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Abstract
The emergence of antibiotic resistance mechanisms among bacterial pathogens increases the demand for novel treatment strategies. Lately, the contribution of non-coding RNAs to antibiotic resistance and their potential value as drug targets became evident. RNA attenuator elements in mRNA leader regions couple expression of resistance genes to the presence of the cognate antibiotic. Trans-encoded small RNAs (sRNAs) modulate antibiotic tolerance by base-pairing with mRNAs encoding functions important for resistance such as metabolic enzymes, drug efflux pumps, or transport proteins. Bacteria respond with extensive changes of their sRNA repertoire to antibiotics. Each antibiotic generates a unique sRNA profile possibly causing downstream effects that may help to overcome the antibiotic challenge. In consequence, regulatory RNAs including sRNAs and their protein interaction partners such as Hfq may prove useful as targets for antimicrobial chemotherapy. Indeed, several compounds have been developed that kill bacteria by mimicking ligands for riboswitches controlling essential genes, demonstrating that regulatory RNA elements are druggable targets. Drugs acting on sRNAs are considered for combined therapies to treat infections. In this review, we address how regulatory RNAs respond to and establish resistance to antibiotics in bacteria. Approaches to target RNAs involved in intrinsic antibiotic resistance or virulence for chemotherapy will be discussed.
Highlights
The emergence and spread of resistance to antibiotics represent a major threat for human health and urgently call for novel antimicrobial compounds and therapies
Efforts to find novel treatment options have focussed on bacterial proteins as drug targets, whereas exploiting regulatory RNA elements was only considered of late
We introduce recent advances in bacterial RNA research demonstrating the impact of various non-coding RNAs (ncRNAs) classes on the resistance and tolerance to antimicrobials and discuss suitability of these riboregulators for antimicrobial chemotherapy
Summary
The emergence and spread of resistance to antibiotics represent a major threat for human health and urgently call for novel antimicrobial compounds and therapies. There is accumulating evidence that trans-encoded sRNAs are key players in regulatory circuits controlling antibiotic resistance (Table 1) These circuits govern various processes (Figure 2), including functions required for antibiotic uptake (Pulvermacher et al, 2009; Salvail et al, 2013; Kim et al, 2015; Lalaouna et al, 2015), modifications of the cell envelope shielding against antimicrobials (Moon and Gottesman, 2009; Acuna et al, 2016), drug efflux pumps expelling antibiotics (Nishino et al, 2011; Parker and Gottesman, 2016), metabolic enzymes conferring resistance (Khan et al, 2016), production of biofilms protecting from antibiotics (Serra et al, 2016) and DNA mutagenesis mechanisms facilitating evolution of novel resistances (Gutierrez et al, 2013).
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