Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 61, Issue 11, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00888-17
Keywords
heteroresistance; rpoB; gyrA; rrs; drug-resistant tuberculosis
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Funding
- Doris Duke Charitable Foundation
- National Institute of Allergy and Infectious Diseases (NIAID)
- South African Medical Research Council (SAMRC)
- National Research Foundation (NRF) Research Career Advancement Award
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Multidrug-resistant tuberculosis (TB) presents a major public health dilemma. Heteroresistance, the coexistence of drug-resistant and drug-susceptible strains or of multiple drug-resistant strains with discrete haplotypes, may affect accurate diagnosis and the institution of effective treatment. Subculture, or passage of cells onto fresh growth medium, is utilized to preserve Mycobacterium tuberculosis cell lines and is universally employed in TB diagnostics. The impact of such passages, typically performed in the absence of drug, on drug-resistant subpopulations is hypothesized to vary according to the competitive costs of genotypic resistance-associated variants. We applied ultradeep next-generation sequencing to 61 phenotypically rifampin-monoresistant (n = 17) and preextensively (n = 41) and extensively (n = 3) drug-resistant isolates with presumptive heteroresistance at two time points in serial subculture. We found significant dynamic loss of minor-variant resistant subpopulations across all analyzed resistance-determining regions, including eight isolates (13%) whose antibiogram data would have transitioned from resistant to susceptible for at least one drug through subculture. Surprisingly, some resistance-associated variants appeared to be selected for in subculture.
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