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MBio Jun 2024() affects patients with immunosuppression or underlying structural lung diseases such as cystic fibrosis (CF). Additionally, poses clinical challenges due to its...
UNLABELLED
() affects patients with immunosuppression or underlying structural lung diseases such as cystic fibrosis (CF). Additionally, poses clinical challenges due to its resistance to multiple antibiotics. Herein, we investigated the synergistic effect of dual β-lactams [sulopenem and cefuroxime (CXM)] or the combination of sulopenem and CXM with β-lactamase inhibitors [BLIs-avibactam (AVI) or durlobactam (DUR)]. The sulopenem-CXM combination yielded low minimum inhibitory concentration (MIC) values for 54 clinical isolates and ATCC19977 (MIC and MIC ≤0.25 µg/mL). Similar synergistic effects were observed in time-kill studies conducted at concentrations achievable in clinical settings. Sulopenem-CXM outperformed monotherapy, yielding ~1.5 Log CFU/mL reduction during 10 days. Addition of BLIs enhanced this antibacterial effect, resulting in an additional reduction of CFUs (~3 Log for sulopenem-CXM and AVI and ~4 Log for sulopenem-DUR). Exploration of the potential mechanisms of the synergy focused on their interactions with L,D-transpeptidases (Ldts; Ldt-Ldt), penicillin-binding-protein B (PBP B), and D,D-carboxypeptidase (DDC). Acyl complexes, identified via mass spectrometry analysis, demonstrated the binding of sulopenem with Ldt-Ldt, DDC, and PBP B and CXM with Ldt and PBP B. Molecular docking and mass spectrometry data suggest the formation of a covalent adduct between sulopenem and Ldt after the nucleophilic attack of the cysteine residue at the β-lactam carbonyl carbon, leading to the cleavage of the β-lactam ring and the establishment of a thioester bond linking the Ldt with sulopenem. In conclusion, we demonstrated the biochemical basis of the synergy of sulopenem-CXM with or without BLIs. These findings potentially broaden the selection of oral therapeutic agents to combat .
IMPORTANCE
Treating infections from (Mab), particularly those resistant to common antibiotics like macrolides, is notoriously difficult, akin to a never-ending struggle for healthcare providers. The rate of treatment failure is even higher than that seen with multidrug-resistant tuberculosis. The role of combination β-lactams in inhibiting L,D-transpeptidation, the major peptidoglycan crosslink reaction in Mab, is an area of intense investigation, and clinicians have utilized this approach in the treatment of macrolide-resistant Mab, with reports showing clinical success. In our study, we found that cefuroxime and sulopenem, when used together, display a significant synergistic effect. If this promising result seen in lab settings, translates well into real-world clinical effectiveness, it could revolutionize current treatment methods. This combination could either replace the need for more complex intravenous medications or serve as a "step down" to an oral medication regimen. Such a shift would be much easier for patients to manage, enhancing their comfort and likelihood of sticking to the treatment plan, which could lead to better outcomes in tackling these tough infections. Our research delved into how these drugs inhibit cell wall synthesis, examined time-kill data and binding studies, and provided a scientific basis for the observed synergy in cell-based assays.
Topics: Mycobacterium abscessus; Anti-Bacterial Agents; Drug Synergism; Microbial Sensitivity Tests; Humans; Cefuroxime; Mycobacterium Infections, Nontuberculous; beta-Lactamase Inhibitors; Molecular Docking Simulation; Prohibitins
PubMed: 38742824
DOI: 10.1128/mbio.00609-24 -
Frontiers in Neurology 2024Nontuberculous mycobacteria (NTM) mediated infections are important to consider in cases with neuroinflammatory presentations. We aimed to characterize cases of NTM with...
INTRODUCTION
Nontuberculous mycobacteria (NTM) mediated infections are important to consider in cases with neuroinflammatory presentations. We aimed to characterize cases of NTM with neurological manifestations at the National Institutes of Health (NIH) Clinical Center and review the relevant literature.
MATERIALS AND METHODS
Between January 1995 and December 2020, six cases were identified. Records were reviewed for demographic, clinical, and radiological characteristics. A MEDLINE search found previously reported cases. Data were extracted, followed by statistical analysis to compare two groups [cases with slow-growing mycobacteria (SGM) vs. those with rapidly growing mycobacteria (RGM)] and evaluate for predictors of survival. NIH cases were evaluated for clinical and radiological characteristics. Cases from the literature were reviewed to determine the differences between SGM and RGM cases and to identify predictors of survival.
RESULTS
Six cases from NIH were identified (age 41 ± 13, 83% male). Five cases were caused by SGM [ complex (MAC) = 4; = 1] and one due to RGM (). Underlying immune disorders were identified only in the SGM cases [genetic ( = 2), HIV ( = 1), sarcoidosis ( = 1), and anti-interferon-gamma antibodies ( = 1)]. All cases were diagnosed using tissue analysis. A literature review found 81 reports on 125 cases (SGM = 85, RGM = 38, non-identified = 2). No immune disorder was reported in 26 cases (21%). Within SGM cases, the most common underlying disease was HIV infection ( = 55, 65%), and seizures and focal lesions were more common. In RGM cases, the most common underlying condition was neurosurgical intervention or implants (55%), and headaches and meningeal signs were common. Tissue-based diagnosis was used more for SGM than RGM (39% vs. 13%, = 0.04). Survival rates were similar in both groups (48% SGM and 55% in RGM). Factors associated with better survival were a solitary CNS lesion (OR 5.9, = 0.01) and a diagnosis made by CSF sampling only (OR 9.9, = 0.04).
DISCUSSION
NTM infections cause diverse neurological manifestations, with some distinctions between SGM and RGM infections. Tissue sampling may be necessary to establish the diagnosis, and an effort should be made to identify an underlying immune disorder.
PubMed: 38742044
DOI: 10.3389/fneur.2024.1360128 -
Respiratory Medicine Jul 2024This study aimed to evaluate the association between the number of non-cystic fibrosis bronchiectasis (bronchiectasis) exacerbations during baseline and follow-up...
BACKGROUND
This study aimed to evaluate the association between the number of non-cystic fibrosis bronchiectasis (bronchiectasis) exacerbations during baseline and follow-up (objective 1) and to identify longitudinal changes in FEV associated with exacerbation frequency (objective 2).
METHODS
This was a retrospective cohort study of adult patients enrolled in the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry September 2008 to March 2020. Objective 1 outcome was association between exacerbations during baseline (24 months) and 0-to-24 month and 24-to-48 month follow-up windows. Objective 2 outcomes were change in FEV and FEV % predicted over 24 months stratified by baseline exacerbation frequency.
RESULTS
Objective 1 cohort (N = 520) baseline frequency of any exacerbations was 59.2%. Overall, 71.4% and 75.0% of patients with ≥1 baseline exacerbations had ≥1 exacerbations during the 0-to-24 and 24-to-48 month follow-ups. Having ≥1 exacerbation during baseline was significantly associated with ≥1 exacerbation during the 0-to-24 month (P = 0.0085) and 24-to-48 month follow-ups (P=<0.0001). Objective 2 cohort (N = 431) baseline FEV was significantly lower in patients who had more exacerbations; however, decline in FEV from baseline was not significantly different between patients with 0, 1, and ≥2 exacerbations. In patients with more baseline exacerbations, FEV % predicted was significantly lower at baseline (P < 0.0001) and at 12 (P = 0.0002) and 24 month follow-ups (P < 0.0001).
CONCLUSIONS
Patients with frequent bronchiectasis exacerbations may be more likely than those with less frequent exacerbations to experience disease progression based on future exacerbation frequency and lower FEV at baseline, although FEV decline may not differ by baseline exacerbation frequency.
Topics: Bronchiectasis; Humans; Male; Female; Forced Expiratory Volume; Disease Progression; Retrospective Studies; Middle Aged; Registries; Aged; Longitudinal Studies; Mycobacterium Infections, Nontuberculous; United States; Adult; Follow-Up Studies
PubMed: 38734153
DOI: 10.1016/j.rmed.2024.107660 -
Journal of Infection in Developing... Apr 2024Mycobacterium marinum infection rarely occurs and has atypical symptoms. It is challenging to distinguish disseminated M. marinum infection from multifocal dermatosis...
INTRODUCTION
Mycobacterium marinum infection rarely occurs and has atypical symptoms. It is challenging to distinguish disseminated M. marinum infection from multifocal dermatosis caused by other factors clinically.
CASE PRESENTATION
Herein, we reported a 68-year-old male patient with Human Immunodeficiency Virus (HIV) who presented redness and swelling in his left hand after being stabbed by marine fish for over 2 months. Mycobacterium tuberculosis infection was considered according to biochemical and pathological examinations, while empirical anti-infection treatment was ineffective.
RESULTS
The metagenomic next-generation sequencing (mNGS) detected a large amount of M. marinum sequences, and the patient was finally diagnosed with M. marinum infection. After one month of combination therapy with ethambutol, rifabutin, moxifloxacin, and linezolid, the swelling disappeared significantly. In this case, the successful application of mNGS in diagnosing and treating M. marinum infection has improved the understanding of the microbe both in the laboratory and clinically, especially in patients with HIV.
CONCLUSIONS
For diseases with atypical symptoms or difficulty in determining the pathogens, mNGS is suggested in clinical procedures for rapid and accurate diagnosis and treatment.
Topics: Humans; Male; Mycobacterium Infections, Nontuberculous; Aged; Mycobacterium marinum; HIV Infections; High-Throughput Nucleotide Sequencing; Metagenomics; Ethambutol; Anti-Bacterial Agents
PubMed: 38728638
DOI: 10.3855/jidc.18114 -
PloS One 2024Increasingly prevalent, nontuberculous mycobacteria (NTM) infections affect approximately 20% of people with cystic fibrosis (CF). Previous studies of CF sputum...
Itaconic acid inhibits nontuberculous mycobacterial growth in pH dependent manner while 4-octyl-itaconic acid enhances THP-1 clearance of nontuberculous mycobacteria in vitro.
Increasingly prevalent, nontuberculous mycobacteria (NTM) infections affect approximately 20% of people with cystic fibrosis (CF). Previous studies of CF sputum identified lower levels of the host metabolite itaconate in those infected with NTM. Itaconate can inhibit the growth of M. tuberculosis (MTB) in vitro via the inhibition of the glyoxylate cycle enzyme (ICL), but its impact on NTM is unclear. To test itaconic acid's (IA) effect on NTM growth, laboratory and CF clinical strains of Mycobacterium abscessus and Mycobacterium avium were cultured in 7H9 minimal media supplemented with 1-10 mM of IA and short-chain fatty acids (SCFA). M. avium and M. abscessus grew when supplemented with SCFAs, whereas the addition of IA (≥ 10 mM) completely inhibited NTM growth. NTM supplemented with acetate or propionate and 5 mM IA displayed slower growth than NTM cultured with SCFA and ≤ 1 mM of IA. However, IA's inhibition of NTM was pH dependent; as similar and higher quantities (100 mM) of pH adjusted IA (pH 7) did not inhibit growth in vitro, while in an acidic minimal media (pH 6.1), 1 to 5 mM of non-pH adjusted IA inhibited growth. None of the examined isolates displayed the ability to utilize IA as a carbon source, and IA added to M. abscessus isocitrate lyase (ICL) decreased enzymatic activity. Lastly, the addition of cell-permeable 4-octyl itaconate (4-OI) to THP-1 cells enhanced NTM clearance, demonstrating a potential role for IA/itaconate in host defense against NTM infections.
Topics: Succinates; Humans; Hydrogen-Ion Concentration; Nontuberculous Mycobacteria; THP-1 Cells; Mycobacterium Infections, Nontuberculous; Mycobacterium avium; Mycobacterium abscessus
PubMed: 38728330
DOI: 10.1371/journal.pone.0303516 -
Tuberculosis (Edinburgh, Scotland) Jul 2024Exposure to Non-tuberculous Mycobacteria (NTM) varies regionally and may partly explain the disparate outcomes of BCG vaccination and tuberculosis (TB) susceptibility.
INTRODUCTION
Exposure to Non-tuberculous Mycobacteria (NTM) varies regionally and may partly explain the disparate outcomes of BCG vaccination and tuberculosis (TB) susceptibility.
METHODS
We examined NTM sputum colonization, associations with clinical characteristics, and tuberculin skin test (TST) responses in an adolescent TB prevalence survey.
RESULTS
Among 5004 adolescents screened, 2281 (45.5 %) were evaluated further. TB and NTM prevalence rates were 0.3 % and 8.0 %, respectively. Among 418 NTM isolates, 103 were unidentifiable, and 315 (75 %) comprised 15 species, the most frequent being M. intracellulare (MAC) (108, 26 %), M. scrofulaceum (96, 23 %) and M. fortuitum (51, 12 %). "NTM colonized" adolescents had less frequent chronic cough and night sweats (adjusted odds ratio [aOR] 0.62, 95 % confidence interval [CI] 0.44-0.87and aOR 0.61, CI 0.42-0.89 respectively), and lower TST induration (median 11 mm (interquartile range [IQR] 0-16) vs 13 mm (IQR 6-17; p = 0.006)) when compared to "NTM not colonized" participants. MAC, but not M. scrofulaceum or M. fortuitum, was associated with decreased TST induration (median 7.5 mm (IQR 0-15) vs 13 mm (IQR 6-17) among "MAC colonized" vs "not colonized", p = 0.001).
CONCLUSION
We observed high NTM prevalence rates with species-specific associations with TST induration, consistent with a model of species-dependent heterologous immunity among mycobacteria.
Topics: Humans; Tuberculin Test; Adolescent; Kenya; Male; Female; Prevalence; Sputum; Mycobacterium avium Complex; Mycobacterium Infections, Nontuberculous; Tuberculosis, Pulmonary; Child; Mycobacterium avium-intracellulare Infection; Predictive Value of Tests; Cross-Sectional Studies
PubMed: 38723342
DOI: 10.1016/j.tube.2024.102514 -
MMWR. Morbidity and Mortality Weekly... May 2024Mycobacterium abscessus is an intrinsically drug-resistant, rapidly growing, nontuberculous mycobacterium; extrapulmonary infections have been reported in association...
Notes from the Field: Potential Outbreak of Extrapulmonary Mycobacterium abscessus subspecies massiliense Infections from Stem Cell Treatment Clinics in Mexico - Arizona and Colorado, 2022.
Mycobacterium abscessus is an intrinsically drug-resistant, rapidly growing, nontuberculous mycobacterium; extrapulmonary infections have been reported in association with medical tourism (1). During November-December 2022, two Colorado hospitals (hospitals A and B) treated patient A, a Colorado woman aged 30-39 years, for M. abscessus meningitis. In October 2022, she had received intrathecal donor embryonic stem cell injections in Baja California, Mexico to treat multiple sclerosis and subsequently experienced headaches and fevers, consistent with meningitis. Her cerebrospinal fluid revealed neutrophilic pleocytosis and grew M. abscessus in culture at hospital A. Hospital A's physicians consulted hospital B's infectious diseases (ID) physicians to co-manage this patient (2).
Topics: Humans; Colorado; Adult; Female; Disease Outbreaks; Mexico; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Arizona; Stem Cell Transplantation
PubMed: 38722805
DOI: 10.15585/mmwr.mm7318a3 -
Vitamin B uptake across the mycobacterial outer membrane is influenced by membrane permeability in .Microbiology Spectrum Jun 2024Vitamin B (B) serves as a critical cofactor within mycobacterial metabolism. While some pathogenic strains can synthesize B , others rely on host-acquired B. In this...
Vitamin B (B) serves as a critical cofactor within mycobacterial metabolism. While some pathogenic strains can synthesize B , others rely on host-acquired B. In this investigation, we studied the transport of vitamin B in using B-auxotrophic and B-sensitive strains by deleting or , respectively. These two enzymes rely on B in different ways to function as methionine synthases. We used these strains to select mutants affecting B scavenging and confirmed their phenotypes during growth experiments . Our analysis of B uptake mechanisms revealed that membrane lipids and cell wall integrity play an essential role in cell envelope transport. Furthermore, we identified a potential transcription regulator that responds to B. Our study demonstrates that can take up exogenous B and that altering mycobacterial membrane integrity affects B uptake. Finally, during zebrafish infection using B-auxotrophic and B-sensitive strains, we found that B is available for virulent mycobacteria .IMPORTANCEOur study investigates how mycobacteria acquire essential vitamin B. These microbes, including those causing tuberculosis, face challenges in nutrient uptake due to their strong outer layer. We focused on , similar to TB bacteria, to uncover its vitamin B absorption. We used modified strains unable to produce their own B and discovered that can indeed absorb it from the environment, even during infections. Changes in the outer layer composition affect this process, and genes related to membrane integrity play key roles. These findings illuminate the interaction between mycobacteria and their environment, offering insights into combatting diseases like tuberculosis through innovative strategies. Our concise research underscores the pivotal role of vitamin B in microbial survival and its potential applications in disease control.
Topics: Mycobacterium marinum; Vitamin B 12; Animals; Zebrafish; Bacterial Outer Membrane; Bacterial Proteins; Cell Membrane Permeability; Biological Transport; Cell Membrane; Mycobacterium Infections, Nontuberculous
PubMed: 38722177
DOI: 10.1128/spectrum.03168-23 -
The Journal of Antibiotics Jul 2024Three new liposidomycin congeners (1, 2, and 4), together with 14 known liposidomycins (3 and 5-17), were isolated from the culture broth of Streptomyces sp. TMPU-20A065...
Three new liposidomycin congeners (1, 2, and 4), together with 14 known liposidomycins (3 and 5-17), were isolated from the culture broth of Streptomyces sp. TMPU-20A065 as anti-Mycobacterium avium complex agents. The structures of liposidomycins were elucidated by spectroscopic analyses, including NMR and MS. Compounds 1, 2, and 4 belong to type-I liposidomycin-containing sulfate groups and methylglutaric acid, each with a different acyl side chain in the structure. Compounds 1-17 exhibited in vitro anti-M. avium and M. intracellulare activities with MIC values ranging between 2.0 and 64 μg ml. Furthermore, 1-17 exerted potent therapeutic effects in an in vivo-mimic silkworm infection model with ED values ranging between 0.12 and 3.7 μg larva g.
Topics: Animals; Streptomyces; Bombyx; Microbial Sensitivity Tests; Anti-Bacterial Agents; Mycobacterium avium Complex; Magnetic Resonance Spectroscopy; Disease Models, Animal; Molecular Structure
PubMed: 38720140
DOI: 10.1038/s41429-024-00724-4 -
Frontiers in Immunology 2024complex (MAC) is a non-tuberculous mycobacterium widely distributed in the environment. Even though MAC infection is increasing in older women and immunocompromised...
complex (MAC) is a non-tuberculous mycobacterium widely distributed in the environment. Even though MAC infection is increasing in older women and immunocompromised patients, to our knowledge there has been no comprehensive analysis of the MAC-infected host-cell transcriptome-and particularly of long non-coding RNAs (lncRNAs). By using cultured primary mouse bone-marrow-derived macrophages (BMDMs) and Cap analysis of gene expression, we analyzed the transcriptional and kinetic landscape of macrophage genes, with a focus on lncRNAs, during MAC infection. MAC infection of macrophages induced the expression of immune/inflammatory response genes and other genes similar to those involved in M1 macrophage activation, consistent with previous reports, although (M1 activation) and (M2 activation) had distinct expression profiles. We identified 31 upregulated and 30 downregulated lncRNA promoters corresponding respectively to 18 and 26 lncRNAs. Upregulated lncRNAs were clustered into two groups-early and late upregulated-predicted to be associated with immune activation and the immune response to infection, respectively. Furthermore, an Ingenuity Pathway Analysis revealed canonical pathways and upstream transcription regulators associated with differentially expressed lncRNAs. Several differentially expressed lncRNAs reported elsewhere underwent expressional changes upon M1 or M2 preactivation and subsequent MAC infection. Finally, we showed that expressional change of lncRNAs in MAC-infected BMDMs was mediated by toll-like receptor 2, although there may be other mechanisms that sense MAC infection. We identified differentially expressed lncRNAs in MAC-infected BMDMs, revealing diverse features that imply the distinct roles of these lncRNAs in MAC infection and macrophage polarization.
Topics: RNA, Long Noncoding; Animals; Macrophages; Mycobacterium avium Complex; Mice; Gene Expression Profiling; Mycobacterium avium-intracellulare Infection; Transcriptome; Macrophage Activation; Mice, Inbred C57BL; Cells, Cultured; Gene Expression Regulation
PubMed: 38711507
DOI: 10.3389/fimmu.2024.1374437