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Clinics in Chest Medicine Dec 2023Rates of nontuberculous mycobacterial pulmonary disease are increasing worldwide, particularly in the United States and other developed countries. While multidrug... (Review)
Review
Rates of nontuberculous mycobacterial pulmonary disease are increasing worldwide, particularly in the United States and other developed countries. While multidrug antimicrobial therapy is the mainstay of treatment, surgical resection has emerged as an important adjunct. In this article, we will review the indications for surgery, preoperative considerations, surgical techniques, and postoperative outcomes.
Topics: Humans; United States; Pneumonectomy; Mycobacterium Infections, Nontuberculous; Lung Diseases; Nontuberculous Mycobacteria
PubMed: 37890922
DOI: 10.1016/j.ccm.2023.06.013 -
Small Methods Sep 2023ESX-3 is a secretion pathway which is essential for mycobactin-mediated iron acquisition under iron-limited conditions. Although present in all Mycobacterium sp., ESX-3...
ESX-3 is a secretion pathway which is essential for mycobactin-mediated iron acquisition under iron-limited conditions. Although present in all Mycobacterium sp., ESX-3 remains to be elucidated in Mycobacterium abscessus. In the study reported here, impaired ESX-3 seriously restricts the growth of M. abscesses under iron-limited conditions; growth is salvaged by functional ESX-3 or iron supplementation. Notably, impaired ESX-3 does not kill M. abscesses when environmental iron is insufficient but induces persistence to bedaquiline, a diarylquinoline class antibiotic used to treat multidrug-resistant mycobacteria. One potential mechanism contributing to persistence is the iron deficiency due to impaired ESX-3 suppressing succinate dehydrogenase activity, which dysregulates the tricarboxylic acid cycle and inactivates bedaquiline. Experiments conducted here also demonstrate that the regulator, MtrA, can bind ESX-3 and promote the survival of M. abscessus. As such, this study suggests that a novel pathway involving MtrA, ESX-3, iron metabolism, and the TCA cycle contributes to bedaquiline persistence in M. abscesses growing under iron-limited conditions.
Topics: Humans; Mycobacterium abscessus; Diarylquinolines; Abscess; Mycobacterium; Iron; Iron Metabolism Disorders
PubMed: 37291735
DOI: 10.1002/smtd.202300183 -
International Journal of Molecular... Dec 2023The human stress hormones catecholamines play a critical role in communication between human microbiota and their hosts and influence the outcomes of bacterial...
The human stress hormones catecholamines play a critical role in communication between human microbiota and their hosts and influence the outcomes of bacterial infections. However, it is unclear how senses and responds to certain types of human stress hormones. In this study, we screened several human catecholamine stress hormones (epinephrine, norepinephrine, and dopamine) for their effects on growth. Our results showed that epinephrine significantly stimulated the growth of in the serum-based medium as well as macrophages. In silico analysis and molecular docking suggested that the extra-cytoplasmic domain of the MprB might be the putative adrenergic sensor. Furthermore, we showed that epinephrine significantly enhances biofilm formation, which has distinct texture composition, antibiotic resistance, and stress tolerance. Together, our data revealed the effect and mechanism of epinephrine on the growth and biofilm formation of , which contributes to the understanding of the environmental perception and antibiotic resistance of and provides important clues for the understanding of bacterial pathogenesis and the development of novel antibacterial therapeutics.
Topics: Humans; Mycobacterium tuberculosis; Molecular Docking Simulation; Epinephrine; Catecholamines; Tuberculosis; Biofilms; Hormones; Mycobacterium smegmatis; Bacterial Proteins
PubMed: 38139199
DOI: 10.3390/ijms242417370 -
Frontiers in Cellular and Infection... 2023Mycobacteria assemble a complex cell wall with cross-linked peptidoglycan (PG) which plays an essential role in maintenance of cell wall integrity and tolerance to...
INTRODUCTION
Mycobacteria assemble a complex cell wall with cross-linked peptidoglycan (PG) which plays an essential role in maintenance of cell wall integrity and tolerance to osmotic pressure. We previously demonstrated that various hydrolytic enzymes are required to remodel PG during essential processes such as cell elongation and septal hydrolysis. Here, we explore the chemistry associated with PG cross-linking, specifically the requirement for amidation of the D-glutamate residue found in PG precursors.
METHODS
Synthetic fluorescent probes were used to assess PG remodelling dynamics in live bacteria. Fluorescence microscopy was used to assess protein localization in live bacteria and CRISPR-interference was used to construct targeted gene knockdown strains. Time-lapse microscopy was used to assess bacterial growth. Western blotting was used to assess protein phosphorylation.
RESULTS AND DISCUSSION
In , we confirmed the essentiality for D-glutamate amidation in PG biosynthesis by labelling cells with synthetic fluorescent PG probes carrying amidation modifications. We also used CRISPRi targeted knockdown of genes encoding the MurT-GatD complex, previously implicated in D-glutamate amidation, and demonstrated that these genes are essential for mycobacterial growth. We show that MurT-rseGFP co-localizes with mRFP-GatD at the cell poles and septum, which are the sites of cell wall synthesis in mycobacteria. Furthermore, time-lapse microscopic analysis of MurT-rseGFP localization, in fluorescent D-amino acid (FDAA)-labelled mycobacterial cells during growth, demonstrated co-localization with maturing PG, suggestive of a role for PG amidation during PG remodelling and repair. Depletion of MurT and GatD caused reduced PG cross-linking and increased sensitivity to lysozyme and β-lactam antibiotics. Cell growth inhibition was found to be the result of a shutdown of PG biosynthesis mediated by the serine/threonine protein kinase B (PknB) which senses uncross-linked PG. Collectively, these data demonstrate the essentiality of D-glutamate amidation in mycobacterial PG precursors and highlight the MurT-GatD complex as a novel drug target.
Topics: Amides; Glutamic Acid; Mycobacterium smegmatis; Cell Wall; Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor; Bacterial Proteins; Peptidoglycan
PubMed: 37692163
DOI: 10.3389/fcimb.2023.1205829 -
European Journal of Medicinal Chemistry Nov 2023A series of 3-methoxy-2-phenylimidazo[1,2-b]pyridazine derivatives which were highly active against autoluminescent Mycobacterium tuberculosis (Mtb) and Mycobacterium...
A series of 3-methoxy-2-phenylimidazo[1,2-b]pyridazine derivatives which were highly active against autoluminescent Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm) in an in vitro assay were identified. SAR analysis showed that the most active compounds, which included a phenyl group bearing fluoro substituent(s) at C2, a methoxy function at C3, and a benzyl-heteroatom moiety at C6, exhibited in vitro MIC values generally around 0.63-1.26 μM against Mtb and Mm. However, these compounds were inactive against Mtb in vivo (mice), and investigations revealed very short metabolic half-lives (<10 min) when incubated with mouse liver microsomes. Multiple observations of side products produced from oxidative cleavage of the imidazole moiety during the chemical synthesis work suggested that this is a likely metabolic pathway leading to the lack of observed activity in vivo.
Topics: Animals; Mice; Mycobacterium tuberculosis; Antitubercular Agents; Mycobacterium marinum; Pyridazines; Microbial Sensitivity Tests
PubMed: 37524009
DOI: 10.1016/j.ejmech.2023.115637 -
Clinics in Chest Medicine Dec 2023Treatment of M avium pulmonary disease requires a three-drug, macrolide-based regimen that is administered for 12 months beyond culture conversion. The regimen can be... (Review)
Review
Treatment of M avium pulmonary disease requires a three-drug, macrolide-based regimen that is administered for 12 months beyond culture conversion. The regimen can be administered 3 days a week in non-cavitary, nodular bronchiectatic disease but should be given daily when cavitary disease is present. For treatment refractory disease, amikacin liposome inhalation suspension is added to the regimen. Parenteral amikacin or streptomycin should be administered in the setting of extensive radiographic involvement or macrolide resistance. Recurrence of disease is common and often due to reinfection. Novel and repurposed agents are being evaluated in clinical trials.
Topics: Humans; Mycobacterium avium Complex; Anti-Bacterial Agents; Amikacin; Mycobacterium avium-intracellulare Infection; Macrolides; Treatment Outcome; Drug Resistance, Bacterial; Lung Diseases
PubMed: 37890915
DOI: 10.1016/j.ccm.2023.06.009 -
Cureus Nov 2023Once considered rare, nontuberculous mycobacterial (NTM) infections have garnered increasing attention in recent years. This comprehensive review provides insights into... (Review)
Review
Once considered rare, nontuberculous mycobacterial (NTM) infections have garnered increasing attention in recent years. This comprehensive review provides insights into the epidemiology, clinical diversity, diagnostic methods, treatment strategies, prevention, and emerging research trends in NTM infections. Key findings reveal the global prevalence of NTM infections, their diverse clinical presentations affecting respiratory and extra-pulmonary systems, and the diagnostic challenges addressed by advances in microbiological, radiological, and immunological methods. Treatment complexities, especially drug resistance and patient adherence, are discussed, along with the vulnerability of special populations. The importance of early detection and management is underscored. Prospects in NTM research, including genomics, diagnostics, drug development, and multidisciplinary approaches, promise to enhance our understanding and treatment of these infections. This review encapsulates the multifaceted nature of NTM infections, offering a valuable resource for clinicians, researchers, and public health professionals.
PubMed: 38054150
DOI: 10.7759/cureus.48270 -
The Journal of Infectious Diseases Aug 2023Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and an increasingly frequent cause of opportunistic infections. Mycobacterium abscessus complex...
BACKGROUND
Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and an increasingly frequent cause of opportunistic infections. Mycobacterium abscessus complex (MABC) is one of the major NTM lung pathogens that disproportionately colonize and infect the lungs of individuals with cystic fibrosis (CF). MABC infection can persist for years, and antimicrobial treatment is frequently ineffective.
METHODS
We sequenced the genomes of 175 isolates longitudinally collected from 30 patients with MABC lung infection. We contextualized our cohort amidst the broader MABC phylogeny and investigated genes undergoing parallel adaptation across patients. Finally, we tested the phenotypic consequences of parallel mutations by conducting antimicrobial resistance and mercury-resistance assays.
RESULTS
We identified highly related isolate pairs across hospital centers with low likelihood of transmission. We further annotated nonrandom parallel mutations in 22 genes and demonstrated altered macrolide susceptibility co-occurring with a nonsynonymous whiB1 mutation. Finally, we highlighted a 23-kb mercury-resistance plasmid whose loss during chronic infection conferred phenotypic susceptibility to organic and nonorganic mercury compounds.
CONCLUSIONS
We characterized parallel genomic processes through which MABC is adapting to promote survival within the host. The within-lineage polymorphisms we observed have phenotypic effects, potentially benefiting fitness in the host at the putative detriment of environmental survival.
Topics: Humans; Mycobacterium abscessus; Clarithromycin; Host Adaptation; Mycobacterium Infections, Nontuberculous; Anti-Bacterial Agents; Genomics
PubMed: 37254795
DOI: 10.1093/infdis/jiad187 -
International Journal of Antimicrobial... Oct 2023Mycobacterium abscessus is an emerging infection in people living with lung diseases, including cystic fibrosis (CF) and bronchiectasis, and it has limited treatment...
OBJECTIVES
Mycobacterium abscessus is an emerging infection in people living with lung diseases, including cystic fibrosis (CF) and bronchiectasis, and it has limited treatment options and low cure rates. The off-label use of novel antibiotics developed for other bacterial pathogens offers potential new therapeutic options. We aimed to describe the in vitro activity of imipenem, imipenem-relebactam and tedizolid against comparator antibiotics in M. abscessus isolates from Australian patients with and without CF.
METHODS
We performed susceptibility testing for imipenem-relebactam, tedizolid and comparator antibiotics by Clinical and Laboratory Standards Institute (CLSI) criteria against 102 clinical M. abscessus isolates, including 46 from people with CF.
RESULTS
In this study, the minimum inhibitory concentration (MICs) of imipenem-relebactam was one-fold dilution less than of imipenem alone. The MIC and MIC of imipenem-relebactam were 8 and 16 mg/L, respectively, whereas for imipenem they were 16 and 32 mg/L. Tedizolid had an MIC and MIC of 2 and 4 mg/L, respectively. Forty non-CF isolates had linezolid susceptibility performed, with MIC and MIC values of 16 and 32 mg/L, respectively, measured.
CONCLUSIONS
This study shows lower MICs for imipenem-relebactam and tedizolid compared to other more commonly used antibiotics and supports their consideration in clinical trials for M. abscessus treatment.
Topics: Humans; Mycobacterium abscessus; Australia; Anti-Bacterial Agents; Imipenem; Microbial Sensitivity Tests
PubMed: 37517624
DOI: 10.1016/j.ijantimicag.2023.106938 -
Clinical Microbiology and Infection :... Jun 2024
Topics: Mycobacterium abscessus; Humans; Mycobacterium Infections, Nontuberculous; Anti-Bacterial Agents
PubMed: 38402955
DOI: 10.1016/j.cmi.2024.02.019