Whole-Genome Sequencing of a Haarlem Extensively Drug-Resistant Mycobacterium tuberculosis Clinical Isolate from Medellín, Colombia

Alvarez, N.; Haft, Daniel H.; Hurtado, U. A.; Robledo, Jaime; Rouzaud, François

doi:10.1128/genomea.00566-16

Cited by 2 publications

(3 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently many unique strains have been reported with no mutation in the typical hot-spots for various drugs, including RIF, INH, fluoroquinolones, and aminoglycoside. 38, 39 Indeed, an alternate mechanism of resistance is now emerging. For example, the resistance of ofloxacin in isolates without any gyr A/B mutation was mapped to a novel mutation in the ecc C5 gene.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Laboratory evolution ofMycobacterium smegmatisin the presence of a fluoroquinolone leads to extreme drug resistance phenotype through the over-expression ofMsmeg_5659-61 efflux pump.

Rai

Padwal

Purkayastha

et al. 2022

Preprint

View full text Add to dashboard Cite

Resistance to multiple drugs is one of the significant barriers in the treatment of tuberculosis (TB). Knowledge of mechanisms of resistance is important to design effective treatment strategies. While mutations in genes coding for drug targets are thought to be the primary source of drug resistance, absence of mutations in these genes in many clinical strains suggests additional mechanisms of resistance. In this study, we employ adaptive laboratory evolution of Mycobacterium smegmatis to understand alternate mechanisms of drug resistance to norfloxacin, a fluoroquinolone (FQ). Results show that, in addition to fluoroquinolones, the evolved strain, Norr, is resistant to first-line drugs, rifampicin and isoniazid, and a second-line drug (amikacin), exhibiting extreme drug resistance phenotype. However, mutations were absent in any of the drug target genes. Drug uptake studies revealed that resistance is an attribute of decreased intracellular accumulation, primarily due to increased efflux. Further, drug transport kinetics demonstrate the involvement of efflux mediated resistance, which was found to be reversed in the presence of efflux pump inhibitors (EPIs). Gene transcript analysis suggests differential upregulation of multiple efflux pumps across the genome of the mutant. Overexpression of one of the upregulated efflux pumps Msmeg_5659-5661, partially explains the XDR phenotype of the mutant, while also suggesting that the contribution of other efflux pumps is significant. Whole-genome sequencing (WGS) of Norr reveals that a mutation in soxR, a transcriptional regulator, could be responsible for the upregulation of the Msmeg_5659-5661 efflux pump by direct regulation, and other efflux pumps via indirect regulation. Thus, the present work demonstrates that high resistance to multiple drugs can arise even when the Mycobacterium was subjected to a single selection pressure. Further, alterations in drug transport is an important mechanism that leads to resistance to multiple drugs simultaneously.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Hence, most studies characterizing MDR/XDR-TB from various geographic regions deal with target mutations. [37][38][39][40][41][42] Accumulation of mutations in multiple genes, including gyrA, gyrB, rpoB, katG, etc. have been reported in MDR/XDR strains.…”

Section: Discussionmentioning

confidence: 99%

Laboratory evolution ofMycobacterium smegmatisin the presence of a fluoroquinolone leads to extreme drug resistance phenotype through the over-expression ofMsmeg_5659-61 efflux pump.

Rai

Padwal

Purkayastha

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Este genotipo pertenece al linaje 4, que es uno de los siete linajes filogeográficos descritos para M. tuberculosis. Anteriormente, se han documentado en Colombia cepas pertenecientes al linaje Haarlem, dada su asociación con patrones extensamente resistentes (XDR-TB) 21 , aunque finalmente no fue el caso de nuestra paciente.…”

Section: Figuraunclassified

Mycobacterium tuberculosis y virus linfotrópico humano, una co-infección fatal

Morales,

Montero

2024

Rev. chil. infectol.

View full text Add to dashboard Cite

Whole-Genome Sequencing of a Haarlem Extensively Drug-Resistant Mycobacterium tuberculosis Clinical Isolate from Medellín, Colombia

Cited by 2 publications

References 18 publications

Laboratory evolution ofMycobacterium smegmatisin the presence of a fluoroquinolone leads to extreme drug resistance phenotype through the over-expression ofMsmeg_5659-61 efflux pump.

Laboratory evolution ofMycobacterium smegmatisin the presence of a fluoroquinolone leads to extreme drug resistance phenotype through the over-expression ofMsmeg_5659-61 efflux pump.

Mycobacterium tuberculosis y virus linfotrópico humano, una co-infección fatal

Contact Info

Product

Resources

About