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1. Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment

Author

Georghiou, Sophia B, Rodwell, Timothy C, Korobitsyn, Alexei, Abbadi, Said H, Ajbani, Kanchan, Alffenaar, Jan-Willem, Alland, David, Alvarez, Nataly, Andres, Sönke, Ardizzoni, Elisa, Aubry, Alexandra, Baldan, Rossella, Ballif, Marie, Barilar, Ivan, Böttger, Erik C, Chakravorty, Soumitesh, Claxton, Pauline M, Cirillo, Daniela M, Comas, Iñaki, Coulter, Chris, Denkinger, Claudia M, Derendinger, Brigitta, Desmond, Edward P, de Steenwinkel, Jurriaan EM, Dheda, Keertan, Diacon, Andreas H, Dolinger, David L, Dooley, Kelly E, Egger, Matthias, Ehsani, Soudeh, Farhat, Maha R, Fattorini, Lanfranco, Finci, Iris, Le Ray, Laure Fournier, Furió, Victoria, Groenheit, Ramona, Gumbo, Tawanda, Heysell, Scott K, Hillemann, Doris, Hoffmann, Harald, Hsueh, Po-Ren, Hu, Yi, Huang, Hairong, Hussain, Alamdar, Ismail, Farzana, Izumi, Kiyohiko, Jagielski, Tomasz, Johnson, John L, Kambli, Priti, Kaniga, Koné, Karunaratne, GHR Eranga, Sharma, Meenu Kaushal, Keller, Peter M, Kelly, Ellis C, Kholina, Margarita, Kohli, Mikashmi, Kranzer, Katharina, Laurenson, Ian F, Limberis, Jason, Lin, S-Y Grace, Liu, Yongge, López-Gavín, Alexandre, Lyander, Anna, Machado, Diana, Martinez, Elena, Masood, Faisal, Mitarai, Satoshi, Mvelase, Nomonde R, Niemann, Stefan, Nikolayevskyy, Vladyslav, Maurer, Florian P, Merker, Matthias, Miotto, Paolo, Omar, Shaheed V, Otto-Knapp, Ralf, Palaci, Moisés, Gutiérrez, Juan José Palacios, Peacock, Sharon J, Peloquin, Charles A, Perera, Jennifer, Pierre-Audigier, Catherine, Pholwat, Suporn, Posey, James E, Prammananan, Therdsak, Rigouts, Leen, Robledo, Jaime, Rockwood, Neesha, Rodrigues, Camilla, Salfinger, Max, Schechter, Marcos C, Seifert, Marva, Sengstake, Sarah, Shinnick, Thomas, Shubladze, Natalia, Sintchenko, Vitali, Sirgel, Frederick, Somasundaram, Sulochana, Sterling, Timothy R, Spitaleri, Andrea, and Streicher, Elizabeth

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Orphan Drug, Emerging Infectious Diseases, Tuberculosis, Biodefense, Antimicrobial Resistance, Infectious Diseases, Rare Diseases, 5.1 Pharmaceuticals, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Antitubercular Agents, Drug Resistance, Bacterial, Drug Resistance, Multiple, Bacterial, Humans, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Tuberculosis, Multidrug-Resistant, Antimycobacterial Susceptibility Testing Group, Medical and Health Sciences, Respiratory System, Cardiovascular medicine and haematology
Abstract

Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance. https://bit.ly/3i43wb6

Published
2022

4. Characterizing the Etiology of Recurrent Tuberculosis Using Whole Genome Sequencing: Alaska, 2008–2020.

Author

Springer, Yuri P, Tompkins, Megan L, Newell, Katherine, Jones, Martin, Burns, Scott, Chandler, Bruce, Cowan, Lauren S, Kammerer, J Steve, Posey, James E, Raz, Kala M, Rothoff, Michelle, Silk, Benjamin J, Vergnetti, Yvette L, McLaughlin, Joseph B, and Talarico, Sarah

Subjects
WHOLE genome sequencing, ALASKA Natives, SINGLE nucleotide polymorphisms, WATCHFUL waiting, GENETIC distance
Abstract

Background Understanding the etiology of recurrent tuberculosis (rTB) is important for effective tuberculosis control. Prior to the advent of whole genome sequencing (WGS), attributing rTB to relapse or reinfection using genetic information was complicated by the limited resolution of conventional genotyping methods. Methods We applied a systematic method of evaluating whole genome single-nucleotide polymorphism (wgSNP) distances and results of phylogenetic analyses to characterize the etiology of rTB in American Indian and Alaska Native (AIAN) persons in Alaska during 2008 to 2020. We contextualized our findings through descriptive analyses of surveillance data and results of a literature search for investigations that characterized rTB etiology using WGS. Results The percentage of tuberculosis cases in AIAN persons in Alaska classified as recurrent episodes (11.8%) was 3 times the national percentage (3.9%). Of 38 recurrent episodes included in genetic analyses, we attributed 25 (65.8%) to reinfection based on wgSNP distances and phylogenetic analyses; this proportion was the highest among 16 published point estimates identified through the literature search. By comparison, we attributed 11 (28.9%) and 6 (15.8%) recurrent episodes to reinfection based on wgSNP distances alone and on conventional genotyping methods, respectively. Conclusions WGS and attribution criteria involving genetic distances and patterns of relatedness can provide an effective means of elucidating rTB etiology. Our findings indicate that rTB occurs at high proportions among AIAN persons in Alaska and is frequently attributable to reinfection, reinforcing the importance of active surveillance and control measures to limit the spread of tuberculosis disease in Alaskan AIAN communities. [ABSTRACT FROM AUTHOR]

Published
2025
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5. Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing

Author

Allix-Béguec, Caroline, Arandjelovic, Irena, Bi, Lijun, Beckert, Patrick, Bonnet, Maryline, Bradley, Phelim, Cabibbe, Andrea M, Cancino-Muñoz, Irving, Caulfield, Mark J, Chaiprasert, Angkana, Cirillo, Daniela, Clifton, David, Comas, Iñaki, Crook, Derrick W, De Filippo, Maria Rosaria, de Neeling, Han, Diel, Roland, Drobniewski, Francis A, Faksri, Kiatichai, Farhat, Maha R, Fleming, Joy, Fowler, Philip, Fowler, Tom A, Gao, Qian, Gardy, Jennifer, Gascoyne-Binzi, Deborah, Cruz, Ana Gibertoni, Gil-Brusola, Ana, Golubchik, Tanya, Gonzalo, Ximena, Grandjean, Louis, He, Guangxue, Guthrie, Jennifer L, Hoosdally, Sarah, Hunt, Martin, Iqbal, Zamin, Ismail, Nazir, Johnston, James, Khanzada, Faisal Masood, Khor, Chiea Chuen, Kohl, Thomas A, Kong, Clare, Lipworth, Sam, Liu, Qingyun, Maphalala, Gugu, Martinez, Elena, Mathys, Vanessa, Merker, Matthias, Miotto, Paolo, Mistry, Nerges, Moore, David, Murray, Megan, Niemann, Stefan, Ong, Rick Twee-Hee, Peto, Tim EA, Posey, James E, Prammananan, Therdsak, Pym, Alexander, Rodrigues, Camilla, Rodrigues, Mabel, Rodwell, Timothy, Rossolini, Gian Maria, Padilla, Elisabeth Sánchez, Schito, Marco, Shen, Xin, Shendure, Jay, Sintchenko, Vitali, Sloutsky, Alex, Smith, E Grace, Snyder, Matthew, Soetaert, Karine, Starks, Angela M, Supply, Philip, Suriyapol, Prapat, Tahseen, Sabira, Tang, Patrick, Teo, Yik-Ying, Thuong, Thuong Nguyen Thuy, Thwaites, Guy, Tortoli, Enrico, Omar, Shaheed Vally, van Soolingen, Dick, Walker, A Sarah, Walker, Timothy M, Wilcox, Mark, Wilson, Daniel J, Wyllie, David, Yang, Yang, Zhang, Hongtai, Zhao, Yanlin, and Zhu, Baoli

Subjects
Genetics, Human Genome, Tuberculosis, Clinical Research, Patient Safety, Prevention, Rare Diseases, Infectious Diseases, Antimicrobial Resistance, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Antitubercular Agents, Drug Resistance, Bacterial, Ethambutol, Genome, Bacterial, Genotype, Humans, Isoniazid, Microbial Sensitivity Tests, Mutation, Mycobacterium tuberculosis, Phenotype, Pyrazinamide, Rifampin, Whole Genome Sequencing, CRyPTIC Consortium and the 100, 000 Genomes Project, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundThe World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear.MethodsWe obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance.ResultsA total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted.ConclusionsGenotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.).

Published
2018

6. Characterizing the etiology of recurrent tuberculosis using whole genome sequencing—Alaska, USA, 2008–2020

Author

Springer, Yuri P, primary, Tompkins, Megan L, additional, Newell, Katherine, additional, Jones, Martin, additional, Burns, Scott, additional, Chandler, Bruce, additional, Cowan, Lauren S, additional, Kammerer, J Steve, additional, Posey, James E, additional, Raz, Kala M, additional, Rothoff, Michelle, additional, Silk, Benjamin J, additional, Vergnetti, Yvette L, additional, McLaughlin, Joseph B, additional, and Talarico, Sarah, additional

Published
2024
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7. Prediction of pyrazinamide resistance in Mycobacterium tuberculosis using structure-based machine-learning approaches

Author

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

Published
2024
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12. Statistical Method to Detect Tuberculosis Outbreaks among Endemic Clusters in a Low-Incidence Setting

Author

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

Subjects
United States. Centers for Disease Control and Prevention -- Analysis, Usage, Analysis, Genetic aspects, Methods, DNA sequencing -- Methods -- Usage -- Analysis, Tuberculosis -- Genetic aspects -- Methods -- Usage -- Analysis, Genomics -- Methods -- Usage -- Analysis
Abstract

We previously reported use of data from the National Tuberculosis Genotyping Service in the United States to predict outbreaks among incident clusters of tuberculosis (TB), defined as clusters in which [...]

Published
2018
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15. Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment

Author

Ministerio de Ciencia e Innovación (España), European Research Council, Comas, Iñaki [0000-0001-5504-9408], Antimycobacterial Susceptibility Testing Group, Georghiou, Sophia B., Rodwell, Timothy C., Korobitsyn, Alexei, Abbadi, Said H., Ajbani, Kanchan, Alffenaar, Jan-Willem, Alland, David, Alvarez, Nataly, Andres, Sönke, Ardizzoni, Elisa, Aubry, Alexandra, Baldan, Rossella, Ballif, Marie, Barilar, Ivan, Böttger, Erik C., Chakravorty, Soumitesh, Claxton, Pauline M., Cirillo, Daniela M., Comas, Iñaki, Coulter, Chris, Denkinger, Claudia M., Derendinger, Brigitta, Desmond, Edward P., Steenwinkel, Jurriaan E. M. de, Dheda, Keertan, Diacon, Andreas H., Dolinger, David L., Dooley, Kelly E., Egger, Matthias, Ehsani, Soudeh, Farhat, Maha R., Fattorini, Lanfranco, Finci, Iris, Fournier Le Ray, Laure, Furió, Victoria, Groenheit, Ramona, Gumbo, Tawanda, Heysell, Scott K., Hillemann, Doris, Hoffmann, Harald, Hsueh, Po-Ren, Hu, Yi, Huang, Hairong, Hussain, Alamdar, Ismail, Farzana, Izumi, Kiyohiko, Jagielski, Tomasz, Johnson, John L., Kambli, Priti, Kaniga, Koné, Karunaratne, G. H. R. Eranga, Sharma, Meenu Kaushal, Keller, Peter M., Kelly, Ellis C., Kholina, Margarita, Kohli, Mikashmi, Kranzer, Katharina, Laurenson, Ian F., Limberis, Jason, Lin, S-Y. Grace, Liu, Yongge, López-Gavín, Alexandre, Lyander, Anna, Machado, Diana, Martínez, Elena, Masood, Faisal, Mitarai, Satoshi, Mvelase, Nomonde R., Niemann, Stefan, Nikolayevskyy, Vladyslav, Maurer, Florian P., Merker, Matthias, Miotto, Paolo, Omar, Shaheed V., Otto-Knapp, Ralf, Palaci, Moisés, Palacios Gutiérrez, Juan José, Peacock, Sharon J., Peloquin, Charles A., Perera, Jennifer, Pierre-Audigier, Catherine, Pholwat, Suporn, Posey, James E., Prammananan, Therdsak, Rigouts, Leen, Robledo, Jaime, Rockwood, Neesha, Rodrigues, Camilla, Salfinger, Max, Schechter, Marcos C., Seifert, Marva, Sengstake, Sarah, Shinnick, Thomas, Shubladze, Natalia, Sintchenko, Vitali, Sirgel, Frederick, Somasundaram, Sulochana, Sterling, Timothy R., Spitaleri, Andrea, Streicher, Elizabeth, Supply, Philip, Svensson, Erik, Tagliani, Elisa, Tahseen, Sabira, Takaki, Akiko, Theron, Grant, Torrea, Gabriela, Van Deun, Armand, van Ingen, Jakko, Van Rie, Annelies, van Soolingen, Dick, Vargas Jr, Roger, Venter, Amour, Veziris, Nicolas, Villellas, Cristina, Viveiros, Miguel, Warren, Robin, Wen, Shu'an, Werngren, Jim, Wilkinson, Robert J., Yang, Caie, Yılmaz, F. Ferda, Zhang, Tingting, Zimenkov, Danila, Ismail, Nazir, Köser, Claudio U., Schön, Thomas, Ministerio de Ciencia e Innovación (España), European Research Council, Comas, Iñaki [0000-0001-5504-9408], Antimycobacterial Susceptibility Testing Group, Georghiou, Sophia B., Rodwell, Timothy C., Korobitsyn, Alexei, Abbadi, Said H., Ajbani, Kanchan, Alffenaar, Jan-Willem, Alland, David, Alvarez, Nataly, Andres, Sönke, Ardizzoni, Elisa, Aubry, Alexandra, Baldan, Rossella, Ballif, Marie, Barilar, Ivan, Böttger, Erik C., Chakravorty, Soumitesh, Claxton, Pauline M., Cirillo, Daniela M., Comas, Iñaki, Coulter, Chris, Denkinger, Claudia M., Derendinger, Brigitta, Desmond, Edward P., Steenwinkel, Jurriaan E. M. de, Dheda, Keertan, Diacon, Andreas H., Dolinger, David L., Dooley, Kelly E., Egger, Matthias, Ehsani, Soudeh, Farhat, Maha R., Fattorini, Lanfranco, Finci, Iris, Fournier Le Ray, Laure, Furió, Victoria, Groenheit, Ramona, Gumbo, Tawanda, Heysell, Scott K., Hillemann, Doris, Hoffmann, Harald, Hsueh, Po-Ren, Hu, Yi, Huang, Hairong, Hussain, Alamdar, Ismail, Farzana, Izumi, Kiyohiko, Jagielski, Tomasz, Johnson, John L., Kambli, Priti, Kaniga, Koné, Karunaratne, G. H. R. Eranga, Sharma, Meenu Kaushal, Keller, Peter M., Kelly, Ellis C., Kholina, Margarita, Kohli, Mikashmi, Kranzer, Katharina, Laurenson, Ian F., Limberis, Jason, Lin, S-Y. Grace, Liu, Yongge, López-Gavín, Alexandre, Lyander, Anna, Machado, Diana, Martínez, Elena, Masood, Faisal, Mitarai, Satoshi, Mvelase, Nomonde R., Niemann, Stefan, Nikolayevskyy, Vladyslav, Maurer, Florian P., Merker, Matthias, Miotto, Paolo, Omar, Shaheed V., Otto-Knapp, Ralf, Palaci, Moisés, Palacios Gutiérrez, Juan José, Peacock, Sharon J., Peloquin, Charles A., Perera, Jennifer, Pierre-Audigier, Catherine, Pholwat, Suporn, Posey, James E., Prammananan, Therdsak, Rigouts, Leen, Robledo, Jaime, Rockwood, Neesha, Rodrigues, Camilla, Salfinger, Max, Schechter, Marcos C., Seifert, Marva, Sengstake, Sarah, Shinnick, Thomas, Shubladze, Natalia, Sintchenko, Vitali, Sirgel, Frederick, Somasundaram, Sulochana, Sterling, Timothy R., Spitaleri, Andrea, Streicher, Elizabeth, Supply, Philip, Svensson, Erik, Tagliani, Elisa, Tahseen, Sabira, Takaki, Akiko, Theron, Grant, Torrea, Gabriela, Van Deun, Armand, van Ingen, Jakko, Van Rie, Annelies, van Soolingen, Dick, Vargas Jr, Roger, Venter, Amour, Veziris, Nicolas, Villellas, Cristina, Viveiros, Miguel, Warren, Robin, Wen, Shu'an, Werngren, Jim, Wilkinson, Robert J., Yang, Caie, Yılmaz, F. Ferda, Zhang, Tingting, Zimenkov, Danila, Ismail, Nazir, Köser, Claudio U., and Schön, Thomas

Abstract

Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance.

Published
2022

17. Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment

Author

Antimycobacterial Susceptibility Testing Group, Georghiou, Sophia B., Rodwell, Timothy C., Korobitsyn, Alexei, Abbadi, Said H., Ajbani, Kanchan, Alffenaar, Jan-Willem, Alland, David, Alvarez, Nataly, Andres, Sönke, Ardizzoni, Elisa, Aubry, Alexandra, Baldan, Rossella, Ballif, Marie, Barilar, Ivan, Böttger, Erik C., Chakravorty, Soumitesh, Claxton, Pauline M., Cirillo, Daniela M., Comas, Iñaki, Coulter, Chris, Denkinger, Claudia M., Derendinger, Brigitta, Desmond, Edward P., Steenwinkel, Jurriaan E. M. de, Dheda, Keertan, Diacon, Andreas H., Dolinger, David L., Dooley, Kelly E., Egger, Matthias, Ehsani, Soudeh, Farhat, Maha R., Fattorini, Lanfranco, Finci, Iris, Fournier Le Ray, Laure, Furió, Victoria, Groenheit, Ramona, Gumbo, Tawanda, Heysell, Scott K., Hillemann, Doris, Hoffmann, Harald, Hsueh, Po-Ren, Hu, Yi, Huang, Hairong, Hussain, Alamdar, Ismail, Farzana, Izumi, Kiyohiko, Jagielski, Tomasz, Johnson, John L., Kambli, Priti, Kaniga, Koné, Karunaratne, G. H. R. Eranga, Sharma, Meenu Kaushal, Keller, Peter M., Kelly, Ellis C., Kholina, Margarita, Kohli, Mikashmi, Kranzer, Katharina, Laurenson, Ian F., Limberis, Jason, Lin, S-Y. Grace, Liu, Yongge, López-Gavín, Alexandre, Lyander, Anna, Machado, Diana, Martínez, Elena, Masood, Faisal, Mitarai, Satoshi, Mvelase, Nomonde R., Niemann, Stefan, Nikolayevskyy, Vladyslav, Maurer, Florian P., Merker, Matthias, Miotto, Paolo, Omar, Shaheed V., Otto-Knapp, Ralf, Palaci, Moisés, Palacios Gutiérrez, Juan José, Peacock, Sharon J., Peloquin, Charles A., Perera, Jennifer, Pierre-Audigier, Catherine, Pholwat, Suporn, Posey, James E., Prammananan, Therdsak, Rigouts, Leen, Robledo, Jaime, Rockwood, Neesha, Rodrigues, Camilla, Salfinger, Max, Schechter, Marcos C., Seifert, Marva, Sengstake, Sarah, Shinnick, Thomas, Shubladze, Natalia, Sintchenko, Vitali, Sirgel, Frederick, Somasundaram, Sulochana, Sterling, Timothy R., Spitaleri, Andrea, Streicher, Elizabeth, Supply, Philip, Svensson, Erik, Tagliani, Elisa, Tahseen, Sabira, Takaki, Akiko, Theron, Grant, Torrea, Gabriela, Van Deun, Armand, van Ingen, Jakko, Van Rie, Annelies, van Soolingen, Dick, Vargas Jr, Roger, Venter, Amour, Veziris, Nicolas, Villellas, Cristina, Viveiros, Miguel, Warren, Robin, Wen, Shu'an, Werngren, Jim, Wilkinson, Robert J., Yang, Caie, Yılmaz, F. Ferda, Zhang, Tingting, Zimenkov, Danila, Ismail, Nazir, Köser, Claudio U., Schön, Thomas, University of Zurich, Antimycobacterial Susceptibility Testing Group, Department of Genetics [Cambridge], University of Cambridge [UK] (CAM), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Médical de l'Institut Pasteur (CMIP), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut de médecine et d'épidémiologie appliquée [AP-HP Hôpital Bichat-Claude Bernard] (IMEA), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), As current or former employees or consultants for FIND, the work of R.B. Baldan, I. Comas, C.M. Denkinger, D.L. Dolinger, S.B. Georghiou, C.U. Köser and T.C. Rodwell on the systematic reviews, including this viewpoint, was supported by Unitaid (grant 2019-32-FIND MDR), BMGF (grant OPP1105925), the German Federal Ministry of Education and Research through KfW, the Dutch Ministry of Foreign Affairs, the Australian Department of Foreign Affairs and Trade, and UK aid from the British people. N. Alvarez and J. Robledo are funded by MinCiencias, Colombia (number 221389666216 CT-783-2018). A. Aubry and N. Veziris work at the Centre National de Reference des Mycobactéries, which receives an annual grant from Santé Publique France and have received research grants from Janssen for studies on bedaquiline. P. Claxton and I.F. Laurenson are funded through National Services Scotland. I. Comas was supported by PID2019-104477RB-I00 from the Spanish Science Ministry and by ERC (CoG 101001038). M. Egger is supported by the Swiss National Science Foundation (grant number 320030_153442 and 189498) and the US National Institutes of Health, National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, the National Institute of Mental Health, the National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Diabetes and Digestive and Kidney Diseases, the Fogarty International Center, and the National Library of Medicine: Asia-Pacific, U01AI069907, CCASAnet, U01AI069923, Central Africa, U01AI096299, East Africa, U01AI069911, NA-ACCORD, U01AI069918, Southern Africa, U01AI069924, West Africa, U01AI069919. M.R. Farhat is supported by NIH NIAID R01AI155765. S.K. Heysell was funded by NIH NIAID grants R01 AI137080 and U01 AI150508. T. Jagielski was supported by a DAINA grant (number 2017/27/L/NZ6/03279) from the National Science Centre, Poland. J.L. Johnson was supported by contracts NO1-AI95383 and NO1-AI-70022 of the US National Institutes of Health. P.M. Keller was supported by Innosuisse 36198.1 IP-LS. C.U. Köser is a research associate at Wolfson College and visiting scientist at the Department of Genetics, University of Cambridge. The Federal Government of Germany supported C.U. Köser as part of his work for the European Laboratory Initiative, WHO Regional Office for Europe. C.U. Köser was further supported by the Royal Society of Tropical Medicine and Hygiene and the National Institute for Health Research Cambridge Biomedical Research Centre and received an observership by the European Society of Clinical Microbiology and Infectious Diseases to the EUCAST Development Laboratory for Bacteria (Växjö, Sweden), hosted by Gunnar Kahlmeter and Erika Matuschek. D. Machado and M. Viveiros are funded in part by Fundação para a Ciência e a Tecnologia, Portugal (PTDC/BIA-MIC/30692/2017, UID/Multi/04413/2020 and DL57/ CEECIND/0256/2017). S. Niemann is supported by the German Center for Infection Research, Excellenz Cluster Precision Medicine in Chronic Inflammation EXC 2167, Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG). S.V. Omar has received funding to prepare and provide training for Janssen Pharmaceutica activities. L. Rigouts is supported by the Belgian Directorate General for Development. T.C. Rodwell was additionally funded in part by FIND and NIH NIAD, grants: P30 AI036214 and R21 AI135756. T. Schön is funded by the Swedish Heart and Lung Foundation and the Swedish Research Council. T.R. Sterling has received funding from the US National Institutes of Health and the Centers for Disease Control and Prevention. G. Theron and R. Warren are supported by baseline funding from the South African Medical Research Council. R.J. Wilkinson receives funding from the Wellcome Trust (203135) and from the Francis Crick Institute, which is supported by Cancer Research UK (FC0010218), UKRI (FC0010218) and the Wellcome Trust (FC0010218), Ministerio de Ciencia e Innovación (España), European Research Council, Comas, Iñaki, Comas, Iñaki [0000-0001-5504-9408], Antimycobacterial Susceptibility T, and Wellcome Trust

Subjects
[SDV]Life Sciences [q-bio], Respiratory System, Drug Resistance, Antitubercular Agents, Infektionsmedicin, Medical and Health Sciences, Drug Resistance, Multiple, Bacterial, Tuberculosis, Multidrug-Resistant, 11 Medical and Health Sciences, Human Biology & Physiology, MESH: Microbial Sensitivity Tests, 10179 Institute of Medical Microbiology, Bacterial, Multidrug-Resistant, Infectious Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Life Sciences & Biomedicine, Multiple, Model organisms, Pulmonary and Respiratory Medicine, Infectious Medicine, Immunology, Infectious Disease, 610 Medicine & health, Microbial Sensitivity Tests, Vaccine Related, Rare Diseases, Clinical Research, Biodefense, MESH: Drug Resistance, Bacterial, Drug Resistance, Bacterial, Tuberculosis, Humans, Science & Technology, MESH: Humans, Antimycobacterial Susceptibility Testing Group, FOS: Clinical medicine, Prevention, MESH: Drug Resistance, Multiple, Bacterial, Mycobacterium tuberculosis, Eucast, MESH: Antitubercular Agents, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Orphan Drug, Emerging Infectious Diseases, Good Health and Well Being, 2740 Pulmonary and Respiratory Medicine, 570 Life sciences, biology, Human medicine, Antimicrobial Resistance, Model
Abstract

11 páginas, 2 figuras, 1 tabla, Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance., I. Comas was supported by PID2019-104477RB-I00 from the Spanish Science Ministry and by ERC (CoG 101001038)

Published
2022
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18. Characterization of the twin-arginine translocase secretion system of Mycobacterium smegmatis

Author

Posey, James E., Shinnick, Thomas M., and Quinn, Frederick D.

Subjects
Mycobacteria -- Genetic aspects, Mycobacteria -- Research, Mycobacterium -- Genetic aspects, Mycobacterium -- Research, Translocation (Genetics) -- Research, Bacterial genetics -- Research, Biological sciences
Abstract

The twin-arginine translocation (TAT) system secretes fully folded proteins that contain a twin-arginine motif within their signal sequence across the cytoplasmic membrane in bacteria. Using a green fluorescent protein fused with a TAT signal sequence, we demonstrated that Mycobacterium smegmatis contains a TAT system. By inactivating individual genes, we showed that three genes (tatA, tatB, and tatC) are required for a functional TAT system in M. smegmatis. The tat mutants exhibited a decreased growth rate and altered colony morphology compared to the parent strain. Comparison of the secreted proteins of the [DELTA]tatC and parent strain by two-dimensional polyacrylamide gel electrophoresis revealed an alteration in the secretion of at least five proteins, and one of the major TAT-dependent secreted proteins was identified as [beta]-lactamase (BlaS). The genome of M. smegmatis was analyzed with the TATFIND program, and 49 putative TAT substrates were identified, including the succinate transporter DctP. Because disruption of the TAT secretion system has a direct effect on the physiology of M. smegmatis and homologs of the TAT proteins are also present in the genome of Mycobacterium tuberculosis, the TAT secretion system or its substrates may be good candidates for drug or vaccine development.

Published
2006

19. Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis from Mycobacterium tuberculosis to overcome kanamycin resistance

Author

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

Published
2021
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20. The 2021 WHO Catalogue of Mycobacterium Tuberculosis Complex Mutations Associated with Drug Resistance: A New Global Standard for Molecular Diagnostics

Author

Walker, Timothy M., primary, Miotto, Paolo, additional, Köser, Claudio U., additional, Fowler, Philip William, additional, Knaggs, Jeff, additional, Iqbal, Zamin, additional, Hunt, Martin, additional, Chindelevitch, Leonid, additional, Farhat, Maha, additional, Cirillo, daniela, additional, Comas, Iñaki, additional, Posey, James E., additional, Omar, Shaheed Vally, additional, Peto, Timothy E. A., additional, Suresh, Anita, additional, Uplekar, Swapna, additional, Laurent, Sacha, additional, Colman, Rebecca, additional, Nathanson, Carl-Michael, additional, Zignol, Matteo, additional, Walker, Ann Sarah, additional, Consortium, The CRyPTIC, additional, Consortium, The Seq&Treat, additional, Crook, Derrick W., additional, Ismail, Nazir, additional, and Rodwell, Timothy C., additional

Published
2021
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21. Treponema pallidium 3-phosphoglycerate mutase is a heat-labile enzyme that may limit the maximum growth temperature for the spirochete

Author

Benoit, Stephane, Posey, James E., Chenoweth, Matthew R., and Gherardini, Frank C.

Subjects
Enzyme kinetics -- Analysis, Spirochetes -- Growth, Syphilis -- Research, Metabolic regulation -- Physiological aspects, Treponema pallidum, Biological sciences
Abstract

Research reveals that enzyme Gpm of the Embden-Meyerhof pathway is responsible for the heat sensitivity of Treponema pallidum. Data indicate that Gpm is stable for four hours at 25 C, losing 50% of the activity at 34 C and completely inactive at 42 C.

Published
2001

23. Structure-Guided Optimization of Inhibitors of Acetyltransferase Eis from Mycobacterium tuberculosis

Author

Punetha, Ankita, primary, Ngo, Huy X., additional, Holbrook, Selina Y. L., additional, Green, Keith D., additional, Willby, Melisa J., additional, Bonnett, Shilah A., additional, Krieger, Kyle, additional, Dennis, Emily K., additional, Posey, James E., additional, Parish, Tanya, additional, Tsodikov, Oleg V., additional, and Garneau-Tsodikova, Sylvie, additional

Published
2020
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24. Discordance in Mycobacterium tuberculosis rifampin susceptibility

Author

Kalokhe, Ameeta S., Shafiq, Majid, Lee, James C., Metchock, Beverly, Posey, James E., Ray, Susan M., Anderson, Albert, Wang, Yun F., and Nguyen, Minh Ly T.

Subjects
Drug therapy, Research, Health aspects, Microbial drug resistance -- Research, Rifampin -- Health aspects -- Research, Tuberculosis -- Drug therapy -- Research, Drug resistance in microorganisms -- Research
Abstract

To the Editor: Multidrug-resistant tuberculosis (MDR TB), i.e., TB resistant to at least the 2 most effective first-line antituberculous drugs (isoniazid [INH] and rifampin [RIF]), is increasing globally. World Health [...]

Published
2012
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26. Pathogen Genomics in Public Health

Author

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

Published
2019
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30. 769. An Outbreak of Multidrug-Resistant Tuberculosis, Minnesota 2016–2017

Author

Desilva, Malini, primary, Moore, Nora, additional, Thai, Dzung, additional, Grimm, Mary Beth, additional, Sabuwala, Nadya, additional, Brueshaber, Milayna, additional, Gordon, Sarah, additional, Andersen, Laura, additional, Hall, Victoria, additional, Buuck, Sean, additional, Hickman, Cynthia, additional, Stinebaugh, Katie, additional, Silk, Benjamin, additional, Raz, Kayla, additional, Talarico, Sarah, additional, Wortham, Jonathan, additional, Kingdon, Elisabeth, additional, Pistulka, Gina, additional, Guerard, Krissie, additional, Cowan, Lauren, additional, Posey, James E, additional, Snippes Vagnone, Paula M, additional, McCullough, Joel, additional, Tsukayama, Dean, additional, Mody, Rajal K, additional, and Ehresmann, Kristen, additional

Published
2018
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31. Potent 1,2,4-Triazino[5,6b]indole-3-thioether Inhibitors of the Kanamycin Resistance Enzyme Eis from Mycobacterium tuberculosis

Author

Ngo, Huy X., primary, Green, Keith D., additional, Gajadeera, Chathurada S., additional, Willby, Melisa J., additional, Holbrook, Selina Y. L., additional, Hou, Caixia, additional, Garzan, Atefeh, additional, Mayhoub, Abdelrahman S., additional, Posey, James E., additional, Tsodikov, Oleg. V., additional, and Garneau-Tsodikova, Sylvie, additional

Published
2018
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32. Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing.

Author

CRyPTIC Consortium and the 100,000 Genomes Project, CRyPTIC Consortium and the 100,000 Genomes Project, Allix-Béguec, Caroline, Arandjelovic, Irena, Bi, Lijun, Beckert, Patrick, Bonnet, Maryline, Bradley, Phelim, Cabibbe, Andrea M, Cancino-Muñoz, Irving, Caulfield, Mark J, Chaiprasert, Angkana, Cirillo, Daniela M, Clifton, David A, Comas, Iñaki, Crook, Derrick W, De Filippo, Maria R, de Neeling, Han, Diel, Roland, Drobniewski, Francis A, Faksri, Kiatichai, Farhat, Maha R, Fleming, Joy, Fowler, Philip, Fowler, Tom A, Gao, Qian, Gardy, Jennifer, Gascoyne-Binzi, Deborah, Gibertoni-Cruz, Ana-Luiza, Gil-Brusola, Ana, Golubchik, Tanya, Gonzalo, Ximena, Grandjean, Louis, He, Guangxue, Guthrie, Jennifer L, Hoosdally, Sarah, Hunt, Martin, Iqbal, Zamin, Ismail, Nazir, Johnston, James, Khanzada, Faisal M, Khor, Chiea C, Kohl, Thomas A, Kong, Clare, Lipworth, Sam, Liu, Qingyun, Maphalala, Gugu, Martinez, Elena, Mathys, Vanessa, Merker, Matthias, Miotto, Paolo, Mistry, Nerges, Moore, David AJ, Murray, Megan, Niemann, Stefan, Omar, Shaheed V, Ong, Rick T-H, Peto, Tim EA, Posey, James E, Prammananan, Therdsak, Pym, Alexander, Rodrigues, Camilla, Rodrigues, Mabel, Rodwell, Timothy, Rossolini, Gian M, Sánchez Padilla, Elisabeth, Schito, Marco, Shen, Xin, Shendure, Jay, Sintchenko, Vitali, Sloutsky, Alex, Smith, E Grace, Snyder, Matthew, Soetaert, Karine, Starks, Angela M, Supply, Philip, Suriyapol, Prapat, Tahseen, Sabira, Tang, Patrick, Teo, Yik-Ying, Thuong, Thuong NT, Thwaites, Guy, Tortoli, Enrico, van Soolingen, Dick, Walker, A Sarah, Walker, Timothy M, Wilcox, Mark, Wilson, Daniel J, Wyllie, David, Yang, Yang, Zhang, Hongtai, Zhao, Yanlin, Zhu, Baoli, CRyPTIC Consortium and the 100,000 Genomes Project, CRyPTIC Consortium and the 100,000 Genomes Project, Allix-Béguec, Caroline, Arandjelovic, Irena, Bi, Lijun, Beckert, Patrick, Bonnet, Maryline, Bradley, Phelim, Cabibbe, Andrea M, Cancino-Muñoz, Irving, Caulfield, Mark J, Chaiprasert, Angkana, Cirillo, Daniela M, Clifton, David A, Comas, Iñaki, Crook, Derrick W, De Filippo, Maria R, de Neeling, Han, Diel, Roland, Drobniewski, Francis A, Faksri, Kiatichai, Farhat, Maha R, Fleming, Joy, Fowler, Philip, Fowler, Tom A, Gao, Qian, Gardy, Jennifer, Gascoyne-Binzi, Deborah, Gibertoni-Cruz, Ana-Luiza, Gil-Brusola, Ana, Golubchik, Tanya, Gonzalo, Ximena, Grandjean, Louis, He, Guangxue, Guthrie, Jennifer L, Hoosdally, Sarah, Hunt, Martin, Iqbal, Zamin, Ismail, Nazir, Johnston, James, Khanzada, Faisal M, Khor, Chiea C, Kohl, Thomas A, Kong, Clare, Lipworth, Sam, Liu, Qingyun, Maphalala, Gugu, Martinez, Elena, Mathys, Vanessa, Merker, Matthias, Miotto, Paolo, Mistry, Nerges, Moore, David AJ, Murray, Megan, Niemann, Stefan, Omar, Shaheed V, Ong, Rick T-H, Peto, Tim EA, Posey, James E, Prammananan, Therdsak, Pym, Alexander, Rodrigues, Camilla, Rodrigues, Mabel, Rodwell, Timothy, Rossolini, Gian M, Sánchez Padilla, Elisabeth, Schito, Marco, Shen, Xin, Shendure, Jay, Sintchenko, Vitali, Sloutsky, Alex, Smith, E Grace, Snyder, Matthew, Soetaert, Karine, Starks, Angela M, Supply, Philip, Suriyapol, Prapat, Tahseen, Sabira, Tang, Patrick, Teo, Yik-Ying, Thuong, Thuong NT, Thwaites, Guy, Tortoli, Enrico, van Soolingen, Dick, Walker, A Sarah, Walker, Timothy M, Wilcox, Mark, Wilson, Daniel J, Wyllie, David, Yang, Yang, Zhang, Hongtai, Zhao, Yanlin, and Zhu, Baoli

Abstract

BackgroundThe World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear.MethodsWe obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance.ResultsA total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profil

Published
2018

33. Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing

Author

Ministerio de Economía y Competitividad (España), European Research Council, Comas, Iñaki [0000-0001-5504-9408], CRyPTIC Consortium and the 100,000 Genomes Project, Allix-Beguec, Caroline, Arandjelovic, Irena, Bi, Lijun, Beckert, Patrick, Bonnet, Maryline, Bradley, Phelim, Cabibbe, Andrea M., Cancino-Muñoz, Irving, Caulfield, Mark J., Chaiprasert, Angkana, Cirillo, Daniela M., Clifton, David A., Comas, Iñaki, Crook, Derrick W., De Filippo, Maria R., de Neeling, Han, Diel, Roland, Drobniewski, Francis A, Faksri, Kiatichai, Farhat, Maha R., Fleming, Joy, Fowler, Philip, Fowler, Tom A, Gao, Qian, Gardy, Jennifer, Gascoyne-Binzi, Deborah, Gibertoni-Cruz, Ana-Luiza, Gil-Brusola, Ana, Golubchik, Tanya, Gonzalo, Ximena, Grandjean, Louis, He, Guangxue, Guthrie, Jennifer L., Hoosdally, Sarah, Hunt, Martin, Iqbal, Zamin, Ismail, Nazir, Johnston, James, Khanzada, Faisal M., Khor, Chiea C., Kohl, Thomas A, Kong, Clare, Lipworth, Sam, Liu, Qingyun, Maphalala, Gugu, Martínez, Elena, Mathys, Vanessa, Merker, Matthias, Miotto, Paolo, Mistry, Nerges, Moore, David A. J., Murray, Megan, Niemann, Stefan, Omar, Shaheed V., Ong, Rick T-H., Peto, Tim E.A., Posey, James E., Prammananan, Therdsak, Pym, Alexander, Rodrigues, Camilla, Rodrigues, Mabel, Rodwell, Timothy, Rossolini, Gian M., Sanchez Padilla, Elisabeth, Schito, Marco, Shen, Xin, Shendure, Jay, Sintchenko, Vitali, Sloutsky, Alex, Smith, E. Grace, Snyder, Matthew, Soetaert, Karine, Starks, Angela M., Supply, Philip, Suriyapol, Prapat, Tahseen, Sabira, Tang, Patrick, Teo, Yik-Ying, Thuong, Thuong N. T., Thwaites, Guy, Tortoli, Enrico, van Soolingen, Dick, Walker, A. Sarah, Walker, Timothy M., Wilcox, Mark, Wilson, Daniel J., Wyllie, David, Yang, Yang, Zhang, Hongtai, Zhao, Yanlin, Zhu, Baoli, Ministerio de Economía y Competitividad (España), European Research Council, Comas, Iñaki [0000-0001-5504-9408], CRyPTIC Consortium and the 100,000 Genomes Project, Allix-Beguec, Caroline, Arandjelovic, Irena, Bi, Lijun, Beckert, Patrick, Bonnet, Maryline, Bradley, Phelim, Cabibbe, Andrea M., Cancino-Muñoz, Irving, Caulfield, Mark J., Chaiprasert, Angkana, Cirillo, Daniela M., Clifton, David A., Comas, Iñaki, Crook, Derrick W., De Filippo, Maria R., de Neeling, Han, Diel, Roland, Drobniewski, Francis A, Faksri, Kiatichai, Farhat, Maha R., Fleming, Joy, Fowler, Philip, Fowler, Tom A, Gao, Qian, Gardy, Jennifer, Gascoyne-Binzi, Deborah, Gibertoni-Cruz, Ana-Luiza, Gil-Brusola, Ana, Golubchik, Tanya, Gonzalo, Ximena, Grandjean, Louis, He, Guangxue, Guthrie, Jennifer L., Hoosdally, Sarah, Hunt, Martin, Iqbal, Zamin, Ismail, Nazir, Johnston, James, Khanzada, Faisal M., Khor, Chiea C., Kohl, Thomas A, Kong, Clare, Lipworth, Sam, Liu, Qingyun, Maphalala, Gugu, Martínez, Elena, Mathys, Vanessa, Merker, Matthias, Miotto, Paolo, Mistry, Nerges, Moore, David A. J., Murray, Megan, Niemann, Stefan, Omar, Shaheed V., Ong, Rick T-H., Peto, Tim E.A., Posey, James E., Prammananan, Therdsak, Pym, Alexander, Rodrigues, Camilla, Rodrigues, Mabel, Rodwell, Timothy, Rossolini, Gian M., Sanchez Padilla, Elisabeth, Schito, Marco, Shen, Xin, Shendure, Jay, Sintchenko, Vitali, Sloutsky, Alex, Smith, E. Grace, Snyder, Matthew, Soetaert, Karine, Starks, Angela M., Supply, Philip, Suriyapol, Prapat, Tahseen, Sabira, Tang, Patrick, Teo, Yik-Ying, Thuong, Thuong N. T., Thwaites, Guy, Tortoli, Enrico, van Soolingen, Dick, Walker, A. Sarah, Walker, Timothy M., Wilcox, Mark, Wilson, Daniel J., Wyllie, David, Yang, Yang, Zhang, Hongtai, Zhao, Yanlin, and Zhu, Baoli

Abstract

BACKGROUND: The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear. METHODS: We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance. RESULTS: A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypi

Published
2018

36. Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis from Mycobacterium tuberculosisto overcome kanamycin resistanceElectronic supplementary information (ESI) available: PDB ID: Eis-haloperidol: 6X10, Eis-droperidol: 6X6G, Eis-SGT543: 6X6I, Eis-SGT572: 6X7A, Eis-SGT1264: 6X6Y. See DOI: 10.1039/d1md00239b

Author

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., and Garneau-Tsodikova, Sylvie

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis(Mtb), is a deadly bacterial disease. Drug-resistant strains of Mtbmake eradication of TB a daunting task. Overexpression of the enhanced intracellular survival (Eis) protein by Mtbconfers resistance to the second-line antibiotic kanamycin (KAN). Eis is an acetyltransferase that acetylates KAN, inactivating its antimicrobial function. Development of Eis inhibitors as KAN adjuvant therapeutics is an attractive path to forestall and overcome KAN resistance. We discovered that an antipsychotic drug, haloperidol (HPD, 1), was a potent Eis inhibitor with IC50= 0.39 ± 0.08 μM. We determined the crystal structure of the Eis-haloperidol (1) complex, which guided synthesis of 34 analogues. The structure–activity relationship study showed that in addition to haloperidol (1), eight analogues, some of which were smaller than 1, potently inhibited Eis (IC50≤ 1 μM). Crystal structures of Eis in complexes with three potent analogues and droperidol (DPD), an antiemetic and antipsychotic, were determined. Three compounds partially restored KAN sensitivity of a KAN-resistant Mtbstrain K204 overexpressing Eis. The Eis inhibitors generally did not exhibit cytotoxicity against mammalian cells. All tested compounds were modestly metabolically stable in human liver microsomes, exhibiting 30–60% metabolism over the course of the assay. While direct repurposing of haloperidol as an anti-TB agent is unlikely due to its neurotoxicity, this study reveals potential approaches to modifying this chemical scaffold to minimize toxicity and improve metabolic stability, while preserving potent Eis inhibition.

Published
2021
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37. Mycobacterium tuberculosis pncA Polymorphisms That Do Not Confer Pyrazinamide Resistance at a Breakpoint Concentration of 100 Micrograms per Milliliter in MGIT: TABLE 1

Author

Sirgel, Frik A., Mercante, Alexandra, Posey, James E., Streicher, Elizabeth M., Whitfield, Michael G., Willby, Melisa, Hughes, Kelsey, van Helden, Paul D., van Rie, Annelies, Birkness, Kris, Sampson, Samantha L., Warren, Robin M., and Morlock, Glenn

Abstract

Sequencing of the Mycobacterium tuberculosis pncA gene allows for pyrazinamide susceptibility testing. We summarize data on pncA polymorphisms that do not confer resistance at a susceptibility breakpoint of 100 μg/ml pyrazinamide in MGIT within a cohort of isolates from South Africa and the U.S. Centers for Disease Control and Prevention.

Published
2015
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38. Combating Enhanced Intracellular Survival (Eis)-Mediated Kanamycin Resistance of Mycobacterium tuberculosis by Novel Pyrrolo[1,5-a]pyrazine-Based Eis Inhibitors

Author

Garzan, Atefeh, primary, Willby, Melisa J., additional, Ngo, Huy X., additional, Gajadeera, Chathurada S., additional, Green, Keith D., additional, Holbrook, Selina Y. L., additional, Hou, Caixia, additional, Posey, James E., additional, Tsodikov, Oleg V., additional, and Garneau-Tsodikova, Sylvie, additional

Published
2017
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39. Using Reduced Inoculum Densities of Mycobacterium tuberculosis in MGIT Pyrazinamide Susceptibility Testing to Prevent False-Resistant Results and Improve Accuracy: A Multicenter Evaluation

Author

Morlock, Glenn P., primary, Tyrrell, Frances C., additional, Baynham, Dorothy, additional, Escuyer, Vincent E., additional, Green, Nicole, additional, Kim, Youngmi, additional, Longley-Olson, Patricia A., additional, Parrish, Nicole, additional, Pennington, Courtney, additional, Tan, Desmond, additional, Austin, Brett, additional, and Posey, James E., additional

Published
2017
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45. Mycobacterium tuberculosis pncA Polymorphisms That Do Not Confer Pyrazinamide Resistance at a Breakpoint Concentration of 100 Micrograms per Milliliter in MGIT

Author

Whitfield, Michael G., primary, Warren, Robin M., additional, Streicher, Elizabeth M., additional, Sampson, Samantha L., additional, Sirgel, Frik A., additional, van Helden, Paul D., additional, Mercante, Alexandra, additional, Willby, Melisa, additional, Hughes, Kelsey, additional, Birkness, Kris, additional, Morlock, Glenn, additional, van Rie, Annelies, additional, and Posey, James E., additional

Published
2015
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50. O-mannosylation of the Mycobacterium tuberculosis Adhesin Apa Is Crucial for T Cell Antigenicity during Infection but Is Expendable for Protection

Author

Nandakumar, Subhadra, primary, Kannanganat, Sunil, additional, Dobos, Karen M., additional, Lucas, Megan, additional, Spencer, John S., additional, Fang, Sunan, additional, McDonald, Melissa A., additional, Pohl, Jan, additional, Birkness, Kristin, additional, Chamcha, Venkateswarlu, additional, Ramirez, Melissa V., additional, Plikaytis, Bonnie B., additional, Posey, James E., additional, Amara, Rama Rao, additional, and Sable, Suraj B., additional

Published
2013
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