Drug resistance in M.tb is commonly believed to be caused by
single-step mutations, but there is now evidence to suggest that, at
least for certain anti-TB drugs, it is the result of a stepwise
acquisition of mutations leading to a gradual decrease in
susceptibility. The first step in this process may involve a mutation
that does not increase the MIC of a drug above the breakpoint for
clinical resistance. These findings highlight the importance of
unveiling the full spectrum of resistance mechanisms towards a
particular drug. However, low-level resistance is often overlooked
because it is not generally thought to be associated with a higher
likelihood of therapeutic failure. Low-level mutants can, nonetheless,
be selected in the presence of suboptimal antibiotic
concentrations and serve as a gateway for the amplification of
resistance.2