Mycobacterium tuberculosis Is Resistant to Isoniazid at a Slow Growth Rate by Single Nucleotide Polymorphisms in katG Codon Ser315.
An important aim for improving TB treatment is to shorten the period of antibiotic therapy without increasing relapse rates or encouraging the development of antibiotic-resistant strains. In any M. tuberculosis population there is a proportion of bacteria that are drug-tolerant; this might be becaus...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4575197?pdf=render |
| _version_ | 1818482444599296000 |
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| author | Rose E Jeeves Alice A N Marriott Steven T Pullan Kim A Hatch Jon C Allnutt Irene Freire-Martin Charlotte L Hendon-Dunn Robert Watson Adam A Witney Richard H Tyler Catherine Arnold Philip D Marsh Timothy D McHugh Joanna Bacon |
| author_facet | Rose E Jeeves Alice A N Marriott Steven T Pullan Kim A Hatch Jon C Allnutt Irene Freire-Martin Charlotte L Hendon-Dunn Robert Watson Adam A Witney Richard H Tyler Catherine Arnold Philip D Marsh Timothy D McHugh Joanna Bacon |
| author_sort | Rose E Jeeves |
| collection | DOAJ |
| description | An important aim for improving TB treatment is to shorten the period of antibiotic therapy without increasing relapse rates or encouraging the development of antibiotic-resistant strains. In any M. tuberculosis population there is a proportion of bacteria that are drug-tolerant; this might be because of pre-existing populations of slow growing/non replicating bacteria that are protected from antibiotic action due to the expression of a phenotype that limits drug activity. We addressed this question by observing populations of either slow growing (constant 69.3h mean generation time) or fast growing bacilli (constant 23.1h mean generation time) in their response to the effects of isoniazid exposure, using controlled and defined growth in chemostats. Phenotypic differences were detected between the populations at the two growth rates including expression of efflux mechanisms and the involvement of antisense RNA/small RNA in the regulation of a drug-tolerant phenotype, which has not been explored previously for M. tuberculosis. Genotypic analyses showed that slow growing bacilli develop resistance to isoniazid through mutations specifically in katG codon Ser315 which are present in approximately 50-90% of all isoniazid-resistant clinical isolates. The fast growing bacilli persisted as a mixed population with katG mutations distributed throughout the gene. Mutations in katG codon Ser315 appear to have a fitness cost in vitro and particularly in fast growing cultures. Our results suggest a requirement for functional katG-encoded catalase-peroxide in the slow growers but not the fast-growing bacteria, which may explain why katG codon Ser315 mutations are favoured in the slow growing cultures. |
| first_indexed | 2024-12-10T11:47:58Z |
| format | Article |
| id | doaj.art-b77774f4b89f45aa86fd10187fd3db40 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T11:47:58Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b77774f4b89f45aa86fd10187fd3db402022-12-22T01:50:01ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01109e013825310.1371/journal.pone.0138253Mycobacterium tuberculosis Is Resistant to Isoniazid at a Slow Growth Rate by Single Nucleotide Polymorphisms in katG Codon Ser315.Rose E JeevesAlice A N MarriottSteven T PullanKim A HatchJon C AllnuttIrene Freire-MartinCharlotte L Hendon-DunnRobert WatsonAdam A WitneyRichard H TylerCatherine ArnoldPhilip D MarshTimothy D McHughJoanna BaconAn important aim for improving TB treatment is to shorten the period of antibiotic therapy without increasing relapse rates or encouraging the development of antibiotic-resistant strains. In any M. tuberculosis population there is a proportion of bacteria that are drug-tolerant; this might be because of pre-existing populations of slow growing/non replicating bacteria that are protected from antibiotic action due to the expression of a phenotype that limits drug activity. We addressed this question by observing populations of either slow growing (constant 69.3h mean generation time) or fast growing bacilli (constant 23.1h mean generation time) in their response to the effects of isoniazid exposure, using controlled and defined growth in chemostats. Phenotypic differences were detected between the populations at the two growth rates including expression of efflux mechanisms and the involvement of antisense RNA/small RNA in the regulation of a drug-tolerant phenotype, which has not been explored previously for M. tuberculosis. Genotypic analyses showed that slow growing bacilli develop resistance to isoniazid through mutations specifically in katG codon Ser315 which are present in approximately 50-90% of all isoniazid-resistant clinical isolates. The fast growing bacilli persisted as a mixed population with katG mutations distributed throughout the gene. Mutations in katG codon Ser315 appear to have a fitness cost in vitro and particularly in fast growing cultures. Our results suggest a requirement for functional katG-encoded catalase-peroxide in the slow growers but not the fast-growing bacteria, which may explain why katG codon Ser315 mutations are favoured in the slow growing cultures.http://europepmc.org/articles/PMC4575197?pdf=render |
| spellingShingle | Rose E Jeeves Alice A N Marriott Steven T Pullan Kim A Hatch Jon C Allnutt Irene Freire-Martin Charlotte L Hendon-Dunn Robert Watson Adam A Witney Richard H Tyler Catherine Arnold Philip D Marsh Timothy D McHugh Joanna Bacon Mycobacterium tuberculosis Is Resistant to Isoniazid at a Slow Growth Rate by Single Nucleotide Polymorphisms in katG Codon Ser315. PLoS ONE |
| title | Mycobacterium tuberculosis Is Resistant to Isoniazid at a Slow Growth Rate by Single Nucleotide Polymorphisms in katG Codon Ser315. |
| title_full | Mycobacterium tuberculosis Is Resistant to Isoniazid at a Slow Growth Rate by Single Nucleotide Polymorphisms in katG Codon Ser315. |
| title_fullStr | Mycobacterium tuberculosis Is Resistant to Isoniazid at a Slow Growth Rate by Single Nucleotide Polymorphisms in katG Codon Ser315. |
| title_full_unstemmed | Mycobacterium tuberculosis Is Resistant to Isoniazid at a Slow Growth Rate by Single Nucleotide Polymorphisms in katG Codon Ser315. |
| title_short | Mycobacterium tuberculosis Is Resistant to Isoniazid at a Slow Growth Rate by Single Nucleotide Polymorphisms in katG Codon Ser315. |
| title_sort | mycobacterium tuberculosis is resistant to isoniazid at a slow growth rate by single nucleotide polymorphisms in katg codon ser315 |
| url | http://europepmc.org/articles/PMC4575197?pdf=render |
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