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201. Drug-Penetration Gradients Associated with Acquired Drug Resistance in Patients with Tuberculosis

Author

Dheda, Keertan, primary, Lenders, Laura, additional, Magombedze, Gesham, additional, Srivastava, Shashikant, additional, Raj, Prithvi, additional, Arning, Erland, additional, Ashcraft, Paula, additional, Bottiglieri, Teodoro, additional, Wainwright, Helen, additional, Pennel, Timothy, additional, Linegar, Anthony, additional, Moodley, Loven, additional, Pooran, Anil, additional, Pasipanodya, Jotam G., additional, Sirgel, Frederick A., additional, van Helden, Paul D., additional, Wakeland, Edward, additional, Warren, Robin M., additional, and Gumbo, Tawanda, additional

Published
2018
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203. Geospatial distribution of Mycobacterium tuberculosis genotypes in Africa

Author

Chihota, Violet N., primary, Niehaus, Antoinette, additional, Streicher, Elizabeth M., additional, Wang, Xia, additional, Sampson, Samantha L., additional, Mason, Peter, additional, Källenius, Gunilla, additional, Mfinanga, Sayoki G., additional, Pillay, Marnomorney, additional, Klopper, Marisa, additional, Kasongo, Webster, additional, Behr, Marcel A., additional, Gey van Pittius, Nicolaas C., additional, van Helden, Paul D., additional, Couvin, David, additional, Rastogi, Nalin, additional, and Warren, Robin M., additional

Published
2018
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204. Unexpected Genomic and Phenotypic Diversity of Mycobacterium africanum Lineage 5 Affects Drug Resistance, Protein Secretion, and Immunogenicity

Author

Ates, Louis S, primary, Dippenaar, Anzaan, additional, Sayes, Fadel, additional, Pawlik, Alexandre, additional, Bouchier, Christiane, additional, Ma, Laurence, additional, Warren, Robin M, additional, Sougakoff, Wladimir, additional, Majlessi, Laleh, additional, van Heijst, Jeroen W J, additional, Brossier, Florence, additional, and Brosch, Roland, additional

Published
2018
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208. The Lancet Respiratory MedicineCommission: 2019 update: epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant and incurable tuberculosis

Author

Dheda, Keertan, Gumbo, Tawanda, Maartens, Gary, Dooley, Kelly E, Murray, Megan, Furin, Jennifer, Nardell, Edward A, Warren, Robin M, Dheda, Keertan, Gumbo, Tawanda, Maartens, Gary, Dooley, Kelly E, Esmail, Aliasgar, Murray, Megan, Furin, Jennifer, Nardell, Edward, London, Leslie, Lessem, Erica, Limberis, Jason, Theron, Grant, McNerney, Ruth, Niemann, Stefan, Dowdy, David, Van Rie, Annelies, Pasipanodya, Jotam G, Rodrigues, Camilla, Clark, Taane G, Sirgel, Frik A, Schaaf, H Simon, Chang, Kwok Chiu, Lange, Christoph, Nahid, Payam, Fourie, Bernard, Ndjeka, Norbert, Nunn, Andrew, Migliori, GB, Udwadia, Zarir F, Horsburgh, C Robert, Churchyard, Gavin J, Menzies, Dick, Hesseling, Anneke C, Seddon, James A, Low, Marcus, Keshavjee, Salmaan, Nuermberger, Eric, McIlleron, Helen, Fennelly, Kevin P, Jindani, Amina, Jaramillo, Ernesto, Padayatchi, Nesri, Barry, Clifton E, and Warren, Robin M

Abstract

The Lancet Respiratory MedicineCommission on drug-resistant tuberculosis was published in 2017, which comprehensively reviewed and provided recommendations on various aspects of the disease. Several key new developments regarding drug-resistant tuberculosis are outlined in this Commission Update. The WHO guidelines on treating drug-resistant tuberculosis were updated in 2019 with a reclassification of second line anti-tuberculosis drugs. An injection-free MDR tuberculosis treatment regimen is now recommended. Over the past 3 years, advances in treatment include the recognition of the safety and mortality benefit of bedaquiline, the finding that the 9–11 month injectable-based ‘Bangladesh’ regimen was non-inferior to longer regimens, and promising interim results of a novel 6 month 3-drug regimen (bedaquiline, pretomanid, and linezolid). Studies of explanted lungs from patients with drug-resistant tuberculosis have shown substantial drug-specific gradients across pulmonary cavities, suggesting that alternative dosing and drug delivery strategies are needed to reduce functional monotherapy at the site of disease. Several controversies are discussed including the optimal route of drug administration, optimal number of drugs constituting a regimen, selection of individual drugs for a regimen, duration of the regimen, and minimal desirable standards of antibiotic stewardship. Newer rapid nucleic acid amplification test platforms, including point-of-care systems that facilitate active case-finding, are discussed. The rapid diagnosis of resistance to other drugs, (notably fluoroquinolones), and detection of resistance by targeted or whole genome sequencing will probably change the diagnostic landscape in the near future.

Published
2019
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209. gyrA mutations and phenotypic susceptibility levels to ofloxacin and moxifloxacin in clinical isolates of Mycobacterium tuberculosis

Author

Sirgel, Frederick A., Warren, Robin M., Streicher, Elizabeth M., Victor, Thomas C., van Helden, Paul D., Böttger, Erik C., Sirgel, Frederick A., Warren, Robin M., Streicher, Elizabeth M., Victor, Thomas C., van Helden, Paul D., and Böttger, Erik C.

Abstract

Objectives To compare mutations in the quinolone resistance-determining region of the gyrA gene and flanking sequences with the MICs of ofloxacin and moxifloxacin for Mycobacterium tuberculosis. Methods The presence of mutations in 177 drug-resistant M. tuberculosis isolates was determined by DNA sequencing and the MICs quantified by MGIT 960. Results Single nucleotide polymorphisms were detected at codons 94 (n = 30), 90 (n = 12), 91 (n = 3), 89 (n = 1), 88 (n = 1) and 80 (n = 1). Four isolates with double mutations D94G plus A90V (n = 2) and D94G plus D94N (n = 2) reflect mixed populations. Agreement between genotypic and phenotypic susceptibility was high (≥97%) for both drugs. Mutant isolates had an MIC50 of 8.0 mg/L and an MIC90 of >10 mg/L for ofloxacin compared with an MIC50 and MIC90 of 2.0 mg/L for moxifloxacin. Codons 94 and 88 were linked to higher levels of fluoroquinolone resistance compared with codons 90, 91 and 89. The MIC distributions for the wild-type isolates ranged from ≤0.5 to 2.0 mg/L for ofloxacin and from ≤0.125 to 0.25 mg/L for moxifloxacin. However, 96% of the isolates with genetic alterations had MICs ≤2.0 mg/L for moxifloxacin, which is within its achievable serum levels. Conclusions This study provides quantitative evidence that the addition of moxifloxacin to extensively drug-resistant tuberculosis (XDR-TB) regimens based on a clinical breakpoint of 2.0 mg/L has merit. The use of moxifloxacin in the treatment of multidrug-resistant tuberculosis may prevent the acquisition of additional mutations and development of XDR-TB

Published
2017

211. A standardised method for interpreting the association between mutations and phenotypic drug resistance inMycobacterium tuberculosis

Author

Miotto, Paolo, primary, Tessema, Belay, additional, Tagliani, Elisa, additional, Chindelevitch, Leonid, additional, Starks, Angela M., additional, Emerson, Claudia, additional, Hanna, Debra, additional, Kim, Peter S., additional, Liwski, Richard, additional, Zignol, Matteo, additional, Gilpin, Christopher, additional, Niemann, Stefan, additional, Denkinger, Claudia M., additional, Fleming, Joy, additional, Warren, Robin M., additional, Crook, Derrick, additional, Posey, James, additional, Gagneux, Sebastien, additional, Hoffner, Sven, additional, Rodrigues, Camilla, additional, Comas, Iñaki, additional, Engelthaler, David M., additional, Murray, Megan, additional, Alland, David, additional, Rigouts, Leen, additional, Lange, Christoph, additional, Dheda, Keertan, additional, Hasan, Rumina, additional, Ranganathan, Uma Devi K., additional, McNerney, Ruth, additional, Ezewudo, Matthew, additional, Cirillo, Daniela M., additional, Schito, Marco, additional, Köser, Claudio U., additional, and Rodwell, Timothy C., additional

Published
2017
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212. Mycobacterial genomic DNA from used Xpert MTB/RIF cartridges can be utilised for accurate second-line genotypic drug susceptibility testing and spoligotyping

Author

Venter, Rouxjeane, primary, Derendinger, Brigitta, additional, de Vos, Margaretha, additional, Pillay, Samantha, additional, Dolby, Tanya, additional, Simpson, John, additional, Kitchin, Natasha, additional, Ruiters, Ashley, additional, van Helden, Paul D., additional, Warren, Robin M., additional, and Theron, Grant, additional

Published
2017
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214. 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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216. HIV-1 and tuberculosis infection

Author

Murray, Jill, Shearer, Stuart, Glynn, Judith R, Godfrey-Faussett, Peter, Helden, Paul D van, and Warren, Robin M

Subjects
HIV infection -- Complications, Tuberculosis -- Risk factors, Miners -- Diseases, South Africa -- Health aspects
Published
2002

218. Proteogenomic Investigation of Strain Variation in Clinical Mycobacterium tuberculosisIsolates

Author

Heunis, Tiaan, Dippenaar, Anzaan, Warren, Robin M., van Helden, Paul D., van der Merwe, Ruben G., Gey van Pittius, Nicolaas C., Pain, Arnab, Sampson, Samantha L., and Tabb, David L.

Abstract

Mycobacterium tuberculosisconsists of a large number of different strains that display unique virulence characteristics. Whole-genome sequencing has revealed substantial genetic diversity among clinical M. tuberculosisisolates, and elucidating the phenotypic variation encoded by this genetic diversity will be of the utmost importance to fully understand M. tuberculosisbiology and pathogenicity. In this study, we integrated whole-genome sequencing and mass spectrometry (GeLC–MS/MS) to reveal strain-specific characteristics in the proteomes of two clinical M. tuberculosisLatin American-Mediterranean isolates. Using this approach, we identified 59 peptides containing single amino acid variants, which covered ∼9% of all coding nonsynonymous single nucleotide variants detected by whole-genome sequencing. Furthermore, we identified 29 distinct peptides that mapped to a hypothetical protein not present in the M. tuberculosisH37Rv reference proteome. Here, we provide evidence for the expression of this protein in the clinical M. tuberculosisSAWC3651 isolate. The strain-specific databases enabled confirmation of genomic differences (i.e., large genomic regions of difference and nonsynonymous single nucleotide variants) in these two clinical M. tuberculosisisolates and allowed strain differentiation at the proteome level. Our results contribute to the growing field of clinical microbial proteogenomics and can improve our understanding of phenotypic variation in clinical M. tuberculosisisolates.

Published
2024
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220. Genetic Determinants of Drug Resistance in Mycobacterium tuberculosis and Their Diagnostic Value

Author

Farhat, Maha R., primary, Sultana, Razvan, additional, Iartchouk, Oleg, additional, Bozeman, Sam, additional, Galagan, James, additional, Sisk, Peter, additional, Stolte, Christian, additional, Nebenzahl-Guimaraes, Hanna, additional, Jacobson, Karen, additional, Sloutsky, Alexander, additional, Kaur, Devinder, additional, Posey, James, additional, Kreiswirth, Barry N., additional, Kurepina, Natalia, additional, Rigouts, Leen, additional, Streicher, Elizabeth M., additional, Victor, Tommie C., additional, Warren, Robin M., additional, van Soolingen, Dick, additional, and Murray, Megan, additional

Published
2016
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221. Mapping of Mycobacterium tuberculosis Complex Genetic Diversity Profiles in Tanzania and Other African Countries

Author

Mbugi, Erasto V., primary, Katale, Bugwesa Z., additional, Streicher, Elizabeth M., additional, Keyyu, Julius D., additional, Kendall, Sharon L., additional, Dockrell, Hazel M., additional, Michel, Anita L., additional, Rweyemamu, Mark M., additional, Warren, Robin M., additional, Matee, Mecky I., additional, van Helden, Paul D., additional, Couvin, David, additional, and Rastogi, Nalin, additional

Published
2016
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222. Characterization of Mycobacterium orygis

Author

van Pittius, Nicolaas C. Gey, van Helden, Paul D., and Warren, Robin M.

Subjects
Mycobacterium -- Physiological aspects -- Genetic aspects -- Research, Mycobacterial infections -- Causes of -- Complications and side effects -- Genetic aspects -- Research, Mycobacteria -- Physiological aspects -- Genetic aspects -- Research, Health
Abstract

To the Editor: In a recently published study, van Ingen et al. (1) described the molecular characterization and phylogenetic position of the oryx bacillus, a member of the Mycobacterium tuberculosis [...]

Published
2012
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223. Mixed Mycobacterium tuberculosis-Strain Infections Are Associated With Poor Treatment Outcomes Among Patients With Newly Diagnosed Tuberculosis, Independent of Pretreatment Heteroresistance.

Author

Shin, Sanghyuk S, Modongo, Chawangwa, Baik, Yeonsoo, Allender, Christopher, Lemmer, Darrin, Colman, Rebecca E, Engelthaler, David M, Warren, Robin M, and Zetola, Nicola M

Subjects
MYCOBACTERIUM tuberculosis, TUBERCULOSIS treatment, TUBERCULOSIS diagnosis, DRUG resistance, TUBERCULOSIS risk factors
Abstract

Background: Heteroresistant Mycobacterium tuberculosis infections (defined as concomitant infection with drug-resistant and drug-susceptible strains) may explain the higher risk of poor tuberculosis treatment outcomes observed among patients with mixed-strain M. tuberculosis infections. We investigated the clinical effect of mixed-strain infections while controlling for pretreatment heteroresistance in a population-based sample of patients with tuberculosis starting first-line tuberculosis therapy in Botswana.Methods: We performed 24-locus mycobacterial interspersed repetitive unit-variable number tandem-repeat analysis and targeted deep sequencing on baseline primary cultured isolates to detect mixed infections and heteroresistance, respectively. Drug-sensitive, micro-heteroresistant, macro-heteroresistant, and fixed-resistant infections were defined as infections in which the frequency of resistance was <0.1%, 0.1%-4%, 5%-94%, and ≥95%, respectively, in resistance-conferring domains of the inhA promoter, the katG gene, and the rpoB gene.Results: Of the 260 patients with tuberculosis included in the study, 25 (9.6%) had mixed infections and 30 (11.5%) had poor treatment outcomes. Micro-heteroresistance, macro-heteroresistance, and fixed resistance were found among 11 (4.2%), 2 (0.8%), and 11 (4.2%), respectively, for isoniazid and 21 (8.1%), 0 (0%), and 10 (3.8%), respectively, for rifampicin. In multivariable analysis, mixed infections but not heteroresistant infections independently predicted poor treatment outcomes.Conclusions: Among patients starting first-line tuberculosis therapy in Botswana, mixed infections were associated with poor tuberculosis treatment outcomes, independent of heteroresistance. [ABSTRACT FROM AUTHOR]

Published
2018
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224. Using routinely collected laboratory data to identify high rifampicin-resistant tuberculosis burden communities in the Western Cape Province, South Africa: A retrospective spatiotemporal analysis.

Author

McIntosh, Avery I., Jenkins, Helen E., White, Laura F., Barnard, Marinus, Thomson, Dana R., Dolby, Tania, Simpson, John, Streicher, Elizabeth M., Kleinman, Mary B., Ragan, Elizabeth J., van Helden, Paul D., Murray, Megan B., Warren, Robin M., and Jacobson, Karen R.

Subjects
TUBERCULOSIS, RIFAMPIN, MICROBIOLOGY, DRUG resistance, PHARMACOLOGY
Abstract

Background: South Africa has the highest tuberculosis incidence globally (781/100,000), with an estimated 4.3% of cases being rifampicin resistant (RR). Control and elimination strategies will require detailed spatial information to understand where drug-resistant tuberculosis exists and why it persists in those communities. We demonstrate a method to enable drug-resistant tuberculosis monitoring by identifying high-burden communities in the Western Cape Province using routinely collected laboratory data.Methods and Findings: We retrospectively identified cases of microbiologically confirmed tuberculosis and RR-tuberculosis from all biological samples submitted for tuberculosis testing (n = 2,219,891) to the Western Cape National Health Laboratory Services (NHLS) between January 1, 2008, and June 30, 2013. Because the NHLS database lacks unique patient identifiers, we performed a series of record-linking processes to match specimen records to individual patients. We counted an individual as having a single disease episode if their positive samples came from within two years of each other. Cases were aggregated by clinic location (n = 302) to estimate the percentage of tuberculosis cases with rifampicin resistance per clinic. We used inverse distance weighting (IDW) to produce heatmaps of the RR-tuberculosis percentage across the province. Regression was used to estimate annual changes in the RR-tuberculosis percentage by clinic, and estimated average size and direction of change was mapped. We identified 799,779 individuals who had specimens submitted from mappable clinics for testing, of whom 222,735 (27.8%) had microbiologically confirmed tuberculosis. The study population was 43% female, the median age was 36 years (IQR 27-44), and 10,255 (4.6%, 95% CI: 4.6-4.7) cases had documented rifampicin resistance. Among individuals with microbiologically confirmed tuberculosis, 8,947 (4.0%) had more than one disease episode during the study period. The percentage of tuberculosis cases with rifampicin resistance documented among these individuals was 11.4% (95% CI: 10.7-12.0). Overall, the percentage of tuberculosis cases that were RR-tuberculosis was spatially heterogeneous, ranging from 0% to 25% across the province. Our maps reveal significant yearly fluctuations in RR-tuberculosis percentages at several locations. Additionally, the directions of change over time in RR-tuberculosis percentage were not uniform. The main limitation of this study is the lack of unique patient identifiers in the NHLS database, rendering findings to be estimates reliant on the accuracy of the person-matching algorithm.Conclusions: Our maps reveal striking spatial and temporal heterogeneity in RR-tuberculosis percentages across this province. We demonstrate the potential to monitor RR-tuberculosis spatially and temporally with routinely collected laboratory data, enabling improved resource targeting and more rapid locally appropriate interventions. [ABSTRACT FROM AUTHOR]

Published
2018
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225. Mycobacterial nucleoid associated proteins: An added dimension in gene regulation.

Author

Kriel, Nastassja L., Gallant, James, van Wyk, Niël, van Helden, Paul, Sampson, Samantha L., Warren, Robin M., and Williams, Monique J.

Abstract

Nucleoid associated proteins (NAPs) are known organisers of chromosomal structure and regulators of transcriptional expression. The number of proposed NAPs in mycobacteria are significantly lower than the number identified in other organisms. An interesting feature of mycobacterial NAPs is their low sequence similarity with those in other species, a property that has hindered their identification. In this review, we discuss the current evidence for the proposed classification of six mycobacterial proteins, Lsr2, EspR, mIHF, HupB, MDP2 and NapM, as NAPs in mycobacterial species with an emphasis on their roles in modulating chromosome structure and transcriptional regulation. In addition, we highlight the technical difficulties associated with investigating and providing evidence for the classification of proteins as NAPs in mycobacteria. We also address the role of mycobacterial NAPs as mediators of stress responses and highlight the recent developments aimed at targeting NAP-DNA interactions for the development of novel anti-TB drugs. [ABSTRACT FROM AUTHOR]

Published
2018
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226. The microbiome and tuberculosis: state of the art, potential applications, and defining the clinical research agenda

Author

Naidoo, Charissa C, Nyawo, Georgina R, Wu, Benjamin G, Walzl, Gerhard, Warren, Robin M, Segal, Leopoldo N, and Theron, Grant

Abstract

The diverse microbial communities within our bodies produce metabolites that modulate host immune responses. Even the microbiome at distal sites has an important function in respiratory health. However, the clinical importance of the microbiome in tuberculosis, the biggest infectious cause of death worldwide, is only starting to be understood. Here, we critically review research on the microbiome's association with pulmonary tuberculosis. The research indicates five main points: (1) susceptibility to infection and progression to active tuberculosis is altered by gut Helicobacterco-infection, (2) aerosol Mycobacterium tuberculosisinfection changes the gut microbiota, (3) oral anaerobes in the lung make metabolites that decrease pulmonary immunity and predict progression, (4) the increased susceptibility to reinfection of patients who have previously been treated for tuberculosis is likely due to the depletion of T-cell epitopes on commensal gut non-tuberculosis mycobacteria, and (5) the prolonged antibiotic treatment required for cure of tuberculosis has long-term detrimental effects on the microbiome. We highlight knowledge gaps, considerations for addressing these knowledge gaps, and describe potential targets for modifying the microbiome to control tuberculosis.

Published
2019
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228. The impact of genotype on the phenotype of Mycobacterium tuberculosis ΔsufR mutants.

Author

Willemse, Danicke, Baatjies, Lucinda, Dippenaar, Anzaan, Warren, Robin M., and Williams, Monique J.

Abstract

Iron-sulphur (FeS) cluster biogenesis is a tightly regulated process in vivo. In Mycobacterium tuberculosis (Mtb), SufR functions as a transcriptional repressor of the operon encoding the primary FeS cluster biogenesis system. Previously, three independently isolated mutants (Δ Rv1460stop _1.19, Δ Rv1460stop _5.19 and Δ Rv1460stop _5.20) harbouring the same deletion in sufR , displayed different growth kinetics in OADC supplemented 7H9 media. To investigate this discrepancy, we performed whole genome sequencing of the 3 mutants and the wild-type progenitor. Single nucleotide polymorphisms (SNPs) were identified in 3 genes in the ΔRv1460stop _1.19 mutant and one gene in the ΔRv1460stop _5.20 mutant. Phenotyping of the ΔRv1460stop_ 5.19 mutant, which had no additional SNPs, revealed increased susceptibility to clofazimine, DMNQ and menadione, while uptake and survival in THP-1 cells were not significantly different from the wild-type strain. Given that these results differ from those reported for other sufR deletion mutants (ΔSufR MTB and MtbΔSufR), they suggest that the position of the sufR deletion and the genotype of the progenitor strain impact the resulting phenotype. [ABSTRACT FROM AUTHOR]

Published
2023
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230. embB 306 Mutations as Molecular Indicators to Predict Ethambutol Susceptibility in Mycobacterium tuberculosis

Author

Sirgel, Frederick A, Warren, Robin M, Streicher, Elizabeth M, Victor, Thomas C, van Helden, Paul D, Böttger, Erik C, University of Zurich, and Sirgel, Frederick A

Subjects
3004 Pharmacology, 10179 Institute of Medical Microbiology, 3002 Drug Discovery, 570 Life sciences, biology, 2736 Pharmacology (medical), 610 Medicine & health, 2730 Oncology, 2725 Infectious Diseases
Published
2012
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231. 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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237. Genetic diversity of Mycobacterium tuberculosis isolated from tuberculosis patients in the Serengeti ecosystem in Tanzania

Author

Mbugi, Erasto V., primary, Katale, Bugwesa Z., additional, Siame, Keith K., additional, Keyyu, Julius D., additional, Kendall, Sharon L., additional, Dockrell, Hazel M., additional, Streicher, Elizabeth M., additional, Michel, Anita L., additional, Rweyemamu, Mark M., additional, Warren, Robin M., additional, Matee, Mecky I., additional, and van Helden, Paul D., additional

Published
2015
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239. Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis

Author

Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., Farhat, Maha R., Shapiro, B. Jesse, Kieser, Karen J., Sultana, Razvan, Jacobson, Karen R., Victor, Thomas C., Warren, Robin M., Streicher, Elizabeth M., Calver, Alistair, Sloutsky, Alex, Kaur, Devinder, Posey, Jamie E., Plikaytis, Bonnie, Oggioni, Marco R., Gardy, Jennifer L., Johnston, James C., Rodrigues, Mabel, Tang, Patrick K. C., Kato-Maeda, Midori, Borowsky, Mark L., Muddukrishna, Bhavana, Kreiswirth, Barry N., Kurepina, Natalia, Galagan, James E., Gagneux, Sebastien, Birren, Bruce W., Rubin, Eric J., Sabeti, Pardis C., Murray, Megan B., Lander, Eric Steven, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., Farhat, Maha R., Shapiro, B. Jesse, Kieser, Karen J., Sultana, Razvan, Jacobson, Karen R., Victor, Thomas C., Warren, Robin M., Streicher, Elizabeth M., Calver, Alistair, Sloutsky, Alex, Kaur, Devinder, Posey, Jamie E., Plikaytis, Bonnie, Oggioni, Marco R., Gardy, Jennifer L., Johnston, James C., Rodrigues, Mabel, Tang, Patrick K. C., Kato-Maeda, Midori, Borowsky, Mark L., Muddukrishna, Bhavana, Kreiswirth, Barry N., Kurepina, Natalia, Galagan, James E., Gagneux, Sebastien, Birren, Bruce W., Rubin, Eric J., Sabeti, Pardis C., Murray, Megan B., and Lander, Eric Steven

Abstract

M. tuberculosis is evolving antibiotic resistance, threatening attempts at tuberculosis epidemic control. Mechanisms of resistance, including genetic changes favored by selection in resistant isolates, are incompletely understood. Using 116 newly sequenced and 7 previously sequenced M. tuberculosis whole genomes, we identified genome-wide signatures of positive selection specific to the 47 drug-resistant strains. By searching for convergent evolution—the independent fixation of mutations in the same nucleotide position or gene—we recovered 100% of a set of known resistance markers. We also found evidence of positive selection in an additional 39 genomic regions in resistant isolates. These regions encode components in cell wall biosynthesis, transcriptional regulation and DNA repair pathways. Mutations in these regions could directly confer resistance or compensate for fitness costs associated with resistance. Functional genetic analysis of mutations in one gene, ponA1, demonstrated an in vitro growth advantage in the presence of the drug rifampicin.

Published
2014

242. Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions

Author

Gey van Pittius, Nicolaas C, Sampson, Samantha L, Lee, Hyeyoung, Kim, Yeun, van Helden, Paul D, and Warren, Robin M

Subjects
Antigens, Bacterial, Sequence Homology, Amino Acid, Evolution, Molecular Sequence Data, Nucleic Acid Hybridization, Genomics, Mycobacterium tuberculosis, Mycobacterium, Evolution, Molecular, Bacterial Proteins, Species Specificity, Multigene Family, RNA, Ribosomal, 16S, QH359-425, Amino Acid Sequence, Genome, Bacterial, Phylogeny, Research Article
Abstract

Background The PE and PPE multigene families of Mycobacterium tuberculosis comprise about 10% of the coding potential of the genome. The function of the proteins encoded by these large gene families remains unknown, although they have been proposed to be involved in antigenic variation and disease pathogenesis. Interestingly, some members of the PE and PPE families are associated with the ESAT-6 (esx) gene cluster regions, which are regions of immunopathogenic importance, and encode a system dedicated to the secretion of members of the potent T-cell antigen ESAT-6 family. This study investigates the duplication characteristics of the PE and PPE gene families and their association with the ESAT-6 gene clusters, using a combination of phylogenetic analyses, DNA hybridization, and comparative genomics, in order to gain insight into their evolutionary history and distribution in the genus Mycobacterium. Results The results showed that the expansion of the PE and PPE gene families is linked to the duplications of the ESAT-6 gene clusters, and that members situated in and associated with the clusters represent the most ancestral copies of the two gene families. Furthermore, the emergence of the repeat protein PGRS and MPTR subfamilies is a recent evolutionary event, occurring at defined branching points in the evolution of the genus Mycobacterium. These gene subfamilies are thus present in multiple copies only in the members of the M. tuberculosis complex and close relatives. The study provides a complete analysis of all the PE and PPE genes found in the sequenced genomes of members of the genus Mycobacterium such as M. smegmatis, M. avium paratuberculosis, M. leprae, M. ulcerans, and M. tuberculosis. Conclusion This work provides insight into the evolutionary history for the PE and PPE gene families of the mycobacteria, linking the expansion of these families to the duplications of the ESAT-6 (esx) gene cluster regions, and showing that they are composed of subgroups with distinct evolutionary (and possibly functional) differences.

Published
2006

243. Implications of Failure to Routinely Diagnose Resistance to Second-Line Drugs in Patients With Rifampicin-Resistant Tuberculosis on Xpert MTB/RIF: A Multisite Observational Study.

Author

Jacobson, Karen R., Barnard, Marinus, Kleinman, Mary B., Streicher, Elizabeth M., Ragan, Elizabeth J., White, Laura F., Shapira, Ofer, Dolby, Tania, Simpson, John, Scott, Lesley, Stevens, Wendy, van Helden, Paul D., Van Rie, Annelies, and Warren, Robin M.

Subjects
MULTIDRUG-resistant tuberculosis, DRUG resistance in microorganisms, RIFAMPIN, ANTITUBERCULAR agents, FLUOROQUINOLONES
Abstract

Background. Xpert MTB/RIF (Xpert) detects rifampicin-resistant tuberculosis (RR-tuberculosis), enabling physicians to rapidly initiate a World Health Organization-recommended 5-drug regimen while awaiting second-line drug-susceptibility test (DST) results. We quantified the second-line DST results time and proportion of patients potentially placed on suboptimal therapy. Methods. We included RR-tuberculosis patients detected using Xpert at the South African National Health Laboratory Services (NHLS) of the Western Cape between November 2011 and June 2013 and at Eastern Cape, Free State, and Gauteng NHLS between November 2012 and December 2013. We calculated time from specimen collection to phenotypic second-line DST results. We identified isoniazid and ethionamide resistance mutations on line probe assay and performed pyrazinamide sequencing. Results. Among 1332 RR-tuberculosis patients, only 44.7% (596) had second-line DST for both fluoroquinolones and second-line injectable: 55.8% (466 of 835) in the Western Cape and 26.2% (130 of 497) in the other provinces. Patients with smear negative disease and age ≤10 years were less likely to have a result (risk ratio [RR] = 0.72; 95% CI, 0.64-0.81 and RR = 0.49; 95% CI, 0.26-0.79). Median time to second-line DST was 53 days (range, 8-259). Of the 252 patients with complete second-line DST, 101 (40.1%) potentially initiated a suboptimal regimen: 46.8% in the Western Cape and 25.3% in the other provinces. Conclusions. Many South Africans diagnosed with RR-tuberculosis by Xpert initiate a suboptimal regimen, with information to adjust therapy available in half of all patients after a median 7 weeks. Algorithm completion and time delays remain challenging. [ABSTRACT FROM AUTHOR]

Published
2017
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246. Rapid Sequencing of the Mycobacterium tuberculosis pncA Gene for Detection of Pyrazinamide Susceptibility

Author

Streicher, Elizabeth M., primary, Maharaj, Kashmeel, additional, York, Talita, additional, Van Heerden, Carel, additional, Barnard, Marinus, additional, Diacon, Andreas, additional, Mendel, Carl M., additional, Bosman, Marlein E., additional, Hepple, Juli A., additional, Pym, Alexander S., additional, Warren, Robin M., additional, and van Helden, Paul D., additional

Published
2014
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250. Proposal of a Consensus Set of Hypervariable Mycobacterial Interspersed Repetitive-Unit–Variable-Number Tandem-Repeat Loci for Subtyping of Mycobacterium tuberculosis Beijing Isolates

Author

Allix-Béguec, Caroline, primary, Wahl, Céline, additional, Hanekom, Madeleine, additional, Nikolayevskyy, Vladyslav, additional, Drobniewski, Francis, additional, Maeda, Shinji, additional, Campos-Herrero, Isolina, additional, Mokrousov, Igor, additional, Niemann, Stefan, additional, Kontsevaya, Irina, additional, Rastogi, Nalin, additional, Samper, Sofia, additional, Sng, Li-Hwei, additional, Warren, Robin M., additional, and Supply, Philip, additional

Published
2014
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