| Summary: | Bacterial persister cells are phenotypic variants of the wild-type that are highly tolerant to bactericidal antibiotics. It is thought that persister cells may be responsible for recurrent bacterial infections due to the inability of antibiotics to eradicate them. We suggest that the recalcitrance of tuberculosis to antibiotic therapy may be due to the presence of persister cells. To identify genes responsible for persister formation in Mycobacterium tuberculosis, we have
generated high-persister mutants in vitro that produce between 10- and 1,000-fold more persisters than the parental strain. Through whole-genome sequencing and transcriptome analysis, we have identified several candidate genes, some of which are involved in glycerol and fatty acid metabolism. The role of these genes in persister cell formation was tested by overexpression and deletion analysis. We speculated that high-persister mutants might also be selected for in vivo, in clinical
isolates. To address this possibility, we tested longitudinal samples from the same patient as well as a large panel of individual clinical isolates against various classes of antibiotics to which the isolates are known to be susceptible. We have observed up to a 1,000-fold difference in persister level between individual clinical isolates that have identical drug susceptibility. Characterization of in vivo high-persister strains in a macrophage model of tuberculosis infection
demonstrated that strain variation in drug tolerance to certain antibiotics in vitro translates to similar variations ex vivo. Demonstrating that persister formation and in vivo drug tolerance are controlled by the same set of genes is the long-term goal of this research. The information provided here will contribute to the identification of persister genes in M. tuberculosis and may provide insight into new therapies for persister cell eradication.
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