Acetylation of isoniazid - a novel mechanism of isoniazid resistance in<i>Mycobacterium tuberculosis</i>

Arun, K.B.; Madhavan, Aravind; Abraham, Billu; Balaji, Madhuri S.; Sivakumar, Krishnankutty C.; Nisha, P.; R, Ajay Kumar

doi:10.1101/2020.02.10.941252

Cited by 3 publications

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“…One example would be the Rv2170 gene, which in our study increases sensitivity to isoniazid and has been shown to confer resistance when its expression is increased because it encodes an acetyl-transferase that inactivates isoniazid. 25 Although we could not find insertion mutants for target isoniazid gene inhA due to its essentiality, non-essential genes in the mycolic acids biosynthesis pathway were functionally more associated with resistance than the rest of the genome, showing that the target pathway can be identified even when the target gene itself is essential. Functional genomics also pointed to redox metabolism as a resistance mechanism for isoniazid, confirming the usefulness of this technique in highlighting resistance determinants not directly tied to the drug’s mode of action and in helping complete the resistance mutations catalog.…”

Section: Discussionmentioning

confidence: 80%

An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance inMycobacterium tuberculosis

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Moreno-Molina

Chiner‐Oms

et al. 2020

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18Efforts to eradicate tuberculosis are hampered by the rise and spread of antibiotic 19 resistance. Several large-scale projects have aimed to specifically link clinical mutations to 20 resistance phenotypes, but they were limited in both their explanatory and predictive powers. 21 Here, we combine functional genomics and phylogenetic associations using clinical strain 22 genomes to decipher the architecture of isoniazid resistance and search for new resistance 23 determinants. This approach has allowed us to confirm the main target route of the antibiotic, 24 determine the clinical relevance of redox metabolism as an isoniazid resistance mechanism 25 and identify novel candidate genes harboring resistance mutations in strains with previously 26 unexplained isoniazid resistance. This approach can be useful for characterizing how the 27 tuberculosis bacilli acquire resistance to new antibiotics and how to forestall them. 28 29 45 we can detect rifampicin resistance with a 92% sensitivity, but the figure drops to 87% for 46 isoniazid and 58% for ethambutol. 6 However, there is still a knowledge gap as the catalog of 47 62 63 One way to unveil the genetic basis of resistance is by means of functional genomics, like 64 transposon mutagenesis approaches. This technique involves the genetic alteration of every 65 gene in the genome for explicit genotype-phenotype associations, 8,9 thus revealing more 66 genetic determinants than regular association studies do. This approach successfully 67 overcomes the shortcomings of genetic association studies: it can be used in a prospective 68 way, as it involves the systematic generation and testing of resistance mutants; it can detect 69 both genes with large and small effects on resistance; and it explicitly detects genes that 70 increase sensitivity when disrupted, thus indicating which genes are most promising for 71 treatments to prevent or reverse the evolution of resistance. However, transposon 72 mutagenesis alters the gene by disrupting it, highly informative about the biology of 73 resistance but limited in clinical explanation potential as most type of mutations found in 74 clinical resistance of M. tuberculosis are single nucleotide polymorphisms. Conversely, the 75 low diversity of the MTBC, clonality and the fact that clinical resistance is encoded in the 76 encoded in the chromosome makes Mycobacterium tuberculosis amenable for phylogenetic 77 association tests 10 which can determine which mutations are associated with resistance in 78 the bacterial phylogeny and are thus clinically relevant. 79 80In this paper, we provide a combined approach that uses functional genomics and 81 phylogenetic inference from clinical data to provide an in-depth picture of resistance to the 82 first-line antibiotic isoniazid. Isoniazid is a well-studied drug, yet we are still unable to 83 determine the causal mutation in around 6% of resistant strains, 11 although some 84 researchers have reported up to 25% in certain settings. 12 Here, we systematically 85 determi...

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Section: Discussionmentioning

confidence: 80%

An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance inMycobacterium tuberculosis

Furió

Moreno-Molina

Chiner‐Oms

et al. 2020

Preprint

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“…Thus, sensitivity-increasing genes can also act as resistance determinants depending on how mutations affect the protein or its expression levels. One example would be the Rv2170 gene, which in our study increases sensitivity to isoniazid and has been shown to confer resistance when its expression is increased because it encodes an acetyl-transferase that inactivates isoniazid [78]. Although we could not find insertion mutants for target isoniazid gene inhA due to its essentiality, non-essential genes in the mycolic acids biosynthesis pathway were functionally more associated with resistance than the rest of the genome, showing that the target pathway can be identified even when the target gene itself is essential.…”

Section: Discussionmentioning

confidence: 98%

Functional and evolutionary genomics of antibiotic resistance in tuberculosis: from biology to global DR-TB control

Moreno Molina

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Antibiotic resistance and tuberculosisMechanisms and evolution of drug resistance in M. tuberculosis Genomics and drug resistance detection in tuberculosisTuberculosis comorbidities and TB-HIV coinfection OBJECTIVES OF THIS DISSERTATION CHAPTER 1 An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance in Mycobacterium tuberculosisComorbidities associated with TB are conditions that occur alongside the TB infection, and can complicate treatment, cause poorer outcomes, or increase the risk of death [50]. The most common comorbidities associated with TB include HIV, diabetes, cardiovascular disease, mental health conditions, and substance use disorders. HIV is the most frequent comorbidity, and is associated with more severe TB, more frequent and longer-lasting symptoms, and

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An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance in Mycobacterium tuberculosis

et al. 2021

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Efforts to eradicate tuberculosis are hampered by the rise and spread of antibiotic resistance. Several large-scale projects have aimed to specifically link clinical mutations to resistance phenotypes, but they were limited in both their explanatory and predictive powers. Here, we combine functional genomics and phylogenetic associations using clinical strain genomes to decipher the architecture of isoniazid resistance and search for new resistance determinants. This approach has allowed us to confirm the main target route of the antibiotic, determine the clinical relevance of redox metabolism as an isoniazid resistance mechanism and identify novel candidate genes harboring resistance mutations in strains with previously unexplained isoniazid resistance. This approach can be useful for characterizing how the tuberculosis bacilli acquire resistance to new antibiotics and how to forestall them.

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Acetylation of isoniazid - a novel mechanism of isoniazid resistance inMycobacterium tuberculosis

Abstract: Isoniazid (INH)

Cited by 3 publications

References 30 publications

An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance inMycobacterium tuberculosis

An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance inMycobacterium tuberculosis

Functional and evolutionary genomics of antibiotic resistance in tuberculosis: from biology to global DR-TB control

An evolutionary functional genomics approach identifies novel candidate regions involved in isoniazid resistance in Mycobacterium tuberculosis

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