AbstractIndividual bacteria can escape killing by bactericidal antibiotics by becoming dormant. Such cells, also known as persisters, naturally occur in bacterial populations at a low frequency. Here we present the finding that antibiotic-resistance mutations in the rpoB gene, encoding the beta subunit of RNA polymerase, increase the frequency of persisters by orders of magnitude. Furthermore, we show that: i) the persistent state depends on the (p)ppGpp transcriptional program and not on (p)ppGpp itself; ii) the high persistence (hip) is associated with increased populational heterogeneity in transcription; iii) indole overproduction, caused by transcriptional changes in the hip mutants, explains 50-80% of the hip phenotype. We report that the analogous rpoB mutations occur frequently in clinical isolates of Acinetobacter baumannii, Mycobacterium tuberculosis and Staphylococcus aureus, and we demonstrate that one of those rpoB mutations causes high persistence in MRSA. We also show that the RpoB-associated hip phenotype can be reversed by inhibiting protein synthesis.ImportancePersistence is an inevitable consequence of antibiotic usage. Although persistence is not a genetically heritable trait, here we demonstrate for the first time that antibiotic resistance, which is heritable, can promote persistence formation. Our finding that resistance to one antibiotic, rifampicin, can boost persistence to other antibiotics, such as ciprofloxacin and ampicillin, may help explain why certain chronic infections are particularly recalcitrant to antibiotic therapies. Out results also emphasize the need to assess the effects of combination antibiotic therapies on persistence.
Autogenous regulation of the RNA polymerase beta subunit of Escherichia coli occurs at the translational level in vivo.
