Bacterial Adaptation to Antibiotics through Regulatory RNAs

Abstract

The extensive use of antibiotics has resulted in a situation where multidrug-resistant pathogens have become a severe menace to human health worldwide. A deeper understanding of the principles used by pathogens to adapt to, respond to, and resist antibiotics would pave the road to the discovery of drugs with novel mechanisms. For bacteria, antibiotics represent clinically relevant stresses that induce protective responses. The recent implication of regulatory RNAs (small RNAs [sRNAs]) in antibiotic response and resistance in several bacterial pathogens suggests that they should be considered innovative drug targets. This minireview discusses sRNA-mediated mechanisms exploited by bacterial pathogens to fight against antibiotics. A critical discussion of the newest findings in the field is provided, with emphasis on the implication of sRNAs in major mechanisms leading to antibiotic resistance, including drug uptake, active drug efflux, drug target modifications, biofilms, cell walls, and lipopolysaccharide (LPS) biosynthesis. Of interest is the lack of knowledge about sRNAs implicated in Gram-positive compared to Gram-negative bacterial resistance.

Keywords: ESKAPE; antibiotic response; antimicrobial resistance; drug targets; gene regulation; multidrug resistance; regulatory RNA; sRNA.

FIG 1

sRNAs regulating antibiotic resistance in bacteria. Mechanisms subjected to sRNA-mediated antibiotic response and resistance were divided into the following five main sections (dotted color boxes): drug uptake (green), active drug efflux (blue), lipopolysaccharide (LPS) and cell wall impairment (orange), biofilm formation (red), and transcription factor (TF) regulation (purple). The antibiotics subjected to sRNA-induced controls are indicated. The sRNA targets involved are presented. Arrows correspond to sRNA-induced target gene expression upregulation; broken lines indicate sRNA-induced target gene downregulation. Riboswitches were excluded. Of interest is the lack of knowledge regarding Gram-positive bacteria relative to Gram-negative bacteria. AMP, antimicrobial peptides.