Abstract
Bacteria that encounter antibiotics can efficiently change their physiology to develop resistance. This intrinsic antibiotic resistance is mediated by multiple pathways, including a regulatory system(s) that activates specific genes. In some Streptomyces and Mycobacterium spp., the WblC/WhiB7 transcription factor is required for intrinsic resistance to translation-targeting antibiotics. Wide conservation of WblC/WhiB7 within Actinobacteria indicates a critical role of WblC/WhiB7 in developing resistance to such antibiotics. Here, we identified 312 WblC target genes in Streptomyces coelicolor, a model antibiotic-producing bacterium, using a combined analysis of RNA sequencing and chromatin immunoprecipitation sequencing. Interestingly, WblC controls many genes involved in translation, in addition to previously identified antibiotic resistance genes. Moreover, WblC promotes translation rate during antibiotic stress by altering the ribosome-associated protein composition. Our genome-wide analyses highlight a previously unappreciated antibiotic resistance mechanism that modifies ribosome composition and maintains the translation rate in the presence of sub-MIC levels of antibiotics.IMPORTANCE The emergence of antibiotic-resistant bacteria is one of the top threats in human health. Therefore, we need to understand how bacteria acquire resistance to antibiotics and continue growth even in the presence of antibiotics. Streptomyces coelicolor, an antibiotic-producing soil bacterium, intrinsically develops resistance to translation-targeting antibiotics. Intrinsic resistance is controlled by the WblC/WhiB7 transcription factor that is highly conserved within Actinobacteria, including Mycobacterium tuberculosis Here, identification of the WblC/WhiB7 regulon revealed that WblC/WhiB7 controls ribosome maintenance genes and promotes translation in the presence of antibiotics by altering the composition of ribosome-associated proteins. Also, the WblC-mediated ribosomal alteration is indeed required for resistance to translation-targeting antibiotics. This suggests that inactivation of the WblC/WhiB7 regulon could be a potential target to treat antibiotic-resistant mycobacteria.
Highlights
Bacteria that encounter antibiotics can efficiently change their physiology to develop resistance
Combined analysis of RNA-seq and ChIP-seq data mbio.asm.org 10. Identified such a large number of genes controlled by WblC, illustrating how Streptomyces develops antibiotic resistance to translation-targeting antibiotics. These include antibiotic export mediated by CmlR2 and Pep [20, 21], antibiotic inactivation by acetylating drugs (Eis and Eis2) [22, 49] or by linearizing the lactone ring (Vgb) [23], and ribosome protection from antibiotics by dislodging tetracycline from the ribosome (TetM) [25] or methylating rRNA (Lrm) [24] (Fig. 8)
We propose these WblC-activated genes involved in translational maintenance as another type of determinant in intrinsic antibiotic resistance, because WblC activates these genes to allow Streptomyces to continue protein synthesis and promote growth at sub-MIC levels of translation-targeting antibiotics (Fig. 5; see Fig. S4 in the supplemental material), thereby contributing to high levels of intrinsic resistance to translation-targeting antibiotics (Fig. 7)
Summary
Bacteria that encounter antibiotics can efficiently change their physiology to develop resistance. ® mbio.asm.org 1 of drugs, an efflux pump decreasing the cytoplasmic concentration of antibiotics, an enzyme(s) inactivating the action of antibiotics, or a physiological adaptation(s) resolving cellular stresses mediated by antibiotics [1, 3] Such intrinsic antibiotic resistance relies on a regulatory protein(s) that activates expression of a specific set of genes in response to antibiotics. Actinomycetes, the genus Streptomyces producing three-fourths of all known antibiotics [4, 5] and pathogenic mycobacteria, including Mycobacterium tuberculosis, are intrinsically resistant to many antibiotics [3, 6] The retention of such intrinsic resistance in both organisms depends on the WblC/WhiB7 transcription factor, which controls expression of several genes involved in antibiotic resistance [7,8,9]. WhiB7 inducers include antibiotics inhibiting DNA replication and metabolism, and physiological stresses inhibiting bacterial growth such as iron starvation, heat shock, and stationary phase [16, 18] that might indirectly affect ribosome availability
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