WhiB7/WblC is a transcriptional factor of actinomycetes conferring intrinsic resistance to multiple translation-inhibitory antibiotics. It positively autoregulates its own transcription in response to the same antibiotics. The presence of a uORF and a potential Rho-independent transcription terminator in the 5′ leader region has suggested a possibility that the whiB7/wblC gene is regulated via a uORF-mediated transcription attenuation. However, experimental evidence for the molecular mechanism to explain how antibiotic stress suppresses the attenuator, if any, and induces transcription of the whiB7/wblC gene has been lacking. Here we report that the 5′ leader sequences of the whiB7/wblC genes in sub-clades of actinomycetes include conserved antiterminator RNA structures. We confirmed that the putative antiterminator in the whiB7/wblC leader sequences of both Streptomyces and Mycobacterium indeed suppresses Rho-independent transcription terminator and facilitates transcription readthrough, which is required for WhiB7/WblC-mediated antibiotic resistance. The antibiotic-mediated suppression of the attenuator can be recapitulated by amino acid starvation, indicating that translational inhibition of uORF by multiple signals is a key to induce whiB7/wblC expression. Our findings of a mechanism leading to intrinsic antibiotic resistance could provide an alternative to treat drug-resistant mycobacteria.
Bibliographical noteFunding Information:
We are grateful to Dr. Mervin Bibb for providing strain M570 and to Dr. Jeong‐Il Oh for providing plasmids pKOTs, pMV306, and strain mc 155. This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning [2017R1A2A1A05000735 to J.‐H.R. and NRF‐2019R1A2C2003460 to E.‐J.L.]. J.‐H.L. was supported by B.K. Plus Fellowship for Biological Sciences at Seoul National University. 2
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ASJC Scopus subject areas
- Molecular Biology