Resource misallocation as a mediator of fitness costs in antibiotic resistance

Antimicrobial resistance poses a threat to global health and the economy. It is widely accepted that, in the absence of antibiotics, drug resistance mutations carry a fitness cost. In the case of rifampicin resistance in fast-growing bacteria, this cost stems from a reduced transcription rate of the RNA polymerase resulting in slower ribosome biosynthesis. However, this relationship does not apply in the slow-growing Mycobacterium tuberculosis, where the true mechanism of fitness cost of rifampicin resistance as well as the impact of compensatory evolution remain unknown. Here we show, using global transcriptomic and proteomic profiling of selected M. tuberculosis mutants and clinical strains, that the fitness cost of rifampicin resistance in M. tuberculosis is the result of the physiological burden caused by aberrant gene expression. We further show that the perceived burden can be increased, effectively suppressing the emergence of drug resistance.