A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance

Sheen, Patricia; Requena, David; Gushiken, Eduardo; Gilman, Robert H.; Antiparra, Ricardo; Lucero, Bryan; Lizárraga, Pilar; Cieza, Basilio; Roncal, Elisa; Grandjean, Louis; Pain, Arnab; McNerney, Ruth; Clark, Taane G.; Moore, D. J.; Zimic, Mirko

doi:10.1186/s12864-017-4146-z

Cited by 32 publications

(21 citation statements)

References 27 publications

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“…a frameshift was previously described in Beijing strains although of a different length and position [31,32]. There are four Mtb strains deposited in NCBI that belongs to Perú (South America) that have the same deletion of 13-bp in kdpD (MDRMA701, SLM036, CSV4519, and M0018684-2) [33]. Deletion in the kdpD gene could conduct the development of nonfunctional proteins KdpD and KdpE.…”

Section: Genomic Differences Among Ut127 and Ut205mentioning

confidence: 92%

Differential determinants of virulence in twoMycobacterium tuberculosisColombian clinical isolates of the LAM09 family

et al. 2019

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The heterogeneity of the clinical outcome of Mycobacterium tuberculosis (Mtb) infection may be due in part to different strategies used by circulating strains to cause disease. This heterogeneity is one of the main limitations to eradicate tuberculosis disease. In this study, we have compared the transcriptional response of two closely related Colombian clinical isolates (UT127 and UT205) of the LAM family under two axenic media conditions. These clinical isolates are phenotypically different at the level of cell death, cytokine production, growth kinetics upon in vitro infection of human tissue macrophages, and membrane vesicle secretion upon culture in synthetic medium. Using RNA-seq, we have identified different pathways that account for two different strategies to cope with the stressful condition of a carbon-poor media such as Sauton's. We showed that the clinical isolate UT205 focus mainly in the activation of virulence systems such as the ESX-1, synthesis of diacyl-trehalose, polyacyltrehalose, and sulfolipids, while UT127 concentrates its efforts mainly in the survival mode by the activation of the DNA replication, cell division, and lipid biosynthesis. This is an example of two Mtb isolates that belong to the same family and lineage, and even though they have a very similar genome, its transcriptional regulation showed important differences. This results in summary highlight the necessity to reach a better understanding of the heterogeneity in the behavior of these circulating Mtb strains which may help us to design better treatments and vaccines and to identify new targets for drugs.

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Section: Genomic Differences Among Ut127 and Ut205mentioning

confidence: 92%

Differential determinants of virulence in twoMycobacterium tuberculosisColombian clinical isolates of the LAM09 family

et al. 2019

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“…The model also does not take into account the introduction of protease cleavage sites or other processing abnormalities. Finally, while most pyrazinamide resistance is caused by mutations in pncA, recent studies have also implicated other genes, notably rpsA, panD, and the putative efflux pumps Rv0191, Rv3756c, Rv3008, and Rv1667c in pyrazinamide resistance 4,[25][26][27][28][29][30][31][32] . Further research is needed to determine if mutations in these genes can be reliably inferred to confer pyrazinamide resistance.…”

Section: Discussionmentioning

confidence: 99%

Prediction of pyrazinamide resistance inMycobacterium tuberculosisusing structure-based machine learning approaches

Carter

Walker

et al. 2019

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Pyrazinamide is one of four first-line antibiotics currently used to treat tuberculosis and has been included in newer treatment regimens undergoing clinical trials due to its unique sterilizing effects and synergy with newer drugs. However, phenotypic antibiotic susceptibility testing for pyrazinamide is problematic. Resistance to pyrazinamide is primarily driven by genetic variation in pncA, which encodes PncA, an enzyme that converts pyrazinamide into its active form. We curated a derivation dataset of 291 non-redundant, missense amino acid mutations in PncA with associated high-confidence phenotypes from studies of clinical isolates and in vitro/in vivo screening studies and then trained machine learning models to predict pyrazinamide resistance based on sequence-and structure-based features of each missense mutation. The clinical relevance of the models was tested by predicting the binary resistance phenotype of 2,292 clinical isolates harboring missense mutations in PncA to pyrazinamide. The probabilities of resistance predicted by the model were also compared with in vitro pyrazinamide minimum inhibitory concentrations of 27 isolates to determine whether the machine learning model could predict the degree of resistance. Finally, we predicted the effect on pyrazinamide resistance of the remaining 814 possible missense mutations caused by single nucleotide polymorphisms in PncA that have not yet been observed in public databases. Overall, this work offers an approach to improve the sensitivity and specificity of pyrazinamide resistance prediction in genetics-based clinical microbiology workflows for tuberculosis, highlights novel mutations for future biochemical investigation, and is a proof of concept for using this approach in other drugs such as bedaquiline.

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“…Notable is the inhibition of fatty acid synthase I (FAS-I) [9,10], the disruption of trans-translation via interaction with ribosomal protein S1 (RpsA) [11], the inhibition of aspartate decarboxylase (PanD) [12], and the inhibition of quinolinic acid phosphoribosyltransferase (QAPRTase) [13]. Several other proteins have been suggested as targets of PZA/POA [14][15][16][17]; however, PanD has recently been suggested by some authors as the likely prevalent target [18].…”

Section: Introductionmentioning

confidence: 99%

N-Pyrazinoyl Substituted Amino Acids as Potential Antimycobacterial Agents—the Synthesis and Biological Evaluation of Enantiomers

et al. 2020

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Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb), each year causing millions of deaths. In this article, we present the synthesis and biological evaluations of new potential antimycobacterial compounds containing a fragment of the first-line antitubercular drug pyrazinamide (PZA), coupled with methyl or ethyl esters of selected amino acids. The antimicrobial activity was evaluated on a variety of (myco)bacterial strains, including Mtb H37Ra, M. smegmatis, M. aurum, Staphylococcus aureus, Pseudomonas aeruginosa, and fungal strains, including Candida albicans and Aspergillus flavus. Emphasis was placed on the comparison of enantiomer activities. None of the synthesized compounds showed any significant activity against fungal strains, and their antibacterial activities were also low, the best minimum inhibitory concentration (MIC) value was 31.25 µM. However, several compounds presented high activity against Mtb. Overall, higher activity was seen in derivatives containing l-amino acids. Similarly, the activity seems tied to the more lipophilic compounds. The most active derivative contained phenylglycine moiety (PC-d/l-Pgl-Me, MIC < 1.95 µg/mL). All active compounds possessed low cytotoxicity and good selectivity towards Mtb. To the best of our knowledge, this is the first study comparing the activities of the d- and l-amino acid derivatives of pyrazinamide as potential antimycobacterial compounds.

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A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance

Cited by 32 publications

References 27 publications

Differential determinants of virulence in twoMycobacterium tuberculosisColombian clinical isolates of the LAM09 family

Differential determinants of virulence in twoMycobacterium tuberculosisColombian clinical isolates of the LAM09 family

Prediction of pyrazinamide resistance inMycobacterium tuberculosisusing structure-based machine learning approaches

N-Pyrazinoyl Substituted Amino Acids as Potential Antimycobacterial Agents—the Synthesis and Biological Evaluation of Enantiomers

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