scholarly journals Genomic signatures of pre-resistance in Mycobacterium tuberculosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Arturo Torres Ortiz ◽  
Jorge Coronel ◽  
Julia Rios Vidal ◽  
Cesar Bonilla ◽  
David A. J. Moore ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Mycobacterium Tuberculosis ◽  
Phylogenetic Trees ◽  
Resistance Mutations ◽  
Resistance Evolution ◽  
Genomic Signatures ◽  
Genome Wide ◽  
A Genome ◽  
Lineage 2 ◽  
Emergence Of Resistance

AbstractRecent advances in bacterial whole-genome sequencing have resulted in a comprehensive catalog of antibiotic resistance genomic signatures in Mycobacterium tuberculosis. With a view to pre-empt the emergence of resistance, we hypothesized that pre-existing polymorphisms in susceptible genotypes (pre-resistance mutations) could increase the risk of becoming resistant in the future. We sequenced whole genomes from 3135 isolates sampled over a 17-year period. After reconstructing ancestral genomes on time-calibrated phylogenetic trees, we developed and applied a genome-wide survival analysis to determine the hazard of resistance acquisition. We demonstrate that M. tuberculosis lineage 2 has a higher risk of acquiring resistance than lineage 4, and estimate a higher hazard of rifampicin resistance evolution following isoniazid mono-resistance. Furthermore, we describe loci and genomic polymorphisms associated with a higher risk of resistance acquisition. Identifying markers of future antibiotic resistance could enable targeted therapy to prevent resistance emergence in M. tuberculosis and other pathogens.

scholarly journals Genomic Signatures of Pre-Resistance in Mycobacterium tuberculosis

2021 ◽  
Author(s):  
Arturo Torres Ortiz ◽  
Jorge Coronel ◽  
Julia Rios Vidal ◽  
Cesar Bonilla ◽  
David Moore ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Phylogenetic Trees ◽  
P Value ◽  
Whole Genome ◽  
Resistance Mutations ◽  
Genomic Signatures ◽  
Future Drug

Abstract Recent advances in bacterial whole-genome sequencing have resulted in the identification of a comprehensive catalogue of genomic signatures of antibiotic resistance in Mycobacterium tuberculosis. With a view to pre-empting the emergence of drug-resistance, we hypothesized that pre-existing balanced polymorphisms in drug susceptible genotypes (“pre-resistance mutations”) could increase the risk of acquiring antimicrobial resistance in the future. In order to identify a pathogen genomic signature of future drug resistance we undertook whole-genome sequencing on 3135 culture positive isolates from different patients sampled over a 17-year period in Lima, Peru. Reconstructing ancestral whole genomes on time-calibrated phylogenetic trees we identified no single drug resistance in Peru predating 1940. Moving forward in evolutionary time through the phylogenetic tree from 1940, we apply a novel genome-wide survival analysis to determine the hazard of drug resistance acquisition at the level of lineage, mono-resistance state, and single-nucleotide polymorphism. We demonstrate that lineage 2 has a significantly higher incidence of drug resistance acquisition than lineage 4 (HR 3.36, 95% CI 2.10 - 5.38,p-value =4.25×10-7) and estimate that the hazard of evolving rifampicin following isoniazid resistance acquisition is 14 times that of genomes with a susceptible background (HR 14.45,95% CI 8.46 - 15.50, p-value<10−15). Our findings are validated in a separate publicly available dataset from Samara, Russia. After controlling for population structure, we also show that a deletion in a gene coding for the cell surface protein lppP predisposes to the acquisition of drug resistance in susceptible genotypes (HR 6.71, 95% CI4.82-11.22, p-value =1.17×10−9). Prediction of future drug resistance in susceptible pathogens together with targeted expanded therapy has the potential to prevent drug resistance emergence in Mycobacterium tuberculosis and other pathogens. Prospective cohort studies of participants with and with-out these polymorphisms should be undertaken with a view to implementing personalized pathogen genomic therapy. This approach could be employed to preempt and prevent the emergence of drug resistance and other important traits in other organisms.

scholarly journals Transition bias influences the evolution of antibiotic resistance in Mycobacterium tuberculosis

2018 ◽  
Author(s):  
Joshua L. Payne ◽  
Fabrizio Menardo ◽  
Andrej Trauner ◽  
Sonia Borrell ◽  
Sebastian M. Gygli ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Mycobacterium Tuberculosis ◽  
Dna Sequence ◽  
Adaptive Evolution ◽  
Gene Promoters ◽  
Human Pathogen ◽  
Resistance Mutations ◽  
Resistance Evolution ◽  
Transition Bias ◽  
Antibiotic Resistance Mutations

AbstractTransition bias, an overabundance of transitions relative to transversions, has been widely reported among studies of mutations spreading under relaxed selection. However, demonstrating the role of transition bias in adaptive evolution remains challenging. We addressed this challenge by analyzing adaptive antibiotic-resistance mutations in the major human pathogen Mycobacterium tuberculosis. We found strong evidence for transition bias in two independently curated datasets comprising 152 and 208 antibiotic resistance mutations. This was true at the level of mutational paths (distinct, adaptive DNA sequence changes) and events (individual instances of the adaptive DNA sequence changes), and across different genes and gene promoters conferring resistance to a diversity of antibiotics. It was also true for mutations that do not code for amino acid changes (in gene promoters and the ribosmal gene rrs), and for mutations that are synonymous to each other and are therefore likely to have similar fitness effects, suggesting that transition bias can be caused by a bias in mutation supply. These results point to a central role for transition bias in determining which mutations drive adaptive antibiotic resistance evolution in a key pathogen.Significance statementWhether and how transition bias influences adaptive evolution remain open questions. We studied 296 DNA mutations that confer antibiotic resistance to the human pathogen Mycobacterium tuberculosis. We uncovered strong transition bias among these mutations and also among the number of times each mutation has evolved in different strains or geographic locations, demonstrating that transition bias can influence adaptive evolution. For a subset of mutations, we were able to rule out an alternative selection-based hypothesis for this bias, indicating that transition bias can be caused by a biased mutation supply. By revealing this bias among M. Tuberculosis resistance mutations, our findings improve our ability to predict the mutational pathways by which pathogens overcome treatment.

scholarly journals Comprehensive Genome-Wide Analysis of The Catalase Enzyme Toolbox In Potato (Solanum Tuberosum L.)

2021 ◽  
Author(s):  
Rania Jbir Koubaa ◽  
Mariem Ayadi ◽  
Mohamed Najib Saidi ◽  
Safa Charfeddine ◽  
Radhia Gargouri Bouzid ◽  
...  
Keyword(s):  
Stress Responses ◽  
Expression Profiling ◽  
Phylogenetic Trees ◽  
Solanum Tuberosum L ◽  
Potato Cultivar ◽  
Promoter Sequence ◽  
3D Protein Structure ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
A Genome

Abstract As antioxidant enzymes, catalase (CAT) protects organisms from oxidative stress via the production of reactive oxygen species (ROS). These enzymes play important roles in diverse biological processes. However, little is known about the CAT genes in potato plants despite its important economical rank of this crop in the world. Yet, abiotic and biotic stresses severely hinder growth and development of the plants which affects the production and quality of the crop. To define the possible roles of CAT genes under various stresses, a genome-wide analysis of CAT gene family has been performed in potato plant.In this study, the StCAT gene’s structure, secondary and 3D protein structure, physicochemical properties, synteny analysis, phylogenetic tree and also expression profiling under various developmental and environmental cues were predicted using bioinformatics tools. The expression analysis by RT-PCR was performed using commercial potato cultivar. Three genes encoding StCAT that code for three proteins each of size 492 aa, interrupted by seven introns have been identified in potatoes. StCAT proteins were found to be localized in the peroxisome which is judged as the main H2O2 cell production site during different processes. Many regulating cis-elements related to stress responses and plant hormones signaling were found in the promoter sequence of each gene. The analysis of motifs and phylogenetic trees showed that StCAT are closer to their homologous in S. lycopersicum and share a 41% – 95% identity with other plants’ CATs. Expression profiling revealed that StCAT1 is the constitutively expressive member; while StCAT2 and StCAT3 are the stress-responsive members.

scholarly journals Antibiotic Resistance Evolution Is Contingent on the Quorum-Sensing Response in Pseudomonas aeruginosa

2019 ◽  
Vol 36 (10) ◽  
pp. 2238-2251 ◽  
Author(s):  
Sara Hernando-Amado ◽  
Fernando Sanz-García ◽  
José Luis Martínez
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Quorum Sensing ◽  
Wild Type ◽  
Resistance Mutations ◽  
Epistatic Interactions ◽  
Adaptive Mutations ◽  
Resistance Evolution ◽  
Evolutionary Trajectories

Abstract Different works have explored independently the evolution toward antibiotic resistance and the role of eco-adaptive mutations in the adaptation to a new habitat (as the infected host) of bacterial pathogens. However, knowledge about the connection between both processes is still limited. We address this issue by comparing the evolutionary trajectories toward antibiotic resistance of a Pseudomonas aeruginosa lasR defective mutant and its parental wild-type strain, when growing in presence of two ribosome-targeting antibiotics. Quorum-sensing lasR defective mutants are selected in P. aeruginosa populations causing chronic infections. Further, we observed they are also selected in vitro as a first adaptation for growing in culture medium. By using experimental evolution and whole-genome sequencing, we found that the evolutionary trajectories of P. aeruginosa in presence of these antibiotics are different in lasR defective and in wild-type backgrounds, both at the phenotypic and the genotypic levels. Recreation of a set of mutants in both genomic backgrounds (either wild type or lasR defective) allowed us to determine the existence of negative epistatic interactions between lasR and antibiotic resistance determinants. These epistatic interactions could lead to mutual contingency in the evolution of antibiotic resistance when P. aeruginosa colonizes a new habitat in presence of antibiotics. If lasR mutants are selected first, this would constraint antibiotic resistance evolution. Conversely, when resistance mutations (at least those studied in the present work) are selected, lasR mutants may not be selected in presence of antibiotics. These results underlie the importance of contingency and epistatic interactions in modulating antibiotic resistance evolution.

scholarly journals Genotypic Analysis of Genes Associated with Independent Resistance and Cross-Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis Clinical Isolates

2015 ◽  
Vol 59 (12) ◽  
pp. 7805-7810 ◽  
Author(s):  
Johana Rueda ◽  
Teresa Realpe ◽  
Gloria Isabel Mejia ◽  
Elsa Zapata ◽  
Juan Carlos Rozo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Resistance Mutations ◽  
Content Type ◽  
Genotypic Analysis ◽  
Mdr Tb ◽  
Proportion Method ◽  
Emergence Of Resistance ◽  
Phenotypic Susceptibility

ABSTRACTEthionamide (ETH) is an antibiotic used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) (MDR-TB), and its use may be limited with the emergence of resistance in theMycobacterium tuberculosispopulation. ETH resistance inM. tuberculosisis phenomenon independent or cross related when accompanied with isoniazid (INH) resistance. In most cases, resistance to INH and ETH is explained by mutations in theinhApromoter and in the following genes:katG,ethA,ethR,mshA,ndh, andinhA. We sequenced the above genes in 64M. tuberculosisisolates (n= 57 ETH-resistant MDR-TB isolates;n= 3 ETH-susceptible MDR-TB isolates; andn= 4 fully susceptible isolates). Each isolate was tested for susceptibility to first- and second-line drugs using the agar proportion method. Mutations were observed in ETH-resistant MDR-TB isolates at the following rates: 100% inkatG, 72% inethA, 45.6% inmshA, 8.7% inndh, and 33.3% ininhAor its promoter. Of the three ETH-susceptible MDR-TB isolates, all showed mutations inkatG; one had a mutation inethA, and another, inmshAandinhA. Finally, of the four fully susceptible isolates, two showed no detectable mutation in the studied genes, and two had mutations inmshAgene unrelated to the resistance. Mutations not previously reported were found in theethA,mshA,katG, andndhgenes. The concordance between the phenotypic susceptibility testing to INH and ETH and the sequencing was 1 and 0.45, respectively. Among isolates exhibiting INH resistance, the high frequency of independent resistance and cross-resistance with ETH in theM. tuberculosisisolates suggests the need to confirm the susceptibility to ETH before considering it in the treatment of patients with MDR-TB.

scholarly journals Predicting nitroimidazole antibiotic resistance mutations in Mycobacterium tuberculosis with protein engineering

2020 ◽  
Vol 16 (2) ◽  
pp. e1008287 ◽  
Author(s):  
Brendon M. Lee ◽  
Liam K. Harold ◽  
Deepak V. Almeida ◽  
Livnat Afriat-Jurnou ◽  
Htin Lin Aung ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Mycobacterium Tuberculosis ◽  
Protein Engineering ◽  
Resistance Mutations ◽  
Antibiotic Resistance Mutations

scholarly journals Mutations in dnaA and a cryptic interaction site increase drug resistance in Mycobacterium tuberculosis

2020 ◽  
Vol 16 (11) ◽  
pp. e1009063
Author(s):  
Nathan D. Hicks ◽  
Samantha R. Giffen ◽  
Peter H. Culviner ◽  
Michael C. Chao ◽  
Charles L. Dulberger ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Genome Wide Association Study ◽  
Critical Concentration ◽  
Drug Susceptibility ◽  
Interaction Site ◽  
Clinical Strains ◽  
Synonymous Mutations ◽  
Genome Wide ◽  
A Genome

Genomic dissection of antibiotic resistance in bacterial pathogens has largely focused on genetic changes conferring growth above a single critical concentration of drug. However, reduced susceptibility to antibiotics—even below this breakpoint—is associated with poor treatment outcomes in the clinic, including in tuberculosis. Clinical strains of Mycobacterium tuberculosis exhibit extensive quantitative variation in antibiotic susceptibility but the genetic basis behind this spectrum of drug susceptibility remains ill-defined. Through a genome wide association study, we show that non-synonymous mutations in dnaA, which encodes an essential and highly conserved regulator of DNA replication, are associated with drug resistance in clinical M. tuberculosis strains. We demonstrate that these dnaA mutations specifically enhance M. tuberculosis survival during isoniazid treatment via reduced expression of katG, the activator of isoniazid. To identify DnaA interactors relevant to this phenotype, we perform the first genome-wide biochemical mapping of DnaA binding sites in mycobacteria which reveals a DnaA interaction site that is the target of recurrent mutation in clinical strains. Reconstructing clinically prevalent mutations in this DnaA interaction site reproduces the phenotypes of dnaA mutants, suggesting that clinical strains of M. tuberculosis have evolved mutations in a previously uncharacterized DnaA pathway that quantitatively increases resistance to the key first-line antibiotic isoniazid. Discovering genetic mechanisms that reduce drug susceptibility and support the evolution of high-level drug resistance will guide development of biomarkers capable of prospectively identifying patients at risk of treatment failure in the clinic.

scholarly journals A genome epidemiological study of mycobacterium tuberculosis in subpopulations with high and low incidence rate in Guangxi, South China

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dingwen Lin ◽  
Junning Wang ◽  
Zhezhe Cui ◽  
Jing Ou ◽  
Liwen Huang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Incidence Rate ◽  
South China ◽  
Demographic History ◽  
Lineage Differentiation ◽  
A Genome ◽  
High Incidence ◽  
History Of ◽  
Lineage 2 ◽  
Low Incidence

Abstract Background Tuberculosis (TB) is caused by a bacterium called Mycobacterium tuberculosis (Mtb). China is the third in top 8 high TB burden countries and Guangxi is one of the high incidence areas in South China. Determine bacterial factors that affected TB incidence rate is a step toward Ending the TB epidemic. Results Genomes of M. tuberculosis cultures from a relatively high and low incidence region in Guangxi have been sequenced. 347 of 358(96.9%) were identified as M. tuberculosis. All the strains belong to Lineage 2 and Lineage 4, except for one in Lineage 1. We found that the genetic structure of the M. tuberculosis population in each county varies enormously. Low incidence rate regions have a lower prevalence of Beijing genotypes than other regions. Four isolates which harbored mutT4-48 also had mutT2-58 mutations. It is suggested that strains from the ancestors of modern Beijing lineage is circulating in Guangxi. Strains of modern Beijing lineage (OR=2.04) were more likely to acquire drug resistances than Lineage 4. Most of the lineage differentiation SNPs are related to cell wall biosynthetic pathways. Conclusions These results provided a higher resolution to better understand the history of transmission of M. tuberculosis from/to South China. And the incidence rate of tuberculosis might be affected by bacterial population structure shaped by demographic history. Our findings also support the hypothesis that Modern Beijing lineage originated in South China.

scholarly journals The evolution of nitroimidazole antibiotic resistance in Mycobacterium tuberculosis

2019 ◽  
Author(s):  
Brendon M. Lee ◽  
Deepak V. Almeida ◽  
Livnat Afriat-Jurnou ◽  
Htin Lin Aung ◽  
Brian M. Forde ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Mycobacterium Tuberculosis ◽  
Structural Analysis ◽  
Human Health ◽  
Reductase Activity ◽  
Complete Loss ◽  
Aerobic Respiration ◽  
Beijing Family ◽  
Emergence Of Resistance

AbstractOur inability to predict whether certain mutations will confer antibiotic resistance has made it difficult to rapidly detect the emergence of resistance, identify pre-existing resistant populations and manage our use of antibiotics to effective treat patients and prevent or slow the spread of resistance. Here we investigated the potential for resistance against the new antitubercular nitroimidazole prodrugs pretomanid and delamanid to emerge in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Deazaflavin-dependent nitroreductase (Ddn) is the only identified enzyme within M. tuberculosis that activates these prodrugs, via an F420H2-dependent reaction. We show that the native menaquinone-reductase activity of Ddn is important in aerobic respiration and essential for emergence from dormancy, which suggests that for resistance to spread and pose a threat to human health, the native activity of Ddn must be at least partially retained. We tested 75 unique mutations, including all known sequence polymorphisms identified among ~15,000 sequenced M. tuberculosis genomes. Several mutations abolished pretomanid activation in vitro, without causing complete loss of the native activity. We confirmed that a transmissible M. tuberculosis isolate from the hypervirulent Beijing family already possesses one such mutation and is resistant to pretomanid, even though it was never exposed to pretomanid. Notably, delamanid was still effective against this strain, which is consistent with structural analysis that indicates delamanid and pretomanid bind to Ddn differently. We suggest that the mutations identified in this work be monitored for informed use of delamanid and pretomanid treatment and to slow the emergence of resistance.

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