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.

Discovery of Small‐Molecule Antibiotics against a Unique tRNA‐Mediated Regulation of Transcription in Gram‐Positive Bacteria

“…The emergence of pathogens resistant to commonly used clinical antibiotics has resulted in a surge of research for new targets and novel, “evolution proof” antibiotics . Regulators of translation and transcription are possible targets for emergent pathogens resistant to commonly used clinical antibiotics . Structural and biochemical properties of tRNA interactions with cognate aminoacyl‐tRNA synthetases, the “second code”, differ between bacterial pathogens and the human host.…”

“…[52,53] Regulators of translation and transcription are possible targets for emergent pathogens resistant to commonly used clinicala ntibiotics. [9,54] Structurala nd biochemical properties of tRNA interactions with cognatea minoacyl-tRNA synthetases, the "second code", differ between bacterialp athogens and the human host. These differences have already been exploited with the bacterial isoleucyl-tRNA synthetase inhibitorM upirocin, and hold promise for other inhibitors.…”

“…New antibiotics are needed to improve the therapeutic outcomes of single‐ and multidrug‐resistant Gram‐positive infections . Antibiotics currently in clinical use function by blocking cell wall, protein, or DNA synthesis, or by inhibiting critical metabolic pathways . Most of these molecules bind to one or two cellular targets, enabling bacteria to rapidly evolve mechanisms to circumvent their mode of action.…”

“…[1,4,7,8] Antibiotics currently in clinical use function by blocking cell wall, protein, or DNA synthesis, or by inhibiting critical metabolic pathways. [8,9] Most of these molecules bind to one or two cellulart argets, enabling bacteria to rapidly evolve mechanisms to circumvent their mode of action. Recently approved antibiotics against MRSA and other drug-resistant Gram-positive pathogens generally recapitulate the strategies and basic chemistries of established therapeutics, and therefore could soon prove ineffective.…”

Host Peptidic Hormones Affecting Bacterial Biofilm Formation and Virulence

“…The medical consequence for the infected host is the persistency of chronic infections in organs in which the biofilm is established [3]. While the molecular mechanisms that allow Gram-negative bacteria to resist to antibiotics within biofilms are well documented, this is not yet the case for Gram-positive bacteria [4, 5]. Based on naturally occurring antimicrobial and host defense peptides, the design of small synthetic peptides with broad-spectrum antibiofilm activity has provided a glimmer of hope in the fight against pan-antibiotic-resistant bacteria, the so-called superbugs [6, 7], providing a really promising start for the development of new antibacterial agents [8].…”