Networks of Resistance: Small RNA Control of Antibiotic Resistance

Recent high-throughput profiling of the RNA interactome has provided snapshots of the regulatory complexity controlled by small (s)RNAs that are rapidly expressed in response to acute antimicrobial stress. Antibiotic-induced regulatory sRNAs control mRNAs involved in essential processes of the bacterial cell envelope and cell-wide physiological changes that promote tolerant bacterial lifestyles. These sRNA-dependant responses have been shown to significantly contribute to antibiotic susceptibility. The golden age of antibiotics has passed, and the threat of untreatable antimicrobial resistant infections is now a reality for many individuals. Understanding how bacteria resist antimicrobial treatment and regulate gene expression in response to antibiotics is an important step towards combating resistance. In this review we focus on a ubiquitous class of bacterial gene regulators termed regulatory small RNAs (sRNAs) and how they contribute to antimicrobial resistance and tolerance. Small RNAs have notable roles in modulating the composition of the bacterial envelope, and through these functions control intrinsic antimicrobial resistance in many human pathogens. Recent technical advances that allow profiling of the ‘sRNA interactome’ have revealed a complex post-transcriptional network of sRNA interactions that can be used to identify network hubs and regulatory bottlenecks. Sequence-specific inhibition of these sRNAs with programmable RNA-targeting therapeutics may present avenues for treating antimicrobial resistant pathogens or resensitizing to our current antibiotics. The golden age of antibiotics has passed, and the threat of untreatable antimicrobial resistant infections is now a reality for many individuals. Understanding how bacteria resist antimicrobial treatment and regulate gene expression in response to antibiotics is an important step towards combating resistance. In this review we focus on a ubiquitous class of bacterial gene regulators termed regulatory small RNAs (sRNAs) and how they contribute to antimicrobial resistance and tolerance. Small RNAs have notable roles in modulating the composition of the bacterial envelope, and through these functions control intrinsic antimicrobial resistance in many human pathogens. Recent technical advances that allow profiling of the ‘sRNA interactome’ have revealed a complex post-transcriptional network of sRNA interactions that can be used to identify network hubs and regulatory bottlenecks. Sequence-specific inhibition of these sRNAs with programmable RNA-targeting therapeutics may present avenues for treating antimicrobial resistant pathogens or resensitizing to our current antibiotics. a group of antibiotics that contain amino groups bonded to carbohydrates. Aminoglycosides bind to the bacterial 30S ribosomal subunit to disrupt protein synthesis; examples are gentamicin and neomycin. a phenotype that allows a bacterium or population of bacteria to withstand transient exposure to an antimicrobial. short synthetic oligomers that hybridize to a specific complementary target RNA sequence to inhibit or manipulate gene expression. a dense surface-associated bacterial community encased within an extracellular matrix composed of polysaccharides, nucleic acids, and cell debris. Biofilms are commonly found in hospital settings and medical devices such as urinary catheters. a large group of antibiotics derived from the mould Cephalosporium that are used to treat Gram-positive bacteria and some Gram-negative bacteria; examples are cephalexin and ceftobiprole. well-characterized in the Gram-negative model E. coli, class I sRNAs are induced during the bacterial stress response and bind to the proximal face and rim sites on the chaperone protein Hfq, as well as base-pairing to ARN-rich sequences of target mRNAs. By contrast, class II sRNAs base-pair with AU-rich sequences of target mRNAs and act as 'silencers'. a group of glycosylated non-ribosomal peptides that were originally identified in various species of soil actinomycetes. Glycopeptides inhibit bacterial cell-wall synthesis by interfering with peptidoglycan formation; examples are vancomycin and teicoplanin. antibiotic resistance that does not involve the exchange of mobile genetic elements (acquired antibiotic resistance). Intrinsic antibiotic resistance is the innate ability of a bacterium to survive antibiotic stress. a molecule found in the outer membrane of Gram-negative bacteria that is composed of lipid and polysaccharide. LPS also functions as an endotoxin. the lowest concentration of an antimicrobial agent that inhibits the growth of a bacterium. an essential sugar precursor of the bacterial cell-wall peptidoglycan. Also see peptidoglycan. a complex heteropolymer of the bacterial cell wall. Peptidoglycan comprises a network of crosslinked glycan chains composed of alternating N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) moieties. a physiological characteristic where cells become dormant in bacteria such as S. aureus and uropathogenic E. coli (UPEC) to withstand stresses such as antibiotic treatment. a selective channel protein that is embedded in the outer membrane of Gram-negative bacteria. Porins facilitates the transport of charged ions across the membrane into the periplasmic space. the regulatory noncoding RNA element of an mRNA (commonly found in the 5′UTR) that controls the expression of mRNA in response to a specific ligand molecule. a type of synthetic broad-spectrum antimicrobial agent that contains a functional sulfonamide group. Examples are sulfadiazine and dapsone.