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MBio Jan 2024As we rapidly approach a post-antibiotic era, bacteriophage (phage) therapy may offer a solution for treating drug-resistant bacteria. is an emerging,...
As we rapidly approach a post-antibiotic era, bacteriophage (phage) therapy may offer a solution for treating drug-resistant bacteria. is an emerging, multidrug-resistant pathogen that causes disease in people with cystic fibrosis, chronic obstructive pulmonary disease, and other underlying lung diseases. can survive inside host cells, a niche that can limit access to antibiotics. As current treatment options for infections often fail, there is an urgent need for alternative therapies. Phage therapy is being used to treat infections as an option of last resort. However, little is known about the ability of phages to kill bacteria in the host environment and specifically in an intracellular environment. Here, we demonstrate the ability of phages to enter mammalian cells and to infect and kill intracellular . These findings support the use of phages to treat intracellular bacterial pathogens.
Topics: Animals; Humans; Mycobacterium abscessus; Bacteriophages; Cystic Fibrosis; Anti-Bacterial Agents; Mammals
PubMed: 38059609
DOI: 10.1128/mbio.02924-23 -
Trends in Microbiology Dec 2023The incidence of infections due to nontuberculous mycobacteria (NTM) has increased rapidly in recent years, surpassing tuberculosis in developed countries. Due to... (Review)
Review
The incidence of infections due to nontuberculous mycobacteria (NTM) has increased rapidly in recent years, surpassing tuberculosis in developed countries. Due to inherent antimicrobial resistance, NTM infections are particularly difficult to treat with low cure rates. There is an urgent need to understand NTM pathogenesis and to develop novel therapeutic approaches for the treatment of NTM diseases. Zebrafish have emerged as an excellent animal model due to genetic amenability and optical transparency during embryonic development, allowing spatiotemporal visualization of host-pathogen interactions. Furthermore, adult zebrafish possess fully functional innate and adaptive immunity and recapitulate important pathophysiological hallmarks of mycobacterial infection. Here, we report recent breakthroughs in understanding the hallmarks of NTM infections using the zebrafish model.
PubMed: 38135617
DOI: 10.1016/j.tim.2023.11.011 -
ACS Infectious Diseases Feb 2024In the recent decade, scientific communities have toiled to tackle the emerging burden of drug-resistant tuberculosis (DR-TB) and rapidly growing opportunistic... (Review)
Review
In the recent decade, scientific communities have toiled to tackle the emerging burden of drug-resistant tuberculosis (DR-TB) and rapidly growing opportunistic nontuberculous mycobacteria (NTM). Among these, two neglected mycobacteria species of the Acinetobacter family, and , are the etiological agents of leprosy and Buruli ulcer infections, respectively, and fall under the broad umbrella of neglected tropical diseases (NTDs). Unfortunately, lackluster drug discovery efforts have been made against these pathogenic bacteria in the recent decade, resulting in the discovery of only a few countable hits and majorly repurposing anti-TB drug candidates such as telacebec (Q203), P218, and TB47 for current therapeutic interventions. Major ignorance in drug candidate identification might aggravate the dramatic consequences of rapidly spreading mycobacterial NTDs in the coming days. Therefore, this Review focuses on an up-to-date account of drug discovery efforts targeting selected druggable targets from both bacilli, including the accompanying challenges that have been identified and are responsible for the slow drug discovery. Furthermore, a succinct discussion of the all-new possibilities that could be alternative solutions to mitigate the neglected mycobacterial NTD burden and subsequently accelerate the drug discovery effort is also included. We anticipate that the state-of-the-art strategies discussed here may attract major attention from the scientific community to navigate and expand the roadmap for the discovery of next-generation therapeutics against these NTDs.
Topics: Humans; Mycobacterium ulcerans; Mycobacterium leprae; Buruli Ulcer; Mycobacterium
PubMed: 38295025
DOI: 10.1021/acsinfecdis.3c00371 -
Nano Letters Oct 2023Nucleoside drugs, which are analogues of natural nucleosides, have been widely applied in the clinical treatment of viral infections and cancers. The development of...
Nucleoside drugs, which are analogues of natural nucleosides, have been widely applied in the clinical treatment of viral infections and cancers. The development of nucleoside drugs, repurposing of existing drugs, and combined use of multiple drug types have made the rapid sensing of nucleoside drugs urgently needed. Nanopores are emerging single-molecule sensors that have high resolution to resolve even minor structural differences between chemical compounds. Here, an engineered porin A hetero-octamer was used to perform general nucleoside drug analysis. Ten nucleoside drugs were simultaneously detected and fully discriminated. An accuracy of >99.9% was consequently reported. This sensing capacity was further demonstrated in direct nanopore analysis of ribavirin buccal tablets, confirming its sensing reliability against complex samples and environments. No sample separation is needed, however, significantly minimizing the complexity of the measurement. This technique may inspire nanopore applications in pharmaceutical production and pharmacokinetics measurements.
Topics: Nanopores; Nucleosides; Reproducibility of Results; Porins; Mycobacterium smegmatis
PubMed: 37818841
DOI: 10.1021/acs.nanolett.3c02872 -
Microbiology (Reading, England) Oct 2023Bacteria use population heterogeneity, the presence of more than one phenotypic variant in a clonal population, to endure diverse environmental challenges - a...
Bacteria use population heterogeneity, the presence of more than one phenotypic variant in a clonal population, to endure diverse environmental challenges - a 'bet-hedging' strategy. Phenotypic variants have been described in many bacteria, but the phenomenon is not well-understood in mycobacteria, including the environmental factors that influence heterogeneity. Here, we describe three reproducible morphological variants in - smooth, rough, and an intermediate morphotype that predominated under typical laboratory conditions. has two recognized morphotypes, smooth and rough. Interestingly, exists in only a rough form. The shift from smooth to rough in both and was observed over time in extended static culture, however the frequency of the rough morphotype was high in pellicle preparations compared to planktonic culture, suggesting a role for an aggregated microenvironment in the shift to the rough form. Differences in growth rate, biofilm formation, cell wall composition, and drug tolerance were noted among and variants. Deletion of the global regulator shifted the intermediate morphotype to a smooth form but did not fully phenocopy the naturally generated smooth morphotype, indicating Lsr2 is likely downstream of the initiating regulatory cascade that controls these morphotypes. Rough forms typically correlate with higher invasiveness and worse outcomes during infection and our findings indicate the shift to this rough form is promoted by aggregation. Our findings suggest that mycobacterial population heterogeneity, reflected in colony morphotypes, is a reproducible, programmed phenomenon that plays a role in adaptation to unique environments and this heterogeneity may influence infection progression and response to treatment.
Topics: Humans; Mycobacterium abscessus; Mycobacterium smegmatis; Mycobacterium Infections, Nontuberculous; Mycobacterium
PubMed: 37862100
DOI: 10.1099/mic.0.001402 -
Clinics in Chest Medicine Dec 2023Mycobacterium abscessus pulmonary disease is highly antibiotic-resistant, and the current armamentarium of antibiotics yields poor treatment outcomes with significant... (Review)
Review
Mycobacterium abscessus pulmonary disease is highly antibiotic-resistant, and the current armamentarium of antibiotics yields poor treatment outcomes with significant drug toxicity. Macrolide susceptibility is a key prognostic factor. Optimal drug combinations, duration of therapy, and management of refractory disease are unknown. Surgical resection, performed at centers with experience in surgical management of nontuberculous mycobacterial pulmonary disease, may produce favorable outcomes in select patients. Multiple emerging therapeutic candidates hold promise for more efficacious and tolerable treatment options.
Topics: Humans; Mycobacterium abscessus; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Lung Diseases; Anti-Bacterial Agents
PubMed: 37890916
DOI: 10.1016/j.ccm.2023.06.010 -
Nature Reviews. Drug Discovery May 2024Tuberculosis (TB) drug discovery and development has undergone nothing short of a revolution over the past 20 years. Successful public-private partnerships and sustained... (Review)
Review
Tuberculosis (TB) drug discovery and development has undergone nothing short of a revolution over the past 20 years. Successful public-private partnerships and sustained funding have delivered a much-improved understanding of mycobacterial disease biology and pharmacology and a healthy pipeline that can tolerate inevitable attrition. Preclinical and clinical development has evolved from decade-old concepts to adaptive designs that permit rapid evaluation of regimens that might greatly shorten treatment duration over the next decade. But the past 20 years also saw the rise of a fatal and difficult-to-cure lung disease caused by nontuberculous mycobacteria (NTM), for which the drug development pipeline is nearly empty. Here, we discuss the similarities and differences between TB and NTM lung diseases, compare the preclinical and clinical advances, and identify major knowledge gaps and areas of cross-fertilization. We argue that applying paradigms and networks that have proved successful for TB, from basic research to clinical trials, will help to populate the pipeline and accelerate curative regimen development for NTM disease.
Topics: Humans; Mycobacterium Infections, Nontuberculous; Antitubercular Agents; Animals; Drug Development; Tuberculosis; Nontuberculous Mycobacteria; Drug Discovery; Lung Diseases
PubMed: 38418662
DOI: 10.1038/s41573-024-00897-5 -
Frontiers in Immunology 2023Controlling pulmonary complex (MAC) disease is difficult because there is no way to know the clinical stage accurately. There have been few attempts to use...
INTRODUCTION
Controlling pulmonary complex (MAC) disease is difficult because there is no way to know the clinical stage accurately. There have been few attempts to use cell-mediated immunity for diagnosing the stage. The objective of this study was to characterize cytokine profiles of CD4+T and CD19+B cells that recognize various -associated antigens in different clinical stages of MAC.
METHODS
A total of 47 MAC patients at different stages based on clinical information (14 before-treatment, 16 on-treatment, and 17 after-treatment) and 17 healthy controls were recruited. Peripheral blood mononuclear cells were cultured with specific antigens (MAV0968, 1160, 1276, and 4925), and the cytokine profiles (IFN-γ, TNF-α, IL-2, IL-10, IL-13, and IL-17) of CD4+/CD3+ and CD19+ cells were analyzed by flow cytometry.
RESULTS
The response of Th1 cytokines such as IFN-γ and TNF-α against various antigens was significantly higher in both the on-treatment and after-treatment groups than in the before-treatment group and control (P < 0.01-0.0001 and P < 0.05-0.0001). An analysis of polyfunctional T cells suggested that the presence of IL-2 is closely related to the stage after the start of treatment (P = 0.0309-P < 0.0001) and is involved in memory function. Non-Th1 cytokines, such as IL-10 and IL-17, showed significantly higher responses in the before-treatment group (P < 0.0001 and P < 0.01-0.0001). These responses were not observed with purified protein derivative (PPD). CD19+B cells showed a response similar to that of CD4+T cells.
CONCLUSION
There is a characteristic cytokine profile at each clinical stage of MAC.
Topics: Humans; Mycobacterium avium Complex; Interleukin-10; Interleukin-17; Interleukin-2; Tumor Necrosis Factor-alpha; Leukocytes, Mononuclear; Mycobacterium avium-intracellulare Infection; Cytokines; Lung Diseases
PubMed: 37520555
DOI: 10.3389/fimmu.2023.1222428 -
Radiologia 2023To describe the epidemiology and CT findings for nontuberculous mycobacterial lung infections and outcomes depending on the treatment.
OBJECTIVE
To describe the epidemiology and CT findings for nontuberculous mycobacterial lung infections and outcomes depending on the treatment.
MATERIAL AND METHODS
We retrospectively studied 131 consecutive patients with positive cultures for nontuberculous mycobacteria between 2005 and 2016. We selected those who met the criteria for nontuberculous mycobacterial lung infection. We analysed the epidemiologic data; clinical, microbiological, and radiological findings; treatment; and outcome according to treatment.
RESULTS
We included 34 patients (mean age, 55 y; 67.6% men); 50% were immunodepressed (58.8% of these were HIV+), 20.6% had COPD, 5.9% had known tumors, 5.9% had cystic fibrosis, and 29.4% had no comorbidities. We found that 20.6% had a history of tuberculosis and 20.6% were also infected with other microorganisms. Mycobacterium avium complex was the most frequently isolated germ (52.9%); 7 (20.6%) were also infected with other organisms. The most common CT findings were nodules (64.7%), tree-in-bud pattern (61.8%), centrilobular nodules (44.1 %), consolidations (41.2%), bronchiectasis (35.3%), and cavities (32.4%). We compared findings between men and women and between immunodepressed and immunocompetent patients. Treatment was antituberculosis drugs in 67.6% of patients (72% of whom showed improvement) and conventional antibiotics in 20.6% (all of whom showed radiologic improvement).
CONCLUSION
The diagnosis of nontuberculous mycobacterial lung infections is complex. The clinical and radiologic findings are nonspecific and a significant percentage of pateints can have other, concomitant infections.
Topics: Male; Humans; Female; Middle Aged; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Retrospective Studies; Cystic Fibrosis; Pneumonia; Antitubercular Agents; Lung
PubMed: 37758330
DOI: 10.1016/j.rxeng.2023.09.001 -
Clinical Microbiology and Infection :... Aug 2023Since 2013, heater-cooler unit (HCU) associated Mycobacterium chimaera infections linked to a global outbreak have been described. These infections were characterised by... (Meta-Analysis)
Meta-Analysis Review
Clinical characteristics and outcome of Mycobacterium chimaera infections after cardiac surgery: systematic review and meta-analysis of 180 heater-cooler unit-associated cases.
OBJECTIVES
Since 2013, heater-cooler unit (HCU) associated Mycobacterium chimaera infections linked to a global outbreak have been described. These infections were characterised by high morbidity and mortality due to delayed diagnosis, as well as challenges in antimycobacterial and surgical therapy. This study aimed to investigate the clinical characteristics and outcome of published cases of HCU-associated M. chimaera infections.
METHODS
We searched PubMed and the Web of Science until 15 June 2022 for case reports, case series, and cohort studies, without language restriction, on patients with M. chimaera infection and a prior history of cardiac surgery. In this systematic review of case reports, no risk of bias assessment could be performed. Clinical, microbiological, and radiological features were recorded. Logistic regression and time-to-event analyses were performed to identify the potential factors associated with better survival.
RESULTS
One hundred eighty patients from 54 publications were included. Most patients underwent surgical aortic valve (67.0%; 118/176 of patients with available data) or combined aortic valve and root replacement (15.3%; 27/176). The median period between the time point of surgery and the first symptoms was 17 months (interquartile range 13-26 months). The overall case fatality rate was 45.5% (80/176), with a median survival of 24 months after the initiation of antimycobacterial therapy or diagnosis. A reoperation (including the removal or exchange of foreign material) was associated with better survival in multivariate logistic regression (OR 0.32 for lethal events; 95% CI 0.12-0.79; p 0.015) and in time-to-event analysis (p 0.0094).
DISCUSSION
This systematic review and meta-analysis confirm the high overall mortality of HCU -associated disseminated M. chimaera infections after cardiac surgery. A reoperation seems to be associated with better survival. Physicians have to stay aware of this infection, as patients might still be present today due to the long latency period.
Topics: Humans; Mycobacterium Infections; Mycobacterium; Cardiac Surgical Procedures; Mycobacterium avium Complex; Equipment Contamination; Mycobacterium Infections, Nontuberculous
PubMed: 36918144
DOI: 10.1016/j.cmi.2023.03.005