Induction of a stable sigma factor SigR by translation-inhibiting antibiotics confers resistance to antibiotics

Abstract

Antibiotic-producing streptomycetes are rich sources of resistance mechanisms against endogenous and exogenous antibiotics. An ECF sigma factor σR (SigR) is known to govern the thiol-oxidative stress response in Streptomyces coelicolor. Amplification of this response is achieved by producing an unstable isoform of σR called σR′. In this work, we present evidence that antibiotics induce the SigR regulon via a redox-independent pathway, leading to antibiotic resistance. The translation-inhibiting antibiotics enhanced the synthesis of stable σR, eliciting a prolonged response. WblC/WhiB7, a WhiB-like DNA-binding protein, is responsible for inducing sigRp1 transcripts encoding the stable σR. The amount of WblC protein and its binding to the sigRp1 promoter in vivo increased upon antibiotic treatment. A similar phenomenon appears to exist in Mycobacterium tuberculosis as well. These findings reveal a novel antibiotic-induced resistance mechanism conserved among actinomycetes, and also give an explicit example of overlap in cellular damage and defense mechanisms between thiol-oxidative and anti- translational stresses.

Regulation of antimicrobial resistance by extracytoplasmic function (ECF) sigma factors

“…One other S. coelicolor ECF sigma factor, σ R , has been tied to antibiotic resistance [96]. In the presence of translation-inhibiting antibiotics such as chloramphenicol and erythromycin, expression of a stable isoform of σ R increases [96].…”

“…In the presence of translation-inhibiting antibiotics such as chloramphenicol and erythromycin, expression of a stable isoform of σ R increases [96]. A sigR mutant is more sensitive than the parent strain to the antibiotics that induce σ R expression, but is not more sensitive to unrelated antibiotics, such as ampicillin [96].…”

“…In the presence of translation-inhibiting antibiotics such as chloramphenicol and erythromycin, expression of a stable isoform of σ R increases [96]. A sigR mutant is more sensitive than the parent strain to the antibiotics that induce σ R expression, but is not more sensitive to unrelated antibiotics, such as ampicillin [96]. The σ R response is therefore likely to induce expression of genes that are important for specifically responding to stalled translation, but antibiotic resistance genes within the σ R regulon have yet to be identified.…”

13. Reactivity of iron-sulfur clusters with nitric oxide

“…Based on phenotypic analysis, WhiD is required for the late stages of sporulation, whereas, disruption of wblC lead to mutants that were hypersensitive to antibiotics, as observed for M. tuberculosis whiB7 mutants [185,186]. Recent work by Yoo et al [187] showed that WblC (WhiB7) induces a stable isoform of the ECF sigma (σ) factor R that governs thiol-oxidative stress, and, that WblC binding to the sigRp1 promoter responds to antibiotic treatment in vivo. A similar phenomenon appears to exist in M. tuberculosis, suggesting an important role for WblC/WhiB7 in innate antibiotic resistance [187].…”

“…Recent work by Yoo et al [187] showed that WblC (WhiB7) induces a stable isoform of the ECF sigma (σ) factor R that governs thiol-oxidative stress, and, that WblC binding to the sigRp1 promoter responds to antibiotic treatment in vivo. A similar phenomenon appears to exist in M. tuberculosis, suggesting an important role for WblC/WhiB7 in innate antibiotic resistance [187].…”