Whole-genome analysis of drug-resistant Mycobacterium tuberculosis reveals novel mutations associated with fluoroquinolone resistance.

Autor: Chaiyachat P; Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, Thailand., Chaiprasert A; Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand., Nonghanphithak D; Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, Thailand., Smithtikarn S; Bureau of Tuberculosis, Department of Disease Control, Ministry of Public Health, Thailand., Kamolwat P; Bureau of Tuberculosis, Department of Disease Control, Ministry of Public Health, Thailand., Pungrassami P; Bureau of Tuberculosis, Department of Disease Control, Ministry of Public Health, Thailand., Reechaipichitkul W; Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand., Ong RT; Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore., Teo YY; Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; Genome Institute of Singapore, Singapore; Department of Statistics and Applied Probability, National University of Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore., Faksri K; Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, Thailand. Electronic address: kiatichai@kku.ac.th.
Jazyk: angličtina
Zdroj: International journal of antimicrobial agents [Int J Antimicrob Agents] 2021 Sep; Vol. 58 (3), pp. 106385. Date of Electronic Publication: 2021 Jun 20.
DOI: 10.1016/j.ijantimicag.2021.106385
Abstrakt: Multidrug-resistant and extensively drug-resistant tuberculosis (M/XDR-TB) remains a global public-health challenge. Known mutations in quinolone resistance-determination regions cannot fully explain phenotypic fluoroquinolone (FQ) resistance in Mycobacterium tuberculosis (Mtb). The aim of this study was to look for novel mutations in Mtb associated with resistance to FQ drugs using whole-genome sequencing analysis. Whole-genome sequences of 659 Mtb strains, including 214 with phenotypic FQ resistance and 445 pan-susceptible isolates, were explored for mutations associated with FQ resistance overall and with resistance to individual FQ drugs (ofloxacin, levofloxacin, moxifloxacin and gatifloxacin). Three novel genes (recC, Rv2005c and PPE59) associated with FQ resistance were identified (P < 0.00001 based on screening analysis and absence of relevant mutations in a pan-susceptible validation set of 360 strains). Nine novel single nucleotide polymorphisms (SNPs), including in gyrB (G5383A and G6773A), gyrA (G7892A), recC (G725900C and G726857T/C), Rv2005c (C2251373G, G2251420C and C2251725T) and PPE59 (C3847269T), were used for diagnostic performance analysis. Enhancing the known SNP set with five of these novel SNPs, including gyrA [G7892A (Leu247Leu)], recC [G725900C (Leu893Leu) and G726857T/C (Arg484Arg)], Rv2005c [G2251420C (Pro205Arg)] and PPE59 [C3847269T (Asn35Asn)] increased the sensitivity of detection of FQ-resistant Mtb from 83.2% (178/214) to 86.9% (186/214) while maintaining 100% specificity (360/360). No specific mutation associated with resistance to only a single drug (ofloxacin, levofloxacin, moxifloxacin or gatifloxacin) was found. In conclusion, this study reports possible additional mutations associated with FQ resistance in Mtb.
(Copyright © 2021 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)
Databáze: MEDLINE
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