Abstract
The length and complexity of tuberculosis (TB) therapy, as well as the propensity of
to develop drug resistance, are major barriers to global TB control efforts.
is known to have the ability to enter into a drug-tolerant state, which may explain many of these impediments to TB treatment. We have identified a mechanism of genetically encoded but rapidly reversible drug tolerance in
caused by transient frameshift mutations in a homopolymeric tract (HT) of 7 cytosines (7C) in the
gene. Inactivating frameshift mutations associated with the 7C HT in
produce small colonies that exhibit heritable multidrug increases in minimal inhibitory concentrations and decreases in drug-dependent killing; however, reversion back to a fully drug-susceptible large-colony phenotype occurs rapidly through the introduction of additional insertions or deletions in the same
HT region. These reversible frameshift mutations in the 7C HT of
occur in clinical isolates, accumulate in
-infected mice with further accumulation during drug treatment, and exhibit a reversible transcriptional profile including induction of
and
and repression of
regulons, similar to that observed in other in vitro models of
tolerance. These results suggest that GlpK phase variation may contribute to drug tolerance, treatment failure, and relapse in human TB. Drugs effective against phase-variant
may hasten TB treatment and improve cure rates.