ORCID Profile
0000-0002-2927-270X
Current Organisations
University of Milan
,
Università degli Studi di Milano
,
National Institute of Allergy and Infectious Diseases
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Publisher: Proceedings of the National Academy of Sciences
Date: 04-11-2013
Abstract: Chronic bacterial infections, such as those caused by Mycobacterium tuberculosis ( Mtb ), continue to claim the lives of millions of people. New antibiotics are needed to treat these infections, but their development is hindered by a lack of targets whose inhibition quickly eradicates bacterial pathogens and prevents the survival of drug-tolerant persisters. We describe a unique dual-control (DUC) switch that combines repression of transcription and controlled proteolysis to silence gene activities in Mtb . By conditionally inactivating Mtb ’s nicotinamide adenine dinucleotide synthetase, we demonstrate that the DUC switch can identify proteins that this pathogen requires for growth and nonreplicating persistence in vitro and during infections. Targeting such proteins holds the promise of yielding drugs that shorten the duration of antibacterial chemotherapies.
Publisher: American Society for Microbiology
Date: 12-2013
DOI: 10.1128/JCM.01743-13
Abstract: The utility of the GeneXpert MTB/RIF (Xpert) assay for detection of Mycobacterium tuberculosis in sputum s les has been extensively studied. However, the performance of the Xpert assay as applied to other readily accessible body fluids such as exhaled breath condensate (EBC), saliva, urine, and blood has not been established. We used the Xpert assay to test EBC, saliva, urine, and blood s les from HIV-negative, smear- and culture-positive pulmonary tuberculosis (TB) patients for the presence of M. tuberculosis . To compare the ability of the assay to perform bacterial load measurements on sputum s les with versus without s le processing, the assay was also performed on paired direct and processed sputum s les from each patient. The Xpert assay detected M. tuberculosis in none of the 26 EBC s les (sensitivity, 0.0% 95% confidence interval [95% CI], 0.0%, 12.9%), 10 of the 26 saliva s les (sensitivity, 38.5% 95% CI, 22.4%, 57.5%), 1 of 26 urine s les (sensitivity, 3.8% 95% CI, 0.7%, 18.9%), and 2 of 24 blood s les (sensitivity, 8.3% 95% CI, 2.3%, 25.8%). For bacterial load measurements in the different types of sputum s les, the cycle thresholds of the two M. tuberculosis -positive sputum types were well correlated (Spearman correlation of 0.834). This study demonstrates that the Xpert assay should not be routinely used to detect M. tuberculosis in EBC, saliva, urine, or blood s les from HIV-negative patients suspected of having pulmonary tuberculosis. As a test of bacterial load, the assay produced similar results when used to test direct versus processed sputum s les. Sputum remains the optimal s le type for diagnosing pulmonary tuberculosis in HIV-negative patients with the Xpert assay.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2021
DOI: 10.1038/S41467-020-20224-X
Abstract: Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis . The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis , by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis . Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis , describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB.
Publisher: Elsevier BV
Date: 05-2019
Publisher: Public Library of Science (PLoS)
Date: 29-09-2011
Publisher: Springer Science and Business Media LLC
Date: 10-02-2020
DOI: 10.1186/S13550-020-0591-9
Abstract: There is a growing interest in the use of F-18 FDG PET-CT to monitor tuberculosis (TB) treatment response. Tuberculosis lung lesions are often complex and diffuse, with dynamic changes during treatment and persisting metabolic activity after apparent clinical cure. This poses a challenge in quantifying scan-based markers of burden of disease and disease activity. We used semi-automated, whole lung quantification of lung lesions to analyse serial FDG PET-CT scans from the Catalysis TB Treatment Response Cohort to identify characteristics that best correlated with clinical and microbiological outcomes. Quantified scan metrics were already associated with clinical outcomes at diagnosis and 1 month after treatment, with further improved accuracy to differentiate clinical outcomes after standard treatment duration (month 6). A high cavity volume showed the strongest association with a risk of treatment failure (AUC 0.81 to predict failure at diagnosis), while a suboptimal reduction of the total glycolytic activity in lung lesions during treatment had the strongest association with recurrent disease (AUC 0.8 to predict pooled unfavourable outcomes). During the first year after TB treatment lesion burden reduced but for many patients, there were continued dynamic changes of in idual lesions. Quantification of FDG PET-CT images better characterised TB treatment outcomes than qualitative scan patterns and robustly measured the burden of disease. In future, validated metrics may be used to stratify patients and help evaluate the effectiveness of TB treatment modalities.
Publisher: Springer Science and Business Media LLC
Date: 25-06-2018
Publisher: Cold Spring Harbor Laboratory
Date: 03-07-2023
DOI: 10.1101/2023.07.03.23292111
Abstract: The evolution of tuberculosis (TB) disease during the clinical latency period remains incompletely understood. 250 HIV-uninfected, adult household contacts of rif icin-resistant TB with a negative symptom screen underwent baseline 18 F-Fluorodeoxyglucose positron emission and computed tomography (PET/CT), repeated in 112 after 5-15 months. Following South African and WHO guidelines, participants did not receive preventive therapy. All participants had intensive baseline screening with spontaneous, followed by induced, sputum s ling and were then observed for an average of 4.7 years for culture-positive disease. Baseline PET/CT abnormalities were evaluated in relation to culture-positive disease. At baseline, 59 (23.6%) participants had lung PET/CT findings consistent with TB of which 29 (11.6%) were defined as Subclinical TB, and 30 (12%) Subclinical TB-inactive. A further 83 (33.2%) had other lung parenchymal abnormalities and 108 (43.2%) had normal lungs. Over 1107-person years of follow-up 14 cases of culture-positive TB were diagnosed. Six cases were detected by intensive baseline screening, all would have been missed by the South African symptom-based screening strategy and only one detected by a WHO-recommended chest X-Ray screening strategy. Those with baseline Subclinical TB lesions on PET/CT were significantly more likely to be diagnosed with culture-positive TB over the study period, compared to those with normal lung parenchyma (10/29 [34.5%] vs 2/108 [1.9%], Hazard Ratio 22.37 [4.89-102.47, p .001]). These findings challenge the latent/active TB paradigm demonstrating that subclinical disease exists up to 4 years prior to microbiological detection and/or symptom onset. There are important implications for screening and management of TB.
Location: United States of America
No related grants have been discovered for Clifton E Barry.