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International Journal of... Apr 2024Environmental mycobacteria are involved in several infections ranging from lung to skin infections. In Côte d'Ivoire, apart from Mycobacterium ulcerans and...
BACKGROUND
Environmental mycobacteria are involved in several infections ranging from lung to skin infections. In Côte d'Ivoire, apart from Mycobacterium ulcerans and Mycobacterium tuberculosis, little information exists on other species. The culture of these species, a real challenge, especially in developing countries like Cote d'Ivoire, limits their identification. However, there are reports in literature of infections caused by these mycobacteria, and few species have never been described in human or animal infections. These are difficult cases to treat because of their resistance to most antituberculosis antibiotics. The aim of our work was to study the diversity of potentially pathogenic mycobacterial species in wastewater drainage channels in different townships and in two hospital effluents in the city of Abidjan.
METHODS
Wastewater samples were cultured, followed by conventional polymerase chain reaction (PCR) targeting mycobacterial 16S ribonucleic acid (16S RNA) using PA/MSHA primers. 16 S RNA identified were sequenced by Sanger techniques. Sequences obtained were analyzed, and a phylogenic tree was built.
RESULTS
Fast-growing mycobacteria, including Mycobacterium fortuitum, Mycobacterium phocaicum, Mycobacterium sp., and others presence, were confirmed both by culture and molecular techniques. M. fortuitum strain was the same in effluents of the Treichville University Hospital and in the wastewater of the township of Koumassi. New species never isolated in Côte d'Ivoire, such as M. phocaicum, have been identified in wastewater of the township of Yopougon.
CONCLUSION
This study showed that the sewer network in the city of Abidjan is colonized by both potentially pathogenic mycobacteria and saprophytic environmental mycobacteria.
Topics: Cote d'Ivoire; Phylogeny; RNA, Ribosomal, 16S; Humans; Nontuberculous Mycobacteria; Wastewater; Polymerase Chain Reaction; DNA, Bacterial; Mycobacterium
PubMed: 38916386
DOI: 10.4103/ijmy.ijmy_96_24 -
International Journal of... Apr 2024GeneXpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) is a conceptually helpful tool for establishing tuberculosis (TB) disease. Negative results from the GeneXpert...
OBJECTIVE
GeneXpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) is a conceptually helpful tool for establishing tuberculosis (TB) disease. Negative results from the GeneXpert test do not exclude the possibility of diagnosing non-tuberculous mycobacteria lung disease (NTMLD) as a chronic pulmonary disease. When a patient is diagnosed on a clinical basis, and there is no bacteriological evidence of TB, it is necessary to consider NTM as one of the causes of disease with TB-like symptoms. The prevalence of non-tuberculous mycobacteria (NTM) disease is rising globally, but its diagnosis is still delayed and often misdiagnosed as multidrug-resistant TB (MDR-TB). This study highlights the implication of negative GeneXpert MTB/RIF results in suspected TB patients who conducted mycobacteria culture and detected the incidence of NTMLD.
METHODS
In this experimental study, the performance of GeneXpert MTB/RIF-negative results with those of mycobacteria cultures and lung abnormalities among suspected TB patients in a referral hospital in Indonesia were evaluated. From January to August 2022, 100 sputum samples from suspected chronic pulmonary TB patients with GeneXpert MTB/RIF assay-negative results were cultured in Lowenstein-Jensen medium, and the implication among negative GeneXpert result MTB/RIF assay.
RESULTS
7% were confirmed to have MTB and 1% had NTM by culture assay. Moreover, 34% were diagnosed with clinical TB and treated with anti-TB drugs.
CONCLUSION
For patients with negative assay results of GeneXpert MTB/RIF regarding clinically suspected chronic TB infection, further diagnostic tests to determine the causative agents of the lung abnormalities should be carried out.
Topics: Humans; Mycobacterium tuberculosis; Rifampin; Male; Sputum; Female; Adult; Middle Aged; Indonesia; Tuberculosis, Pulmonary; Mycobacterium Infections, Nontuberculous; Tuberculosis, Multidrug-Resistant; Nontuberculous Mycobacteria; Aged; Young Adult
PubMed: 38916385
DOI: 10.4103/ijmy.ijmy_100_24 -
International Journal of... Apr 2024Microbiological diagnosis of mycobacteriosis is often difficult, as it is necessary to differentiate between transient colonization and active infection.
Construction of Composite Correlation Index Matrix and Analysis of Cultural Properties of Representatives of Mycobacterium abscessus Complex Isolated from Patients with Cystic Fibrosis.
BACKGROUND
Microbiological diagnosis of mycobacteriosis is often difficult, as it is necessary to differentiate between transient colonization and active infection.
METHODS
We studied the cultural properties of Mycobacterium abscessus complex (MABSc) strains obtained from cystic fibrosis patients, and also analyzed composite correlation index (CCI) values in patients with repeated MABSc inoculation and their correlation with the presence of clinical and radiological manifestations of mycobacteriosis.
RESULTS
As a result, MABSc more often grew in S-form colonies in patients without clinical manifestations of chronic infection, while R-form colonies were characteristic of patients with chronic infection and clinical symptoms. At the same time, in patients examined once, no growth of colonies in the R-form was recorded, and all strains produced growth in the form of either S-colonies or in the S- and R-forms simultaneously. Statistically significant results were obtained for the relationship of the CCI with the clinical and radiological picture. In addition, a heterogeneous MABSc population with low CCI score values correlated with the development of mycobacteriosis in patients. In patients with high CCI score values (homogeneity of isolated strains), on the contrary, there were no radiological or clinical signs of the disease.
CONCLUSION
These data make it possible to build a strategy for monitoring patients depending on changes in CCI score values. The use of CCI matrix to evaluate microorganisms' identification results is a potentially new method that expands the use of matrix-assisted laser desorption ionization time-of-flight mass spectrometry.
Topics: Humans; Cystic Fibrosis; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Female; Male
PubMed: 38916382
DOI: 10.4103/ijmy.ijmy_70_24 -
Microbiology Spectrum Jun 2024() as well as nontuberculous mycobacteria are intracellular pathogens whose treatment is extensive and increasingly impaired due to the rise of mycobacterial drug...
UNLABELLED
() as well as nontuberculous mycobacteria are intracellular pathogens whose treatment is extensive and increasingly impaired due to the rise of mycobacterial drug resistance. The loss of antibiotic efficacy has raised interest in the identification of host-directed therapeutics (HDT) to develop novel treatment strategies for mycobacterial infections. In this study, we identified amiodarone as a potential HDT candidate that inhibited both intracellular and in primary human macrophages without directly impairing bacterial growth, thereby confirming that amiodarone acts in a host-mediated manner. Moreover, amiodarone induced the formation of (auto)phagosomes and enhanced autophagic targeting of mycobacteria in macrophages. The induction of autophagy by amiodarone is likely due to enhanced transcriptional regulation, as the nuclear intensity of the transcription factor EB, the master regulator of autophagy and lysosomal biogenesis, was strongly increased. Furthermore, blocking lysosomal degradation with bafilomycin impaired the host-beneficial effect of amiodarone. Finally, amiodarone induced autophagy and reduced bacterial burden in a zebrafish embryo model of tuberculosis, thereby confirming the HDT activity of amiodarone . In conclusion, we have identified amiodarone as an autophagy-inducing antimycobacterial HDT that improves host control of mycobacterial infections.
IMPORTANCE
Due to the global rise in antibiotic resistance, there is a strong need for alternative treatment strategies against intracellular bacterial infections, including () and non-tuberculous mycobacteria. Stimulating host defense mechanisms by host-directed therapy (HDT) is a promising approach for treating mycobacterial infections. This study identified amiodarone, an antiarrhythmic agent, as a potential HDT candidate that inhibits the survival of and in primary human macrophages. The antimycobacterial effect of amiodarone was confirmed in an tuberculosis model based on infection of zebrafish embryos. Furthermore, amiodarone induced autophagy and inhibition of the autophagic flux effectively impaired the host-protective effect of amiodarone, supporting that activation of the host (auto)phagolysosomal pathway is essential for the mechanism of action of amiodarone. In conclusion, we have identified amiodarone as an autophagy-inducing HDT that improves host control of a wide range of mycobacteria.
PubMed: 38916320
DOI: 10.1128/spectrum.00167-24 -
The Journal of Infection Jun 2024The clinical relevance of Mycobacterium malmoense isolation from pulmonary specimens has been considered high compared with other non-tuberculous mycobacteria. In this... (Review)
Review
INTRODUCTION
The clinical relevance of Mycobacterium malmoense isolation from pulmonary specimens has been considered high compared with other non-tuberculous mycobacteria. In this study, we aimed to analyse all published clinical data of patients with M. malmoense isolation to investigate the clinical spectrum, relevance, and outcomes of infections with this uncommon mycobacterium.
METHODS
A systematic review of PubMed, Web of Science, Embase, and Scopus was performed to identify all clinical data about M. malmoense. Random effects meta-analyses of proportions were calculated for clinical relevance, treatment success, and mortality, as well as for other clinical characteristics. A logistic regression analysis, investigating predictors of mortality, as well as Kaplan-Meier survival analyses, were performed.
RESULTS
188 patients with individual data from 112 articles and 671 patients with pooled data from 12 articles were included in the meta-analyses. Of patients with individual data, pulmonary infection was the most common manifestation (n=106/188, 56.4%). One third (n=61/188, 32.4%) suffered from isolated extra-pulmonary and 21/188 (11.2%) from disseminated disease. In 288 patients with pooled data and pulmonary affection, clinical relevance was high with 68% (95% CI 44-85%) of patients fulfilling criteria for clinical disease. Macrolide and rifamycin-containing regimens were associated with improved survival (adjusted OR 0.12, 95% CI 0.03-0.42, p=0.002, and 0.23, 95% CI 0.04-0.86, p=0.03, for lethal events, respectively).
CONCLUSION
In this study, we provide a detailed clinical description of M. malmoense infections. The pathogen is of high clinical relevance for the individual patient with more than 2 out of 3 patients having relevant disease and >40% of manifestations being extra-pulmonary or disseminated. Macrolide and rifamycin-containing regimens are associated with improved survival.
PubMed: 38906266
DOI: 10.1016/j.jinf.2024.106203 -
Nature Communications Jun 2024Aerobic life is powered by membrane-bound redox enzymes that shuttle electrons to oxygen and transfer protons across a biological membrane. Structural studies suggest...
Aerobic life is powered by membrane-bound redox enzymes that shuttle electrons to oxygen and transfer protons across a biological membrane. Structural studies suggest that these energy-transducing enzymes operate as higher-order supercomplexes, but their functional role remains poorly understood and highly debated. Here we resolve the functional dynamics of the 0.7 MDa IIIIV obligate supercomplex from Mycobacterium smegmatis, a close relative of M. tuberculosis, the causative agent of tuberculosis. By combining computational, biochemical, and high-resolution (2.3 Å) cryo-electron microscopy experiments, we show how the mycobacterial supercomplex catalyses long-range charge transport from its menaquinol oxidation site to the binuclear active site for oxygen reduction. Our data reveal proton and electron pathways responsible for the charge transfer reactions, mechanistic principles of the quinone catalysis, and how unique molecular adaptations, water molecules, and lipid interactions enable the proton-coupled electron transfer (PCET) reactions. Our combined findings provide a mechanistic blueprint of mycobacterial supercomplexes and a basis for developing drugs against pathogenic bacteria.
Topics: Mycobacterium smegmatis; Electron Transport; Cryoelectron Microscopy; Oxidation-Reduction; Bacterial Proteins; Protons; Electron Transport Complex III; Oxygen; Electron Transport Complex IV; Catalytic Domain; Models, Molecular
PubMed: 38902248
DOI: 10.1038/s41467-024-49628-9 -
Medical Microbiology and Immunology Jun 2024Endogenous antimicrobial peptides (AMPs) play a key role in the host defense against pathogens. AMPs attack pathogens preferentially at the site of entry to prevent...
Endogenous antimicrobial peptides (AMPs) play a key role in the host defense against pathogens. AMPs attack pathogens preferentially at the site of entry to prevent invasive infection. Mycobacterium tuberculosis (Mtb) enters its host via the airways. AMPs released into the airways are therefore likely candidates to contribute to the clearance of Mtb immediately after infection. Since lysozyme is detectable in airway secretions, we evaluated its antimicrobial activity against Mtb. We demonstrate that lysozyme inhibits the growth of extracellular Mtb, including isoniazid-resistant strains. Lysozyme also inhibited the growth of non-tuberculous mycobacteria. Even though lysozyme entered Mtb-infected human macrophages and co-localized with the pathogen we did not observe antimicrobial activity. This observation was unlikely related to the large size of lysozyme (14.74 kDa) because a smaller lysozyme-derived peptide also co-localized with Mtb without affecting the viability. To evaluate whether the activity of lysozyme against extracellular Mtb could be relevant in vivo, we incubated Mtb with fractions of human serum and screened for antimicrobial activity. After several rounds of sub-fractionation, we identified a highly active fraction-component as lysozyme by mass spectrometry. In summary, our results identify lysozyme as an antimycobacterial protein that is detectable as an active compound in human serum. Our results demonstrate that the activity of AMPs against extracellular bacilli does not predict efficacy against intracellular pathogens despite co-localization within the macrophage. Ongoing experiments are designed to unravel peptide modifications that occur in the intracellular space and interfere with the deleterious activity of lysozyme in the extracellular environment.
Topics: Muramidase; Humans; Mycobacterium tuberculosis; Macrophages; Antimicrobial Peptides; Microbial Sensitivity Tests; Microbial Viability
PubMed: 38900248
DOI: 10.1007/s00430-024-00793-0 -
BMC Infectious Diseases Jun 2024Although the Mini Nutritional Assessment (MNA) is recognized as a useful tool for evaluating nutritional status in patients with various diseases, its applicability in...
Usefulness of the mini nutritional assessment short-form for evaluating nutritional status in patients with nontuberculous mycobacterial pulmonary disease: a prospective cross-sectional study.
BACKGROUND
Although the Mini Nutritional Assessment (MNA) is recognized as a useful tool for evaluating nutritional status in patients with various diseases, its applicability in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) remains undetermined.
METHODS
We designed a prospective cross-sectional study to investigate whether the MNA Short-Form (MNA-SF) score can serve as a screening tool to assess the nutritional status of patients with NTM-PD. The MNA-SF was conducted upon patient enrollment, and correlation analyses were performed to compare MNA-SF scores with other nutritional measurements and disease severity. Multivariable logistic regression analyses were conducted to evaluate the association between MNA-SF scores and NTM-PD severity.
RESULTS
The 194 patients with NTM-PD included in the analysis had a median age of 65.0 (59.0-69.0) years; 59.3% (n = 115) had low MNA-SF scores (< 12). The low MNA-SF group exhibited a lower body mass index (19.7 vs. 22.4 kg/m, p < 0.001) and fat-free mass index (14.7 vs. 15.6 kg/m, p < 0.001) than the normal MNA-SF group, as well as higher incidences of sarcopenia (20.0% vs. 6.3%, p = 0.008) and adipopenia (35.7% vs. 5.1%, p < 0.001). However, no significant differences in calorie and protein intakes were observed between the two groups. Low MNA-SF scores were associated with radiographic severity (adjusted odds ratio 2.72, 95% confidence interval 1.38-5.36) but not with forced vital capacity.
CONCLUSIONS
The MNA-SF can effectively assess the nutritional status of patients with NTM-PD and can serve as an important clinical indicator in NTM-PD where treatment timing is determined by clinical judgment.
Topics: Humans; Cross-Sectional Studies; Male; Female; Aged; Middle Aged; Prospective Studies; Nutritional Status; Nutrition Assessment; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Lung Diseases
PubMed: 38898397
DOI: 10.1186/s12879-024-09499-3 -
ELife Jun 2024Tuberculosis is a major global health problem and is one of the top 10 causes of death worldwide. There is a pressing need for new treatments that circumvent emerging...
Tuberculosis is a major global health problem and is one of the top 10 causes of death worldwide. There is a pressing need for new treatments that circumvent emerging antibiotic resistance. parasitises macrophages, reprogramming them to establish a niche in which to proliferate, therefore macrophage manipulation is a potential host-directed therapy if druggable molecular targets could be identified. The pseudokinase Tribbles1 (Trib1) regulates multiple innate immune processes and inflammatory profiles making it a potential drug target in infections. Trib1 controls macrophage function, cytokine production, and macrophage polarisation. Despite wide-ranging effects on leukocyte biology, data exploring the roles of Tribbles in infection in vivo are limited. Here, we identify that human Tribbles1 is expressed in monocytes and is upregulated at the transcript level after stimulation with mycobacterial antigen. To investigate the mechanistic roles of Tribbles in the host response to mycobacteria in vivo, we used a zebrafish (Mm) infection tuberculosis model. Zebrafish Tribbles family members were characterised and shown to have substantial mRNA and protein sequence homology to their human orthologues. overexpression was host-protective against Mm infection, reducing burden by approximately 50%. Conversely, knockdown/knockout exhibited increased infection. Mechanistically, overexpression significantly increased the levels of proinflammatory factors and nitric oxide. The host-protective effect of was found to be dependent on the E3 ubiquitin kinase Cop1. These findings highlight the importance of Trib1 and Cop1 as immune regulators during infection in vivo and suggest that enhancing macrophage TRIB1 levels may provide a tractable therapeutic intervention to improve bacterial infection outcomes in tuberculosis.
Topics: Animals; Protein Serine-Threonine Kinases; Zebrafish; Humans; Intracellular Signaling Peptides and Proteins; Mycobacterium marinum; Disease Models, Animal; Mycobacterium Infections, Nontuberculous; Monocytes; Macrophages; Host-Pathogen Interactions
PubMed: 38896446
DOI: 10.7554/eLife.95980 -
BioRxiv : the Preprint Server For... Jun 2024Machine learning (ML) algorithms are necessary to efficiently identify potent drug combinations within a large candidate space to combat drug resistance. However,...
Machine learning (ML) algorithms are necessary to efficiently identify potent drug combinations within a large candidate space to combat drug resistance. However, existing ML approaches cannot be applied to emerging and under-studied pathogens with limited training data. To address this, we developed a transfer learning and crowdsourcing framework (TACTIC) to train ML models on data from multiple bacteria. TACTIC was built using 2,965 drug interactions from 12 bacterial strains and outperformed traditional ML models in predicting drug interaction outcomes for species that lack training data. Top TACTIC model features revealed genetic and metabolic factors that influence cross-species and species-specific drug interaction outcomes. Upon analyzing ~600,000 predicted drug interactions across 9 metabolic environments and 18 bacterial strains, we identified a small set of drug interactions that are selectively synergistic against Gram-negative (e.g., ) and non-tuberculous mycobacteria (NTM) pathogens. We experimentally validated synergistic drug combinations containing clarithromycin, ampicillin, and mecillinam against , an emerging pathogen with growing levels of antibiotic resistance. Lastly, we leveraged TACTIC to propose selectively synergistic drug combinations to treat bacterial eye infections (endophthalmitis).
PubMed: 38895385
DOI: 10.1101/2024.06.04.597386