Abstract
ABSTRACTThe spread of multidrug-resistant (MDR) tuberculosis (TB) and extensively drug-resistant (XDR) TB hampers global efforts in the fight against tuberculosis. To enhance the development and evaluation of diagnostic tests quickly and efficiently, well-characterized strains and samples from drug-resistant tuberculosis patients are necessary. In this project, the Foundation for Innovative New Diagnostics (FIND) has focused on the collection, characterization, and storage of such well-characterized reference materials and making them available to researchers and developers. The collection is being conducted at multiple centers in Southeast Asia, South America, Eastern Europe, and soon the sub-Saharan Africa regions. Strains are characterized for their phenotypic resistances and MICs to first-line drugs (FLDs) and second-line drugs (SLDs) using the automated MGIT 960 system following validated procedures and WHO criteria. Analysis of resistance-associated mutations is done by whole-genome sequencing (WGS) using the Illumina NextSeq system. Mycobacterial interspersed repetitive-unit–variable-number tandem-repeat analysis and WGS are used to determine strain lineages. All strains are maintained frozen at −80°C ± 10°C as distinct mother and daughter lots. All strains are extensively quality assured. The data presented here represent an analysis of the initial part of the collection. Currently, the bank contains 118 unique strains with extracted genomic DNA and matched sputum, serum, and plasma samples and will be expanded to a minimum of 1,000 unique strains over the next 3 years. Analysis of the current strains by phenotypic resistance testing shows 102 (86.4%), 10 (8.5%), and 6 (5.1%) MDR, XDR, and mono/poly resistant strains, respectively. Two of the strains are resistant to all 11 drugs that were phenotypically tested. WGS mutation analysis revealed FLD resistance-associated mutations in the rpoB, katG, inhA, embB, embA, and pncA genes; SLD resistance in the gyrA, gyrB, rrs, eis, and tlyA genes; and ethionamide resistance in the ethA genes. Most important lineages are represented in the bank, and further collections have been initiated to increase geographic and lineage diversity. The bank provides highly characterized and high-quality strains as a resource for researchers and developers in support of the development and evaluation of new diagnostics and drug resistance detection tools.
Highlights
The spread of multidrug-resistant (MDR) tuberculosis (TB) and extensively drug-resistant (XDR) TB hampers global efforts in the fight against tuberculosis
A better understanding of the genotypic basis of resistance can only be achieved through large databases and data sets that correlate phenotypic and genotypic resistance characterization, such as the ReSeqTB initiative of FIND, Critical Path (C-Path), United States Centers for Disease Control and Prevention (CDC), World Health Organization (WHO), and the Bill and Melinda Gates Foundation (BMGF) [7]
FIND has established a strain bank that is complementary to the existing banks by focusing on MDR, pre-XDR, and XDR strains with extensive lineage backgrounds
Summary
The spread of multidrug-resistant (MDR) tuberculosis (TB) and extensively drug-resistant (XDR) TB hampers global efforts in the fight against tuberculosis. For the majority of drugs, multiple genes are involved, mutations may be scattered over long gene sequences, and a percentage of resistance-associated genomic markers or mechanisms may not have been identified These factors complicate the development of new rapid molecular tests to detect resistance in the Mycobacterium tuberculosis complex (MTC) [5, 6]. A better understanding of the genotypic basis of resistance can only be achieved through large databases and data sets that correlate phenotypic and genotypic resistance characterization, such as the ReSeqTB initiative of FIND, Critical Path (C-Path), United States Centers for Disease Control and Prevention (CDC), WHO, and the Bill and Melinda Gates Foundation (BMGF) [7] Existing strain banks, such as the Special Programme for Research and Training in Tropical Diseases (TDR), in collaboration with the Institute of Tropical Medicine (ITM), Antwerp, Belgium, have made M. tuberculosis isolates available upon request [8, 9]. We describe the current collection of strains within the FIND TB strain bank, the characterization of strains, the nature of services provided to researchers and developers, and future plans
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