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Article ; Online: Tuberculosis Vaccine Development: Progress in Clinical Evaluation.

Sable, Suraj B / Posey, James E / Scriba, Thomas J

2019 Volume 33, Issue 1

Abstract: Tuberculosis (TB) is the leading killer among all infectious diseases worldwide despite extensive use of ... ...

Abstract	Tuberculosis (TB) is the leading killer among all infectious diseases worldwide despite extensive use of the
MeSH term(s)	Animals ; Host-Pathogen Interactions/immunology ; Humans ; Immunity, Innate ; Mycobacterium bovis/immunology ; Mycobacterium tuberculosis/immunology ; Outcome Assessment, Health Care ; Research ; Tuberculosis/prevention & control ; Tuberculosis Vaccines/administration & dosage ; Tuberculosis Vaccines/immunology
Chemical Substances	Tuberculosis Vaccines
Language	English
Publishing date	2019-10-30
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	645015-5
ISSN	1098-6618 ; 0893-8512
ISSN (online)	1098-6618
ISSN	0893-8512
DOI	10.1128/CMR.00100-19
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Article ; Online: Prediction of pyrazinamide resistance in

Carter, Joshua J / Walker, Timothy M / Walker, A Sarah / Whitfield, Michael G / Morlock, Glenn P / Lynch, Charlotte I / Adlard, Dylan / Peto, Timothy E A / Posey, James E / Crook, Derrick W / Fowler, Philip W

JAC-antimicrobial resistance

2024 Volume 6, Issue 2, Page(s) dlae037

Abstract: Background: Pyrazinamide is one of four first-line antibiotics used to treat tuberculosis; however, antibiotic susceptibility testing for pyrazinamide is challenging. Resistance to pyrazinamide is primarily driven by genetic variation in : Methods: ... ...

Abstract	Background: Pyrazinamide is one of four first-line antibiotics used to treat tuberculosis; however, antibiotic susceptibility testing for pyrazinamide is challenging. Resistance to pyrazinamide is primarily driven by genetic variation in Methods: We curated a dataset of 664 non-redundant, missense amino acid mutations in PncA with associated high-confidence phenotypes from published studies and then trained three different machine-learning models to predict pyrazinamide resistance. All models had access to a range of protein structural-, chemical- and sequence-based features. Results: The best model, a gradient-boosted decision tree, achieved a sensitivity of 80.2% and a specificity of 76.9% on the hold-out test dataset. The clinical performance of the models was then estimated by predicting the binary pyrazinamide resistance phenotype of 4027 samples harbouring 367 unique missense mutations in Conclusions: This work demonstrates how machine learning can enhance the sensitivity/specificity of pyrazinamide resistance prediction in genetics-based clinical microbiology workflows, highlights novel mutations for future biochemical investigation, and is a proof of concept for using this approach in other drugs.
Language	English
Publishing date	2024-03-18
Publishing country	England
Document type	Journal Article
ISSN	2632-1823
ISSN (online)	2632-1823
DOI	10.1093/jacamr/dlae037
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Article ; Online: Molecular surveillance for large outbreaks of tuberculosis in the United States, 2014-2018.

Raz, Kala M / Talarico, Sarah / Althomsons, Sandy P / Kammerer, J Steve / Cowan, Lauren S / Haddad, Maryam B / McDaniel, Clinton J / Wortham, Jonathan M / France, Anne Marie / Powell, Krista M / Posey, James E / Silk, Benjamin J

Tuberculosis (Edinburgh, Scotland)

2022 Volume 136, Page(s) 102232

Abstract: Objective: This study describes characteristics of large tuberculosis (TB) outbreaks in the United States detected using novel molecular surveillance methods during 2014-2016 and followed for 2 years through 2018.: Methods: We developed 4 genotype- ... ...

Abstract	Objective: This study describes characteristics of large tuberculosis (TB) outbreaks in the United States detected using novel molecular surveillance methods during 2014-2016 and followed for 2 years through 2018. Methods: We developed 4 genotype-based detection algorithms to identify large TB outbreaks of ≥10 cases related by recent transmission during a 3-year period. We used whole-genome sequencing and epidemiologic data to assess evidence of recent transmission among cases. Results: There were 24 large outbreaks involving 518 cases; patients were primarily U.S.-born (85.1%) racial/ethnic minorities (84.1%). Compared with all other TB patients, patients associated with large outbreaks were more likely to report substance use, homelessness, and having been diagnosed while incarcerated. Most large outbreaks primarily occurred within residences among families and nonfamilial social contacts. A source case with a prolonged infectious period and difficulties in eliciting contacts were commonly reported contributors to transmission. Conclusion: Large outbreak surveillance can inform targeted interventions to decrease outbreak-associated TB morbidity.
MeSH term(s)	Disease Outbreaks ; Genotype ; Ill-Housed Persons ; Humans ; Mycobacterium tuberculosis/genetics ; Tuberculosis/diagnosis ; Tuberculosis/epidemiology ; United States/epidemiology
Language	English
Publishing date	2022-08-09
Publishing country	Scotland
Document type	Journal Article
ZDB-ID	2046804-0
ISSN	1873-281X ; 1472-9792
ISSN (online)	1873-281X
ISSN	1472-9792
DOI	10.1016/j.tube.2022.102232
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Article ; Online: Discovery of substituted benzyloxy-benzylamine inhibitors of acetyltransferase Eis and their anti-mycobacterial activity.

Pang, Allan H / Green, Keith D / Chandrika, Nishad Thamban / Garzan, Atefeh / Punetha, Ankita / Holbrook, Selina Y L / Willby, Melisa J / Posey, James E / Tsodikov, Oleg V / Garneau-Tsodikova, Sylvie

European journal of medicinal chemistry

2022 Volume 242, Page(s) 114698

Abstract: A clinically significant mechanism of tuberculosis resistance to the aminoglycoside kanamycin (KAN) is its acetylation catalyzed by upregulated Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. In search for inhibitors of Eis, we discovered an ... ...

Abstract	A clinically significant mechanism of tuberculosis resistance to the aminoglycoside kanamycin (KAN) is its acetylation catalyzed by upregulated Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. In search for inhibitors of Eis, we discovered an inhibitor with a substituted benzyloxy-benzylamine scaffold. A structure-activity relationship study of 38 compounds in this structural family yielded highly potent (IC
MeSH term(s)	Acetyltransferases/chemistry ; Aminoglycosides/pharmacology ; Animals ; Anti-Bacterial Agents/metabolism ; Anti-Bacterial Agents/pharmacology ; Antitubercular Agents/chemistry ; Bacterial Proteins ; Benzylamines/pharmacology ; Kanamycin/chemistry ; Kanamycin/pharmacology ; Mammals/metabolism ; Mycobacterium tuberculosis/metabolism
Chemical Substances	Aminoglycosides ; Anti-Bacterial Agents ; Antitubercular Agents ; Bacterial Proteins ; Benzylamines ; Kanamycin (59-01-8) ; Acetyltransferases (EC 2.3.1.-)
Language	English
Publishing date	2022-08-18
Publishing country	France
Document type	Journal Article
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2022.114698
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Article ; Online: Molecular Evaluation of Fluoroquinolone Resistance in Serial Mycobacterium tuberculosis Isolates from Individuals Diagnosed with Multidrug-Resistant Tuberculosis.

Willby, Melisa / Chopra, Paige / Lemmer, Darrin / Klein, Katherine / Dalton, Tracy L / Engelthaler, David M / Cegielski, J Peter / Posey, James E

Antimicrobial agents and chemotherapy

2020 Volume 65, Issue 1

Abstract: Fluoroquinolones (FQ) are crucial components of multidrug-resistant tuberculosis (MDR TB) treatment. Differing levels of resistance are associated with specific mutations within ... ...

Abstract	Fluoroquinolones (FQ) are crucial components of multidrug-resistant tuberculosis (MDR TB) treatment. Differing levels of resistance are associated with specific mutations within the
MeSH term(s)	Antitubercular Agents/pharmacology ; DNA Gyrase/genetics ; Drug Resistance, Multiple, Bacterial/genetics ; Fluoroquinolones/pharmacology ; Humans ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis/genetics ; Tuberculosis, Multidrug-Resistant/drug therapy
Chemical Substances	Antitubercular Agents ; Fluoroquinolones ; DNA Gyrase (EC 5.99.1.3)
Language	English
Publishing date	2020-12-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.01663-20
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Article ; Online: Pathogen Genomics in Public Health.

Armstrong, Gregory L / MacCannell, Duncan R / Taylor, Jill / Carleton, Heather A / Neuhaus, Elizabeth B / Bradbury, Richard S / Posey, James E / Gwinn, Marta

The New England journal of medicine

2019 Volume 381, Issue 26, Page(s) 2569–2580

Abstract: Rapid advances in DNA sequencing technology ("next-generation sequencing") have inspired optimism about the potential of human genomics for "precision medicine." Meanwhile, pathogen genomics is already delivering "precision public health" through more ... ...

Abstract	Rapid advances in DNA sequencing technology ("next-generation sequencing") have inspired optimism about the potential of human genomics for "precision medicine." Meanwhile, pathogen genomics is already delivering "precision public health" through more effective investigations of outbreaks of foodborne illnesses, better-targeted tuberculosis control, and more timely and granular influenza surveillance to inform the selection of vaccine strains. In this article, we describe how public health agencies have been adopting pathogen genomics to improve their effectiveness in almost all domains of infectious disease. This momentum is likely to continue, given the ongoing development in sequencing and sequencing-related technologies.
MeSH term(s)	Animals ; Bacteria/genetics ; Disease Outbreaks ; Foodborne Diseases/diagnosis ; Foodborne Diseases/epidemiology ; Foodborne Diseases/microbiology ; Foodborne Diseases/parasitology ; Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; Influenza, Human/diagnosis ; Influenza, Human/epidemiology ; Influenza, Human/microbiology ; Metagenomics ; Parasites/genetics ; Public Health ; Tuberculosis/diagnosis ; Tuberculosis/epidemiology ; Viruses/genetics
Keywords	covid19
Language	English
Publishing date	2019-12-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJMsr1813907
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Article ; Online: Isoniazid and Rifampin-Resistance Mutations Associated With Resistance to Second-Line Drugs and With Sputum Culture Conversion.

Click, Eleanor S / Kurbatova, Ekaterina V / Alexander, Heather / Dalton, Tracy L / Chen, Michael P / Posey, James E / Ershova, Julia / Cegielski, J Peter

The Journal of infectious diseases

2019 Volume 221, Issue 12, Page(s) 2072–2082

Abstract: Background: Mutations in the genes inhA, katG, and rpoB confer resistance to anti-tuberculosis (TB) drugs isoniazid and rifampin. We questioned whether specific mutations in these genes were associated with different clinical and microbiological ... ...

Abstract	Background: Mutations in the genes inhA, katG, and rpoB confer resistance to anti-tuberculosis (TB) drugs isoniazid and rifampin. We questioned whether specific mutations in these genes were associated with different clinical and microbiological characteristics. Methods: In a multicountry prospective cohort study of multidrug-resistant TB, we identified inhA, katG, and rpoB mutations in sputum isolates using the Hain MTBDRplus line probe assay. For specific mutations, we performed bivariate analysis to determine relative risk of baseline or acquired resistance to other TB drugs. We compared time to sputum culture conversion (TSCC) using Kaplan-Meier curves and stratified Cox regression. Results: In total, 447 participants enrolled from January 2005 to December 2008 from 7 countries were included. Relative to rpoB S531L, isolates with rpoB D516V had less cross-resistance to rifabutin, increased baseline resistance to other drugs, and increased acquired fluoroquinolone resistance. Relative to mutation of katG only, mutation of inhA promoter and katG was associated with baseline extensively drug resistant (XDR) TB, increased acquired fluoroquinolone resistance, and slower TSCC (125.5 vs 89.0 days). Conclusions: Specific mutations in inhA and katG are associated with differences in resistance to other drugs and TSCC. Molecular testing may make it possible to tailor treatment and assess additional drug resistance risk according to specific mutation profile.
MeSH term(s)	Antitubercular Agents/pharmacology ; Antitubercular Agents/therapeutic use ; Bacterial Proteins/genetics ; Catalase/genetics ; DNA Mutational Analysis ; DNA, Bacterial/genetics ; DNA, Bacterial/isolation & purification ; DNA-Directed RNA Polymerases/genetics ; Drug Resistance, Multiple, Bacterial/genetics ; Genes, Bacterial/genetics ; Humans ; Isoniazid/pharmacology ; Isoniazid/therapeutic use ; Microbial Sensitivity Tests ; Mutation ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/isolation & purification ; Oxidoreductases/genetics ; Promoter Regions, Genetic/genetics ; Prospective Studies ; Rifampin/pharmacology ; Rifampin/therapeutic use ; Sputum/microbiology ; Tuberculosis, Multidrug-Resistant/drug therapy ; Tuberculosis, Multidrug-Resistant/microbiology
Chemical Substances	Antitubercular Agents ; Bacterial Proteins ; DNA, Bacterial ; rpoB protein, Mycobacterium tuberculosis ; Oxidoreductases (EC 1.-) ; Catalase (EC 1.11.1.6) ; katG protein, Mycobacterium tuberculosis (EC 1.11.1.6) ; InhA protein, Mycobacterium (EC 1.3.1.9) ; DNA-Directed RNA Polymerases (EC 2.7.7.6) ; Isoniazid (V83O1VOZ8L) ; Rifampin (VJT6J7R4TR)
Language	English
Publishing date	2019-11-26
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Observational Study ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiaa042
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Article ; Online: Disparities in capreomycin resistance levels associated with the rrs A1401G mutation in clinical isolates of Mycobacterium tuberculosis.

Reeves, Analise Z / Campbell, Patricia J / Willby, Melisa J / Posey, James E

Antimicrobial agents and chemotherapy

2015 Volume 59, Issue 1, Page(s) 444–449

Abstract: As the prevalence of multidrug-resistant and extensively drug-resistant tuberculosis strains continues to rise, so does the need to develop accurate and rapid molecular tests to complement time-consuming growth-based drug susceptibility testing. ... ...

Abstract	As the prevalence of multidrug-resistant and extensively drug-resistant tuberculosis strains continues to rise, so does the need to develop accurate and rapid molecular tests to complement time-consuming growth-based drug susceptibility testing. Performance of molecular methods relies on the association of specific mutations with phenotypic drug resistance and while considerable progress has been made for resistance detection of first-line antituberculosis drugs, rapid detection of resistance for second-line drugs lags behind. The rrs A1401G allele is considered a strong predictor of cross-resistance between the three second-line injectable drugs, capreomycin (CAP), kanamycin, and amikacin. However, discordance is often observed between the rrs A1401G mutation and CAP resistance, with up to 40% of rrs A1401G mutants being classified as CAP susceptible. We measured the MICs to CAP in 53 clinical isolates harboring the rrs A1401G mutation and found that the CAP MICs ranged from 8 μg/ml to 40 μg/ml. These results were drastically different from engineered A1401G mutants generated in isogenic Mycobacterium tuberculosis, which exclusively exhibited high-level CAP MICs of 40 μg/ml. These data support the results of prior studies, which suggest that the critical concentration of CAP (10 μg/ml) used to determine resistance by indirect agar proportion may be too high to detect all CAP-resistant strains and suggest that a larger percentage of resistant isolates could be identified by lowering the critical concentration. These data also suggest that differences in resistance levels among clinical isolates are possibly due to second site or compensatory mutations located elsewhere in the genome.
MeSH term(s)	Amikacin/therapeutic use ; Antibiotics, Antitubercular/therapeutic use ; Capreomycin/therapeutic use ; Drug Resistance, Multiple, Bacterial/genetics ; Humans ; Kanamycin/therapeutic use ; Microbial Sensitivity Tests/methods ; Mutation ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/isolation & purification ; Tuberculosis, Multidrug-Resistant/drug therapy ; Tuberculosis, Multidrug-Resistant/genetics ; Tuberculosis, Multidrug-Resistant/microbiology
Chemical Substances	Antibiotics, Antitubercular ; Capreomycin (11003-38-6) ; Kanamycin (59-01-8) ; Amikacin (84319SGC3C)
Language	English
Publishing date	2015-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.04438-14
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Article ; Online: Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis from

Punetha, Ankita / Green, Keith D / Garzan, Atefeh / Thamban Chandrika, Nishad / Willby, Melisa J / Pang, Allan H / Hou, Caixia / Holbrook, Selina Y L / Krieger, Kyle / Posey, James E / Parish, Tanya / Tsodikov, Oleg V / Garneau-Tsodikova, Sylvie

RSC medicinal chemistry

2021 Volume 12, Issue 11, Page(s) 1894–1909

Abstract: Tuberculosis (TB), caused ... ...

Abstract	Tuberculosis (TB), caused by
Language	English
Publishing date	2021-10-05
Publishing country	England
Document type	Journal Article
ISSN	2632-8682
ISSN (online)	2632-8682
DOI	10.1039/d1md00239b
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Article ; Online: Statistical Method to Detect Tuberculosis Outbreaks among Endemic Clusters in a Low-Incidence Setting.

Althomsons, Sandy P / Hill, Andrew N / Harrist, Alexia V / France, Anne Marie / Powell, Krista M / Posey, James E / Cowan, Lauren S / Navin, Thomas R

Emerging infectious diseases

2018 Volume 24, Issue 3, Page(s) 573–575

Abstract: We previously reported use of genotype surveillance data to predict outbreaks among incident tuberculosis clusters. We propose a method to detect possible outbreaks among endemic tuberculosis clusters. We detected 15 possible outbreaks, of which 10 had ... ...

Abstract	We previously reported use of genotype surveillance data to predict outbreaks among incident tuberculosis clusters. We propose a method to detect possible outbreaks among endemic tuberculosis clusters. We detected 15 possible outbreaks, of which 10 had epidemiologic data or whole-genome sequencing results. Eight outbreaks were corroborated.
MeSH term(s)	Cluster Analysis ; Disease Outbreaks ; Genome, Bacterial ; Genomics/methods ; Genotype ; Humans ; Incidence ; Models, Statistical ; Molecular Epidemiology ; Mycobacterium tuberculosis/genetics ; Polymorphism, Single Nucleotide ; Prevalence ; Tuberculosis/diagnosis ; Tuberculosis/epidemiology ; Tuberculosis/microbiology ; United States
Language	English
Publishing date	2018-02-22
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1380686-5
ISSN	1080-6059 ; 1080-6040
ISSN (online)	1080-6059
ISSN	1080-6040
DOI	10.3201/eid2403.171613
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