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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 -
Epidemiology of Nontuberculous Mycobacteria in Tuberculosis suspects, Southwest of China, 2017-2022.Frontiers in Cellular and Infection... 2023This study summarizes the epidemiological characteristics, species distribution, and drug sensitivity of clinical nontuberculous mycobacteria (NTM) isolates at the...
OBJECTIVES
This study summarizes the epidemiological characteristics, species distribution, and drug sensitivity of clinical nontuberculous mycobacteria (NTM) isolates at the Public Health Clinical Center of Chengdu, China, from January 2017 to December 2022.
METHODS
We retrospectively analyzed data from patients with clinically isolated NTM strains. Chi-square analysis assessed the rate of strain isolation over 6 years.
RESULTS
The number of samples tested for (MTB) and/or NTM increased each year, while MTB detection decreased and NTM detection rose significantly each year (P=0.03). The average age of NTM patients was 51 ± 17.53 years, with a 14.1% HIV infection rate. The predominant isolates were (MAC) and /, with 96.4% of cases being of Han ethnicity. Amikacin, moxifloxacin, and clarithromycin were effective against and ; linezolid, amikacin, and cefoxitin were effective against /. Over 90% of NTM cases originated from the respiratory tract.
CONCLUSION
The NTM isolation rate in Southwest China has risen in recent years, primarily among elderly patients with a high HIV co-infection rate. The main NTM isolates were MAC and /. Amikacin, moxifloxacin, clarithromycin, and linezolid exhibited strong antibacterial activity against SGM, while amikacin and linezolid displayed relatively better antibacterial activity against RGM. The prevalence of NTM infection may be positively associated with regional economic development and health conditions.
Topics: Humans; Aged; Adult; Middle Aged; Nontuberculous Mycobacteria; Clarithromycin; Amikacin; Linezolid; HIV Infections; Moxifloxacin; Retrospective Studies; Anti-Bacterial Agents; Mycobacterium Infections, Nontuberculous; Tuberculosis; China; Microbial Sensitivity Tests
PubMed: 38029240
DOI: 10.3389/fcimb.2023.1282902 -
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 -
Microbial Drug Resistance (Larchmont,... Jul 2023There is a scarcity of data regarding the antimicrobial susceptibility testing profiles of nontuberculous mycobacterial (NTM) in Israel and other Middle Eastern...
There is a scarcity of data regarding the antimicrobial susceptibility testing profiles of nontuberculous mycobacterial (NTM) in Israel and other Middle Eastern countries. We aimed to describe the antimicrobial susceptibility profiles of NTM in Israel. A total of 410 clinical isolates of NTM, identified to the species level using matrix-assisted laser desorption ionization-time of flight mass spectrometry or gene sequencing, were included. Minimum inhibitory concentrations for slowly growing mycobacteria (SGM) and rapidly growing mycobacteria (RGM) for 12 and 11 drugs were determined using the Sensititre SLOMYCOI and RAPMYCOI broth microdilution plates, respectively. complex (MAC) was the most frequently isolated species ( = 148; 36%), followed by ( = 93; 23%), group ( = 62; 15%), ( = 27; 7%), and ( = 22; 5%) accounting together for 86% of isolates. The most active agents against SGM were amikacin (98%/85%/100%) and clarithromycin (97%/99%/100%), followed by moxifloxacin (25%/10%/100%) and linezolid (3%/6%/100%) for MAC, , and , respectively. For RGM, the most active agents were amikacin (98%/100%/88%) followed by linezolid (48%/80%/100%) and clarithromycin (39%/28%/94%) for group, , and , respectively. These findings can assist in guiding the treatment of NTM infections.
Topics: Humans; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Linezolid; Anti-Bacterial Agents; Amikacin; Clarithromycin; Israel; Microbial Sensitivity Tests
PubMed: 37219996
DOI: 10.1089/mdr.2023.0024 -
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