High clustering rate and genotypic drug-susceptibility screening for the newly recommended anti-tuberculosis drugs among global extensively drug-resistant Mycobacterium tuberculosis isolates

Kanwara Trisakul; Ditthawat Nonghanphithak; Pratchakan Chaiyachat; Orawee Kaewprasert; Kankanon Sakmongkoljit; Wipa Reechaipichitkul; Angkana Chaiprasert; David Blair; Taane G Clark; Kiatichai Faksri

doi:10.1080/22221751.2022.2099304

High clustering rate and genotypic drug-susceptibility screening for the newly recommended anti-tuberculosis drugs among global extensively drug-resistant Mycobacterium tuberculosis isolates

Emerg Microbes Infect. 2022 Dec;11(1):1857-1866. doi: 10.1080/22221751.2022.2099304.

Authors

Kanwara Trisakul^{1

2}, Ditthawat Nonghanphithak^{1

2}, Pratchakan Chaiyachat^{1

2}, Orawee Kaewprasert^{1

2}, Kankanon Sakmongkoljit³, Wipa Reechaipichitkul^{1

2}, Angkana Chaiprasert⁴, David Blair⁵, Taane G Clark⁶, Kiatichai Faksri^{1

2}

Affiliations

¹ Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
² Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, Thailand.
³ Department of Geotechnology, Faculty of Technology, Khon Kaen University, Khon Kaen, Thailand.
⁴ Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
⁵ James Cook University, Townsville, Australia.
⁶ London School of Hygiene and Tropical Medicine, London, UK.

Abstract

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) make TB difficult to control. Global susceptibility data for six newly recommended anti-TB drugs against M/XDR-TB are still limited. Using publicly available whole-genome sequences, we determined the proportion of 513 phenotypically XDR-TB isolates that carried mutations associated with resistance against these drugs (bedaquiline, clofazimine, linezolid, delamanid, pretomanid and cycloserine). Mutations of Rv0678 and Rv1979c were detected in 69/513 isolates (13.5%) for bedaquiline resistance and 79/513 isolates (15.4%) for clofazimine resistance with additional mmpL5 mutations. Mutations conferring resistance to delamanid were detected in fbiB and ddn genes for 11/513 isolates (2.1%). For pretomanid, a mutation was detected in the ddn gene for 3/513 isolates (0.6%). Nineteen mutations of pykA, cycA, ald, and alr genes, conferring resistance to cycloserine, were found in 153/513 isolates (29.8%). No known mutations associated with linezolid resistance were detected. Cluster analysis showed that 408/513 isolates fell within 99 clusters and that 354 of these isolates were possible primary drug-resistant TB (292 XDR-TB, 57 pre-XDR-TB and 5 MDR-TB). Clonal transmission of primary XDR isolates might contribute significantly to the high prevalence of DR-TB globally.

Keywords: XDR-TB; bedaquiline; clofazimine; cycloserine; delamanid; linezolid; pretomanid.

MeSH terms

Antitubercular Agents / pharmacology
Antitubercular Agents / therapeutic use
Clofazimine
Cluster Analysis
Cycloserine / pharmacology
Drug Resistance, Multiple, Bacterial / genetics
Extensively Drug-Resistant Tuberculosis* / epidemiology
Extensively Drug-Resistant Tuberculosis* / microbiology
Humans
Linezolid
Microbial Sensitivity Tests
Mycobacterium tuberculosis*
Tuberculosis, Multidrug-Resistant* / microbiology

Substances

Antitubercular Agents
Cycloserine
Clofazimine
Linezolid

Grants and funding

This research project is supported by National Research Council of Thailand (NRCT): NRCT5-RGJ63003-047 and NRC MHESI 483/2563. This work is partly Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, Thailand. AC is funded by the Medical Research Council UK and NSTDA Thailand (grant number P-18-50228). TGC is funded by the Medical Research Council UK (grant number MR/M01360X/1, MR/N010469/1, MR/R025576/1, and MR/R020973/1).