in pulmonary infections: a systematic review and meta-analysis.

BACKGROUND: The increasing prevalence of non-tuberculous mycobacteria pulmonary disease (NTM PD) is a burden to public health. Successful management of NTM PD critically depends on accurate species identification and reliable drug susceptibility testing to guide appropriate antibiotic therapy. Emerging molecular technologies offer rapid diagnostic solutions compared to conventional methods, but their performance varies. This study aims to provide a comprehensive evaluation of current molecular techniques for NTM identification and to present a global antibiotic resistance profile. METHODS: A systematic literature search was conducted in PubMed and Web of Science for studies published between 2005 and 2024. Studies applying molecular methods for NTM identification and resistance detection in humans were included. Data on study characteristics, diagnostic methods, sample types, sample sizes, identification sensitivity, and drug susceptibility results were extracted. Meta-analysis was performed using R with the meta4diag package. The quality of included studies was assessed using the QUADAS-2 tool. RESULTS: The analysis included 49 studies on NTM identification and 33 studies on antibiotic resistance. For species identification, all evaluated molecular technologies (MALDI-TOF MS, PCR-based methods, Sequencing, DNA chip, and DNA strip) demonstrated high pooled sensitivities (>0.92). Subgroup analysis revealed that sample type significantly affected performance for MALDI-TOF MS. Preliminary analysis of antibiotic resistance rates revealed varying patterns. For slowly growing mycobacteria, a significantly high Ethambutol resistance rate was observed in M. avium (69.20%). Among rapidly growing mycobacteria, resistance to Imipenem was notable (54.22%), and Clarithromycin resistance varied significantly within the Mycobacterium abscessus complex. CONCLUSION: Emerging molecular technologies have revolutionized the methodology for NTM identification with excellent performance. However, their performance can be influenced by sample type, particularly for MALDI-TOF MS. The alarming and heterogeneous antibiotic resistance patterns also highlight the critical need for rapid and accurate species identification and drug susceptibility testing to inform effective therapeutic strategies. Key messagesMolecular technologies demonstrate high accuracy for NTM identification.Antibiotic resistance is a serious concern with variations among NTM species and subspecies.Rapid and accurate species identification and drug susceptibility testing are crucial for guiding effective clinical management of NTM PD.

Humans↗
PubMed2026

Effectiveness of mass spectrometry and genomic analysis in the surveillance of nontuberculous Mycobacterium in Taiwan.

Nontuberculous mycobacteria (NTM) are diverse, and species-level identification remains challenging in routine diagnostics. We analyzed NTM isolates collected at three regional centers of the National Taiwan University Hospital (NTUH) from 2019 to 2024 to assess geographic variation and identification performance after implementation of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Among 3,188 cases meeting the microbiological criteria for probable pulmonary NTM disease, the species distribution differed by region: Mycobacterium avium complex predominated in central Taiwan (Yunlin, 47.3%), whereas M. abscessus complex (Taipei, 26.5%) and M. kansasii (Hsinchu, 12.4%) were more common in northern Taiwan. In 2019, 14.5% of isolates were reported to be unidentified by MALDI-TOF MS; with workflow optimization and database updates, this percentage decreased but plateaued at 4.5-4.8%. Whole-genome sequencing (WGS) of 61 randomly selected persistently unidentified isolates revealed eight average nucleotide identity (ANI)-defined clusters; 55 isolates (90.2%) could not be assigned to known species using current reference databases. Two clusters detected only in Hsinchu were phylogenetically closest to M. kyorinense, with ANI values below the species demarcation threshold. Overall, we observed marked regional heterogeneity of NTM in Taiwan and a persistent identification gap that remained after MALDI-TOF MS optimization and follow-up WGS.IMPORTANCEThis study characterized regional differences in the NTM species distribution across Taiwan, and the results highlight the limitations of current identification approaches. MALDI-TOF MS identifies most isolates, but locally circulating lineages represent a persistent gap in global reference libraries. Even with whole-genome sequencing (WGS), 90.2% (55/61) of persistently unresolved isolates could not be assigned to known species in the current reference databases despite the formation of clear ANI- and phylogeny-defined clusters. These findings show that both proteomic and genomic reference resources for clinical NTM remain incomplete. Expanding regionally representative databases and performing WGS for isolates that remain unresolved by MALDI-TOF MS will be necessary to improve species-level resolution for surveillance and clinical interpretation.

Taiwan↗
PubMed2025

Species distribution of nontuberculous mycobacteria isolated from respiratory specimens at a tertiary care hospital in South Korea, 2017-2022.

The clinical relevance and drug resistance patterns of nontuberculous mycobacteria (NTM) vary by species. This study investigated the species distribution of NTM isolated from respiratory specimens at a tertiary care hospital in South Korea from 2017 to 2022. A retrospective analysis was conducted on laboratory data from respiratory specimens submitted for acid-fast bacilli culture. NTM isolates were identified using a line probe assay, and those unidentifiable at the species or complex level underwent multigene sequencing of the 16S rRNA, rpoB, and hsp65 genes. Among all mycobacterial isolates, the proportion of NTM showed an increasing trend, rising from 87.4% in 2017 to 93.3% in 2022. The eight most common species were M. avium complex (61.9%), M. abscessus (14.2%), M. fortuitum complex (8.4%), M. gordonae (5.3%), M. simiae complex (3.4%), M. kansasii complex (1.9%), M. terrae complex (1.5%), and M. chelonae (1.2%), accounting for 97.7% of all NTM isolates. Among the remaining isolates (2.3%, n = 169), 161 were classified into 24 species and groups, the majority with proportions below 0.1%. Two of the eight isolates that could not be identified at the species or group level despite multigene sequencing underwent whole-genome sequencing, which suggested they likely represent novel Mycobacterium species. This study provides valuable insights into the distribution of NTM species, particularly rarely encountered species, isolated from respiratory specimens in South Korea. These findings may aid in optimizing diagnostic strategies and selecting appropriate treatment options.IMPORTANCEGiven the significant variations in clinical relevance and drug resistance patterns among nontuberculous mycobacteria (NTM) species, understanding their geographic distribution is essential for selecting appropriate treatment options and improving patient outcomes. This study investigated the distribution of NTM species isolated from respiratory specimens at a tertiary care hospital in South Korea from 2017 to 2022. Our findings revealed an increasing proportion of NTM, with M. avium complex and M. abscessus remaining predominant. Additionally, we identified 24 rarely encountered species and groups, along with two strains that likely represent novel Mycobacterium species. Our study advances the understanding of the evolving NTM epidemiology in South Korea, contributing to the optimization of diagnostic strategies and improvement of patient management.

Republic of Korea↗