Christian Utpatel

Research Center Borstel - Leibniz Lung Center

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Stefan Niemann

Research Center Borstel - Leibniz Lung Center

Thomas A. Kohl

Research Center Borstel - Leibniz Lung Center

Matthias Merker

Research Center Borstel - Leibniz Lung Center

Ivan Barilar

Research Center Borstel - Leibniz Lung Center

Viola Dreyer

Research Center Borstel - Leibniz Lung Center

Harald Hoffmann

Synlab (Germany)

Margo Diricks

Research Center Borstel - Leibniz Lung Center

Daniela María Cirillo

Vita-Salute San Raffaele University

Florian P. Maurer

Research Center Borstel - Leibniz Lung Center

Jan Rupp

University of Lübeck

Cooperative Institutions

University of KwaZulu-Natal

133

Stellenbosch University

122

German Center for Infection Research

103

Africa Centres for Disease Control and Prevention

Kenya Medical Research Institute

University of Oxford

Research Center Borstel - Leibniz Lung Center

Institut Pasteur

Centre National de la Recherche Scientifique

Inserm

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Emergence of bedaquiline resistance in a high tuberculosis burden country

European Respiratory Journal (2021)

Elena Chesov Dumitru Chesov Florian P. Maurer Sönke Andres Christian Utpatel

Bedaquiline has been classified as a group A drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) by the World Health Organization; however, globally emerging resistance threatens the effectivity of novel MDR-TB treatment regimens.

Bedaquiline

10.1183/13993003.00621-2021

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Citations (84)

MTBseq: a comprehensive pipeline for whole genome sequence analysis of Mycobacterium tuberculosis complex isolates

PeerJ (2018)

Thomas A. Kohl Christian Utpatel Viola Schleusener Maria Rosaria De Filippo Patrick Beckert

Analyzing whole-genome sequencing data of Mycobacterium tuberculosis complex (MTBC) isolates in a standardized workflow enables both comprehensive antibiotic resistance profiling and outbreak surveillance with highest resolution up to the identification of recent transmission chains. Here, we present MTBseq, a bioinformatics pipeline for next-generation genome sequence data analysis of MTBC isolates. Employing a reference mapping based workflow, MTBseq reports detected variant positions annotated with known association to antibiotic resistance and performs a lineage classification based on phylogenetic single nucleotide polymorphisms (SNPs). When comparing multiple datasets, MTBseq provides a joint list of variants and a FASTA alignment of SNP positions for use in phylogenomic analysis, and identifies groups of related isolates. The pipeline is customizable, expandable and can be used on a desktop computer or laptop without any internet connection, ensuring mobile usage and data security. MTBseq and accompanying documentation is available from https://github.com/ngs-fzb/MTBseq_source.

Mycobacterium tuberculosis complex

10.7717/peerj.5895

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Phylogenomic and genomic analysis reveals unique and shared genetic signatures of Mycobacterium kansasii complex species

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Edson Machado Sidra Ezídio Gonçalves Vasconcellos Lia Lima Gomes Marcos Catanho Jesus Pais Ramos

Species belonging to the Mycobacterium kansasii complex (MKC) are frequently isolated from humans and the environment and can cause serious diseases. The most common MKC infections are caused by the species M. kansasii (stricto sensu), leading to tuberculosis-like disease. However, a broad spectrum of virulence, antimicrobial resistance and pathogenicity of these non-tuberculous mycobacteria (NTM) are observed across the MKC. Many genomic aspects of the MKC that relate to these broad phenotypes are not well elucidated. Here, we performed genomic analyses from a collection of 665 MKC strains, isolated from environmental, animal and human sources. We inferred the MKC pangenome, mobilome, resistome, virulome and defense systems and show that the MKC species harbors unique and shared genomic signatures. High frequency of presence of prophages and different types of defense systems was observed. We found that the M. kansasii species splits into four lineages, of which three are lowly represented and mainly in Brazil, while one lineage is dominant and globally spread. Moreover, we show that four sub-lineages of this most distributed M. kansasii lineage emerged during the 20th century. Further analysis of the M. kansasii genomes revealed almost 300 regions of difference contributing to genomic diversity, as well as fixed mutations that may explain the M. kansasii's increased virulence and drug resistance.

Mycobacterium kansasii

Prophage

Lineage (genetic)

10.1101/2024.02.14.579889

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Phylogroup-specific variation shapes the clustering of antimicrobial resistance genes and defence systems across regions of genome plasticity in Pseudomonas aeruginosa

EBioMedicine (2023)

João Botelho Leif Tüffers Janina Fuß Florian Buchholz Christian Utpatel

10.1016/j.ebiom.2023.104532

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Implementation of whole genome sequencing for tuberculosis diagnostics in a low-middle income, high MDR-TB burden country

Scientific Reports (2021)

Monica Vogel Christian Utpatel Caroline S. Corbett Thomas A. Kohl Altyn Iskakova

Whole genome sequencing (WGS) is revolutionary for diagnostics of TB and its mutations associated with drug-resistances, but its uptake in low- and middle-income countries is hindered by concerns of implementation feasibility. Here, we provide a proof of concept for its successful implementation in such a setting. WGS was implemented in the Kyrgyz Republic. We estimated needs of up to 55 TB-WGS per week and chose the MiSeq platform (Illumina, USA) because of its capacity of up to 60 TB-WGS per week. The project's timeline was completed in 93-weeks. Costs of large equipment and accompanying costs were 222,065 USD and 8462 USD, respectively. The first 174 WGS costed 277 USD per sequence, but this was skewed by training inefficiencies. Based on real prices and presuming optimal utilization of WGS capacities, WGS costs could drop to 167 and 141 USD per WGS using MiSeq Reagent Kits v2 (500-cycles) and v3 (600-cycles), respectively. Five trainings were required to prepare the staff for autonomous WGS which cost 48,250 USD. External assessment confirmed excellent performance of WGS by the Kyrgyz laboratory in an interlaboratory comparison of 30 M. tuberculosis genomes showing complete agreeance of results.

10.1038/s41598-021-94297-z

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Citations (20)

Additional file 3 of Whole genome sequencing-based classification of human-related Haemophilus species and detection of antimicrobial resistance genes

Figshare (2022)

Margo Diricks Thomas A. Kohl Nadja Käding Vladislav Leshchinskiy Susanne Hauswaldt

Additional file 3: Table S3. Metadata and classification results for all samples from German cohort.

10.6084/m9.figshare.19151311

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Citations (0)

Biofilm reduction potential of 0.02% polyhexanide irrigation solution in several types of urethral catheters

Research Square (Research Square) (2021)

F.H.H. Brill Julia Hambach Christian Utpatel Diana Mogrovejo Henrik Gabriel

Abstract Background Long-term use of urethral catheters is associated with high risk of urinary tract infection (UTI) and blockage. Microbial biofilms are a common cause of catheter blockage, reducing their lifetime and significantly increasing morbidity of UTIs. A 0.02% polyhexanide irrigation solution developed for routine mechanical rinsing shows potential for bacterial decolonization of urethral catheters and has the potential to reduce or prevent biofilm formation. Methods Using an in vitro assay with standard market-leading types of catheters artificially contaminated with clinically relevant bacteria, assays were carried out to evaluate the biofilm reduction and prevention potential of a 0.02% polyhexanide solution vs. no intervention (standard approach) and irrigation with saline solution (NaCl 0.9%). The efficiency of decolonization was measured through microbial plate count and membrane filtration. Results Irrigation using a 0.02% polyhexanide solution is suitable for the decolonization of a variety of transurethral catheters. The effect observed is significant compared to irrigation with 0.9% saline solution ( p = 0.001) or no treatment ( p = 0.018). No significant difference was found between irrigation with 0.9% saline solution and no treatment ( p = 0.94). Conclusions The polyhexanide and standard saline solutions are able to reduce bacterial biofilm from urinary catheters, showing a combination of mechanical and antibacterial effects. The data supports a prevention strategy to reduce thick biofilms, which are characteristically difficult to be efficiently removed. Further research is required to evaluate the long-term tolerability and efficacy of polyhexanide in clinical practice.

10.21203/rs.3.rs-58172/v2

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Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid

Journal of Antimicrobial Chemotherapy (2022)

Matthew Bates Julio Ortiz Canseco Timothy D. McHugh Adam A. Witney Silke Feuerriegel

Abstract Objectives To develop a robust phenotypic antimicrobial susceptibility testing (AST) method with a correctly set breakpoint for pretomanid (Pa), the most recently approved anti-tuberculosis drug. Methods The Becton Dickinson Mycobacterial Growth Indicator Tube™ (MGIT) system was used at six laboratories to determine the MICs of a phylogenetically diverse collection of 356 Mycobacterium tuberculosis complex (MTBC) strains to establish the epidemiological cut-off value for pretomanid. MICs were correlated with WGS data to study the genetic basis of differences in the susceptibility to pretomanid. Results We observed ancient differences in the susceptibility to pretomanid among various members of MTBC. Most notably, lineage 1 of M. tuberculosis, which is estimated to account for 28% of tuberculosis cases globally, was less susceptible than lineages 2, 3, 4 and 7 of M. tuberculosis, resulting in a 99th percentile of 2 mg/L for lineage 1 compared with 0.5 mg/L for the remaining M. tuberculosis lineages. Moreover, we observed that higher MICs (≥8 mg/L), which probably confer resistance, had recently evolved independently in six different M. tuberculosis strains. Unlike the aforementioned ancient differences in susceptibility, these recent differences were likely caused by mutations in the known pretomanid resistance genes. Conclusions In light of these findings, the provisional critical concentration of 1 mg/L for MGIT set by EMA must be re-evaluated. More broadly, these findings underline the importance of considering the global diversity of MTBC during clinical development of drugs and when defining breakpoints for AST.

Mycobacterium tuberculosis complex

Lineage (genetic)

10.1093/jac/dkac070

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Citations (46)

Design of Multidrug-Resistant Tuberculosis Treatment Regimens Based on DNA Sequencing

Clinical Infectious Diseases (2021)

Hans-Peter Grobbel Matthias Merker Niklas Köhler Sönke Andres Harald Hoffmann

Abstract Background Comprehensive and reliable drug susceptibility testing (DST) is urgently needed to provide adequate treatment regimens for patients with multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). We determined whether next-generation sequencing (NGS) analysis of Mycobacterium tuberculosis complex isolates and genes implicated in drug resistance can guide the design of effective MDR/RR-TB treatment regimens. Methods NGS-based genomic DST predictions of M. tuberculosis complex isolates from MDR/RR-TB patients admitted to a TB reference center in Germany between 1 January 2015 and 30 April 2019 were compared with phenotypic DST results of mycobacteria growth indicator tubes (MGIT). Standardized treatment algorithms were applied to design individualized therapies based on either genomic or phenotypic DST results, and discrepancies were further evaluated by determination of minimal inhibitory drug concentrations (MICs) using Sensititre MYCOTBI and UKMYC microtiter plates. Results In 70 patients with MDR/RR-TB, agreement among 1048 pairwise comparisons of genomic and phenotypic DST was 86.3%; 76 (7.2%) results were discordant, and 68 (6.5%) could not be evaluated due to the presence of polymorphisms with yet unknown implications for drug resistance. Importantly, 549 of 561 (97.9%) predictions of drug susceptibility were phenotypically confirmed in MGIT, and 27 of 64 (42.2%) false-positive results were linked to previously described mutations mediating a low or moderate MIC increase. Virtually all drugs (99.0%) used in combination therapies that were inferred from genomic DST were confirmed to be susceptible by phenotypic DST. Conclusions NGS-based genomic DST can reliably guide the design of effective MDR/RR-TB treatment regimens.

10.1093/cid/ciab359

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Citations (31)

Sub-Lineage Specific Phenolic Glycolipid Patterns in the Mycobacterium tuberculosis Complex Lineage 1

Frontiers in Microbiology (2022)

Nicolas Gisch Christian Utpatel Lisa M. Gronbach Thomas A. Kohl Ursula Schombel

"Ancestral" Mycobacterium tuberculosis complex (MTBC) strains of Lineage 1 (L1, East African Indian) are a prominent tuberculosis (TB) cause in countries around the Indian Ocean. However, the pathobiology of L1 strains is insufficiently characterized. Here, we used whole genome sequencing (WGS) of 312 L1 strains from 43 countries to perform a characterization of the global L1 population structure and correlate this to the analysis of the synthesis of phenolic glycolipids (PGL) - known MTBC polyketide-derived virulence factors. Our results reveal the presence of eight major L1 sub-lineages, whose members have specific mutation signatures in PGL biosynthesis genes, e.g., pks15/1 or glycosyltransferases Rv2962c and/or Rv2958c. Sub-lineage specific PGL production was studied by NMR-based lipid profiling and strains with a completely abolished phenolphthiocerol dimycoserosate biosynthesis showed in average a more prominent growth in human macrophages. In conclusion, our results show a diverse population structure of L1 strains that is associated with the presence of specific PGL types. This includes the occurrence of mycoside B in one sub-lineage, representing the first description of a PGL in an M. tuberculosis lineage other than L2. Such differences may be important for the evolution of L1 strains, e.g., allowing adaption to different human populations.

Lineage (genetic)

Mycobacterium tuberculosis complex

10.3389/fmicb.2022.832054

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Citations (8)