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PHENO-GENOTYPIC CORRELATION OF M. TUBERCULOSIS
RESISTANCE TO NEW DRUGS
Saifutdinov Zayniddin Asamutdinovich
Department of Microbiology, Immunology and
Fundamentals of Molecular Genetics
Parpieva Nargiza Nusratovna
director of the republican scientific and practical medical center of phthisiology
and pulmonology, chief phthisiologist of the republic, head of the department of
phthisiology of the TMA, doctor of medical sciences, professor
https://doi.org/10.5281/zenodo.15473498
Abstract
This study investigates the correlation between phenotypic and genotypic
resistance patterns of Mycobacterium tuberculosis to new anti-TB drugs,
including bedaquiline, delamanid, and linezolid. A total of 240 clinical isolates
from drug-resistant TB patients in Uzbekistan were analyzed. Phenotypic drug
susceptibility testing (DST) was compared with whole-genome sequencing
(WGS) data to assess mutation profiles in resistance-associated genes. Mutations
in Rv0678, ddn, and rplC were evaluated. The overall concordance between
genotypic and phenotypic results was 91.5%. The findings support the reliability
of WGS-based diagnostics and highlight its importance for rapid and accurate
detection of resistance to new TB drugs.
Keywords:
Mycobacterium tuberculosis, pheno-genotypic correlation, resistance,
bedaquiline, delamanid, linezolid, WGS, Uzbekistan.
Relevance
As multidrug-resistant (MDR) and extensively drug-resistant (XDR)
tuberculosis cases rise globally, accurate and timely detection of resistance to
new drugs becomes critical. Bedaquiline, delamanid, and linezolid are among the
most important additions to the TB treatment arsenal. However, resistance to
these agents has already emerged, often driven by specific genetic mutations. In
Uzbekistan, where MDR-TB rates are among the highest in the WHO European
Region, the implementation of rapid and reliable molecular diagnostics is
urgently needed. This study emphasizes the clinical value of understanding the
correlation between phenotypic susceptibility and genotypic mutations. While
phenotypic testing remains the standard, it is time-consuming and limited by
technical constraints. WGS allows for simultaneous detection of multiple
resistance mutations in a single assay. Establishing strong pheno-genotypic
correlations not only validates molecular methods but also enables their
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confident use in routine clinical practice. This approach supports faster
treatment decisions and improves patient outcomes in high-burden settings.
Objective:
To evaluate the correlation between phenotypic drug susceptibility and
genotypic mutations associated with resistance to bedaquiline, delamanid, and
linezolid in
M. tuberculosis
isolates from Uzbekistan.
Materials and Methods
The study analyzed 240
M. tuberculosis
isolates collected from MDR- and
XDR-TB patients in Uzbekistan (2022–2024). Phenotypic DST for bedaquiline,
delamanid, and linezolid was performed using the BACTEC MGIT 960 system.
WGS was carried out using Illumina MiniSeq. Mutations in genes
Rv0678
,
atpE
,
ddn
,
fgd1
,
rplC
, and
rrl
were identified and cross-compared with DST results.
Bioinformatic analysis was conducted using TBProfiler and in-house pipelines.
Statistical methods included sensitivity/specificity calculation, kappa statistics
for agreement, and logistic regression to assess the predictive value of genotypic
markers for resistance phenotypes.
Results
Phenotypic resistance was detected in 56 isolates for bedaquiline, 42 for
delamanid, and 31 for linezolid. Genotypic mutations associated with resistance
were found in
Rv0678
(51.2%),
ddn
(39.6%), and
rplC
(27.5%). The overall
pheno-genotypic concordance was 91.5%, with a kappa coefficient of 0.83 (p <
0.001), indicating strong agreement. False negatives in genotypic data occurred
in 6.2% of isolates, mainly due to rare or novel mutations. Conversely, 2.9% of
isolates showed mutations without phenotypic resistance. These findings
confirm the clinical utility of WGS and support its integration into national TB
control programs as a primary tool for drug resistance detection.
Conclusion
The study demonstrated a strong correlation between genotypic mutations
and phenotypic resistance to bedaquiline, delamanid, and linezolid in
M.
tuberculosis
isolates from Uzbekistan. WGS provided rapid and accurate
detection of resistance-associated mutations, supporting early clinical decision-
making. Although rare discrepancies exist, the overall agreement validates the
use of genotypic methods in routine diagnostics. Adoption of WGS in TB
programs may significantly reduce diagnostic delays and improve treatment
outcomes for MDR/XDR-TB patients. These results encourage national
implementation of molecular diagnostics and development of updated
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resistance mutation panels for the detection of emerging forms of drug
resistance in TB management.
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