Mycobacterium tuberculosis Gene Expression Associated With Fluoroquinolone Resistance and Efflux Pump Inhibition.
J Infect Dis
; 228(4): 469-478, 2023 08 16.
Article
en En
| MEDLINE
| ID: mdl-37079382
BACKGROUND: We evaluated the relationship between response to efflux pump inhibition in fluoroquinolone-resistant Mycobacterium tuberculosis (Mtb) isolates and differences in gene expression and expression quantitative trait loci (eQTL). METHODS: We determined ofloxacin minimum inhibitory concentration (MIC) for ofloxacin-resistant and -susceptible Mtb isolates without and with the efflux pump inhibitor verapamil. We performed RNA sequencing (RNA-seq), whole genome sequencing (WGS), and eQTL analysis, focusing on efflux pump, transport, and secretion-associated genes. RESULTS: Of 42 ofloxacin-resistant Mtb isolates, 27 had adequate WGS coverage and acceptable RNA-seq quality. Of these 27, 7 had >2-fold reduction in ofloxacin MIC with verapamil; 6 had 2-fold reduction, and 14 had <2-fold reduction. Five genes (including Rv0191) had significantly increased expression in the MIC fold change >2 compared to <2 groups. Among regulated genes, 31 eQTLs (without ofloxacin) and 35 eQTLs (with ofloxacin) had significant allele frequency differences between MIC fold change >2 and <2 groups. Of these, Rv1410c, Rv2459, and Rv3756c (without ofloxacin) and Rv0191 and Rv3756c (with ofloxacin) have previously been associated with antituberculosis drug resistance. CONCLUSIONS: In this first reported eQTL analysis in Mtb, Rv0191 had increased gene expression and significance in eQTL analysis, making it a candidate for functional evaluation of efflux-mediated fluoroquinolone resistance in Mtb.
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Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Mycobacterium tuberculosis
Tipo de estudio:
Risk_factors_studies
Idioma:
En
Revista:
J Infect Dis
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos