Mixed Infections and Drug Resistance in Mycobacterium tuberculosis

Mycobacterium tuberculosis remains a leading cause of infectious mortality worldwide, with drug resistance presenting an escalating challenge to global control efforts. Mixed infections, in which two or more genetically distinct strains co-exist within a single host, can drive the emergence and amplification of resistant populations. Such co-infections complicate diagnosis, as standard phenotypic assays and genotyping techniques may miss minority variants, and they undermine the efficacy of treatment regimens when resistant and sensitive strains respond differently to therapy. Advances in whole-genome sequencing and statistical deconvolution methods have begun to reveal the true prevalence of mixed infections, illuminating their role in transmission dynamics, treatment failure and the rise of multidrug-resistant tuberculosis (MDR-TB). A deeper understanding of mixed infection biology is essential for refining diagnostic algorithms, tailoring individualised therapy and informing public-health strategies to interrupt transmission of resistant lineages.

Research from Nature Portfolio

Recent large-scale whole-genome analyses of over 50 000 M. tuberculosis isolates have uncovered that about 1% of samples harbour mixed sub-lineage infections, including combinations of drug-resistant and pan-sensitive strains. The deployment of Gaussian mixture modelling to deconvolute sequence data has achieved over 93% accuracy in predicting lineage-specific resistance profiles, enabling precise characterisation of heteroresistant infections at lineage resolution. Earlier work using variable-number tandem repeat profiling of clinical samples demonstrated that more than half of patients can carry multiple strains, nearly half displaying divergent drug-susceptibility patterns, and that such heteroresistance correlates strongly with treatment failure. Investigations in high-burden urban settings have further shown that a majority of drug-resistant cases among previously treated patients arise from exogenous reinfection rather than acquired resistance, underscoring the need for transmission-focused interventions.

Mixed Infections and Drug Resistance in Mycobacterium tuberculosis publication trend

The graph below shows the total number of articles in mixed infections and drug resistance in mycobacterium tuberculosis across all publications each year (not limited to Nature Index journals).

Technical terms

Mixed infection: Co-existence of two or more genetically distinct M. tuberculosis strains in a single host.

Heteroresistance: Presence of both drug-resistant and drug-sensitive bacterial subpopulations within the same clinical sample.

MDR-TB (Multidrug-resistant tuberculosis): TB caused by strains resistant to at least isoniazid and rifampicin.

Whole-genome sequencing (WGS): High-throughput DNA sequencing that captures the complete genetic material of an organism.

Variable-number tandem repeat (VNTR) typing: Molecular method that assesses the number of short repeat units at multiple genomic loci for strain differentiation.

Gaussian mixture model (GMM): Statistical approach that represents a distribution of data points as a combination of multiple normal distributions, used here to deconvolute mixed genetic signals.

References

1. Mixed infections in genotypic drug-resistant Mycobacterium tuberculosis. Scientific Reports (2023).
2. Whole-Genome Sequencing Exhibits Better Diagnostic Performance than Variable-Number Tandem Repeats for Identifying Mixed Infections of Mycobacterium tuberculosis. Microbiology Spectrum (2023).
3. Identifying mixed Mycobacterium tuberculosis infections from whole genome sequence data. BMC Genomics (2018).
4. Evaluation of the impact of polyclonal infection and heteroresistance on treatment of tuberculosis patients. Scientific Reports (2017).
5. QuantTB – a method to classify mixed Mycobacterium tuberculosis infections within whole genome sequencing data. BMC Genomics (2020).
6. Transmission is a Noticeable Cause of Resistance Among Treated Tuberculosis Patients in Shanghai, China. Scientific Reports (2017).