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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 -
Microorganisms Jul 2023Skin and soft tissue infections caused by non-tuberculous mycobacteria are occurring more frequently in recent years. However, chronic skin and soft tissue lesions... (Review)
Review
Skin and soft tissue infections caused by non-tuberculous mycobacteria are occurring more frequently in recent years. However, chronic skin and soft tissue lesions present a challenge for clinicians, as the diagnostic work-up and definitive diagnosis require knowledge and available laboratory resources. We present here the case of a 66-year-old male patient who presented with painful abscess-like nodules on his right hand and forearm, which worsened after treatment with an anti-TNF-a agent. The fluid specimen taken from the lesion was positive for mycobacteria according to the acid-fast stain. was identified, first by next-generation sequencing and finally grown on culture, after eight weeks. Acknowledging the complexity of diagnosing and managing infections by non-tuberculous mycobacteria, and especially , we provide a review of the current epidemiology, clinical characteristics, diagnosis and management of infection.
PubMed: 37512971
DOI: 10.3390/microorganisms11071799 -
Immunity, Inflammation and Disease Jul 2023Sepsis is characterized by an endotoxin tolerance phenotype that occurs in the stage of infection. Persistent bacterial infection can lead to immune cell exhaustion....
INTRODUCTION
Sepsis is characterized by an endotoxin tolerance phenotype that occurs in the stage of infection. Persistent bacterial infection can lead to immune cell exhaustion. Triad3A, an E3 ubiquitin ligase, negatively regulates its activation by TLR4. However, the effect of Triad3A on endotoxin tolerance and bactericidal ability in the state of endotoxin tolerance remains unclear.
METHODS
Using single dose LPS and repeated LPS stimulated macrophage cell lines at indicated times, we investigated miR-191, Tirad3A, TRAF3, TLR4, p-P65, TNF-α, IL-1β, and iNOS expression, the effect of miR-191 on Triad3A and TRAF3, gene loss-of-function analyses, the effect of Triad3A on TLR4, p-P65, cytokine, and mycobactericidal activity in endotoxin tolerant cells infected with Mycobacterium marinum.
RESULTS
Here we found that Triad3A is involved in regulating endotoxin tolerance. Our result also displayed that miR-191 expression is downregulated in macrophages in the state of endotoxin tolerance. miR-191 can directly bind to Triad3A and TRAF3. Additionally, knockdown of Triad3A can reverse the effect of decreasing TNF-α and IL-1β in endotoxin tolerant macrophages. Furthermore, we demonstrated that the TLR4-NF-κB-NO pathway was associated with Triad3A and responsible for the killing of intracellular mycobacteria in a tuberculosis sepsis model.
CONCLUSIONS
These results provide new insight into the mechanisms of Triad3A induced tolerogenic phenotype in macrophages, which can help the better comprehension of the pathogenesis involved in septic shock with infection of Mycobacterium tuberculosis, and suggest that Triad3A may be a potential drug target for the treatment of severe septic tuberculosis.
Topics: Humans; NF-kappa B; Nitric Oxide; Lipopolysaccharides; Tumor Necrosis Factor-alpha; Toll-Like Receptor 4; Endotoxin Tolerance; TNF Receptor-Associated Factor 3; Endotoxins; Sepsis; MicroRNAs
PubMed: 37506157
DOI: 10.1002/iid3.925 -
Frontiers in Cellular and Infection... 2023The clinical practicability of DNA microarray chip in detecting the presence of mycobacterial species/isolates directly in the skin tissues has not been evaluated, nor...
INTRODUCTION
The clinical practicability of DNA microarray chip in detecting the presence of mycobacterial species/isolates directly in the skin tissues has not been evaluated, nor the efficacy of DNA microarray chip as a novel diagnostic tool for the early diagnosis of cutaneous mycobacterial infections is known.
METHODS
The present study analyzed the incidence of cutaneous mycobacterial infections in Shanghai and explored the efficacy of a novel DNA microarray chip assay for the clinical diagnosis of the disease from skin tissue specimens compared to traditional detection methods. A total of 60 participants fulfilling the defined diagnostic criteria and confirmed positive for cutaneous mycobacterial infections from 2019 to 2021 were enrolled in the study. Subsequent to recording the participants' medical history and clinical characteristics, the skin tissue specimens were collected for analyses. The specimens underwent histopathological analyses, skin tissue culture, and DNA microarray chip assay.
RESULTS
Increased incidence of cutaneous mycobacterial infection was detected from 2019 to 2021. The most common infecting pathogen was followed by . The sensitivity, specificity and accuracy of the skin tissue culture method were 70%, 100% and 76.62%, respectively, while that of the DNA microarray chip assay were 91.67%, 100% and 93.51%, respectively. The sensitivity and accuracy of the DNA microarray chip assay were significantly higher than those of the skin tissue culture method. The positive likelihood and diagnostic odds ratio were >10 and >1, respectively for both the methods. The negative likelihood ratio was significantly higher (30% vs 8.33%) and the Youden's index was significantly lower (70.00% vs 91.67%) in the skin culture method compared to that of the DNA microarray chip assay. There was a significant association of false negative results with a history of antibiotic use in the skin tissue culture method.
DISCUSSION
Given the increasing incidence of cutaneous mycobacterial infections, early diagnosis remains a prime clinical focus. The DNA microarray chip assay provides a simple, rapid, high-throughput, and reliable method for the diagnosis of cutaneous mycobacterial infections with potential for clinical application.
Topics: Humans; Oligonucleotide Array Sequence Analysis; China; Mycobacterium Infections; Mycobacterium; Skin Diseases, Bacterial; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria
PubMed: 37457951
DOI: 10.3389/fcimb.2023.1183078 -
Cureus Jun 2023is a non-tuberculous mycobacterium that presents as a nodular granulomatous disease. The bacillus can infect humans when broken skin is exposed to a contaminated...
is a non-tuberculous mycobacterium that presents as a nodular granulomatous disease. The bacillus can infect humans when broken skin is exposed to a contaminated aquatic environment. infections are usually isolated to the skin and soft tissues and can spread in a lymphatic distribution. A 26-year-old male cut his right ankle while spelunking in Tulum, Mexico. He presented to his primary care physician three months after he sustained the laceration with a nonhealing wound on the right lateral posterior ankle. Examination of the lesion demonstrated erythematous, violaceous, and hyperpigmented indurated plaques with satellite lesions noted at the right medial, posterior, and lateral ankle. The lesion characteristics raised initial suspicion for an invasive fungal infection. Biopsy of the lesion demonstrated epidermal ulceration covered by neutrophilic serum, marked underlying dermal acute inflammation, and granulation tissue. A mild perivascular, predominantly lymphocytic infiltrate was present in the deep dermis with no evidence of granuloma. Acid-fast bacilli culture plated onto chocolate agar confirmed the species
PubMed: 37404425
DOI: 10.7759/cureus.39908 -
Pathogens (Basel, Switzerland) Jun 2023Prior to the COVID-19 pandemic, tuberculosis (TB) was the leading cause of death globally attributable to a single infectious agent, ranking higher than HIV/AIDS....
Prior to the COVID-19 pandemic, tuberculosis (TB) was the leading cause of death globally attributable to a single infectious agent, ranking higher than HIV/AIDS. Consequently, TB remains an urgent public health crisis worldwide. Oridonin (7a,20-Epoxy-1a,6b,7,14-tetrahydroxy-Kaur-16-en-15-one Isodonol, CHO, Ori), derived from the plant, is a natural compound that exhibits antioxidant, anti-inflammatory, and antibacterial properties. Our objective was to investigate whether Ori's antioxidant and antibacterial effects could be effective against the infection ()-infected cells and zebrafish. We observed that Ori treatment significantly impeded infection in lung epithelial cells, while also suppressing inflammatory response and oxidative stress in -infected macrophages. Further investigation revealed that Ori supplementation inhibited the proliferation of in zebrafish, as well as reducing oxidative stress levels in infected zebrafish. Additionally, Ori promoted the expression of NRF2/HO-1/NQO-1 and activated the AKT/AMPK-α1/GSK-3β signaling pathway, which are both associated with anti-inflammatory and antioxidant effects. In summary, our results demonstrate that Ori exerts inhibitory effects on infection and proliferation in cells and zebrafish, respectively. Additionally, Ori regulates oxidative stress by modulating the NRF2/HO-1/NQO-1 and AKT/AMPK-α1/GSK-3β signaling pathways.
PubMed: 37375489
DOI: 10.3390/pathogens12060799 -
Biology Jun 2023Existing drug treatment against tuberculosis is no match against the increasing number of multi-drug resistant strains of its causative agent, (). A better...
Existing drug treatment against tuberculosis is no match against the increasing number of multi-drug resistant strains of its causative agent, (). A better understanding of how mycobacteria subvert the host immune defenses is crucial for developing novel therapeutic strategies. A potential approach is enhancing the activity of the autophagy machinery, which can direct bacteria to autophagolysosomal degradation. However, the interplay specifics between mycobacteria and the autophagy machinery must be better understood. Here, we analyzed live imaging data from the zebrafish model of tuberculosis to characterize mycobacteria-autophagy interactions during the early stages of infection in vivo. For high-resolution imaging, we microinjected fluorescent () into the tail fin tissue of zebrafish larvae carrying the GFP-LC3 autophagy reporter. We detected phagocytosed clusters and LC3-positive -containing vesicles within the first hour of infection. LC3 associations with these vesicles were transient and heterogeneous, ranging from simple vesicles to complex compound structures, dynamically changing shape by fusions between -containing and empty vesicles. LC3--vesicles could adopt elongated shapes during cell migration or alternate between spacious and compact morphologies. LC3--vesicles were also observed in cells reverse migrating from the infection site, indicating that the autophagy machinery fails to control infection before tissue dissemination.
PubMed: 37372102
DOI: 10.3390/biology12060817 -
Scientific Reports Jun 2023Lipids are highly structurally diverse molecules involved in a wide variety of biological processes. The involvement of lipids is even more pronounced in mycobacteria,...
Lipids are highly structurally diverse molecules involved in a wide variety of biological processes. The involvement of lipids is even more pronounced in mycobacteria, including the human pathogen Mycobacterium tuberculosis, which produces a highly complex and diverse set of lipids in the cell envelope. These lipids include mycolic acids, which are among the longest fatty acids in nature and can contain up to 90 carbon atoms. Mycolic acids are ubiquitously found in mycobacteria and are alpha branched and beta hydroxylated lipids. Discrete modifications, such as alpha, alpha', epoxy, methoxy, keto, and carboxy, characterize mycolic acids at the species level. Here, we used high precision ion mobility-mass spectrometry to build a database including 206 mass-resolved collision cross sections (CCSs) of mycolic acids originating from the strict human pathogen M. tuberculosis, the opportunistic strains M. abscessus, M. marinum and M. avium, and the nonpathogenic strain M. smegmatis. Primary differences between the mycolic acid profiles could be observed between mycobacterial species. Acyl tail length and modifications were the primary structural descriptors determining CCS magnitude. As a resource for researchers, this work provides a detailed catalogue of the mass-resolved collision cross sections for mycolic acids along with a workflow to generate and analyse the dataset generated.
Topics: Humans; Mycolic Acids; Mycobacterium tuberculosis; Fatty Acids; Mass Spectrometry
PubMed: 37369807
DOI: 10.1038/s41598-023-37641-9 -
Bioorganic & Medicinal Chemistry Letters Aug 2023A series of 2-(tetrazol-5-yl)sulfonylacetamide derivatives were synthesized and evaluated for their in vitro inhibitory activity against Mycobacterium tuberculosis (Mtb)...
A series of 2-(tetrazol-5-yl)sulfonylacetamide derivatives were synthesized and evaluated for their in vitro inhibitory activity against Mycobacterium tuberculosis (Mtb) and Mycobacterium marinum (Mm). The most active compounds exhibited in vitro MIC values of 1.25 μg/mL against Mtb, but they were less effective against Mm (MIC ≥ 10 μg/mL). Despite the most active compounds having favourable physicochemical properties and one of them having a half-life of ∼3 h when incubated with mouse liver microsomes, two representative highly active compounds showed strong chemical reactivity to cysteine derivatives, as surrogate in vivo sulfur-centred nucleophiles, indicating excessive electrophilicity, and therefore, likely indiscriminate chemical reactivity in vivo, representing an unacceptably high risk of general toxicity, and low likelihood of being therapeutically effective.
Topics: Animals; Mice; Mycobacterium tuberculosis; Antitubercular Agents; Mycobacterium marinum; Microbial Sensitivity Tests; Structure-Activity Relationship
PubMed: 37369331
DOI: 10.1016/j.bmcl.2023.129391