Regulatory Small RNAs as Antimicrobial Drug Targets

RNA-based therapies have emerged as a diverse and potent arsenal for combating multidrug-resistant (MDR) bacteria, specifically emphasizing Enterobacteriaceae exhibiting resistance to beta-lactams, carbapenems (KPC), polymyxins, and methicillin-resistant staphylococcal species. This chapter explores noncoding small RNAs (sRNAs) as promising targets in bacterial pathogens, unraveling their multifaceted roles. We initiate an in-depth examination of the genetic locations of sRNAs, encompassing intergenic and intragenic regions, along with the 5′ and 3′ untranslated regions (UTRs). Special attention is given to sRNAs derived from the 5′ and 3′ UTRs, antisense strands of mRNAs, and more specific localizations such as within operons and the CRISPR/Cas system. The regulatory dynamics of sRNAs are explored comprehensively, covering transcriptional and post-transcriptional aspects. Transcriptional expression focuses on transcription factors (TFs) controlling sRNA expression and the influential role of sigma factors. Two-component systems involved in the biogenesis of sRNAs are highlighted as crucial players in this regulatory scenario. The subsequent exploration shifts to post-transcriptional regulation, unraveling intricate mechanisms such as stability/activity, RNase-mediated processes, RNA-binding protein modulation, and direct interactions between sRNAs and mRNAs. This comprehensive analysis sheds light on the complex regulatory machinery governing sRNA biogenesis. Next, we examine the diverse functions of sRNAs, ranging from inhibition and activation of transcription to target protection, degradation, and sponge effect. This thorough exploration highlights the versatility of sRNAs in modulating bacterial protein expression. The major sRNA regulatory databases are underscored, providing essential resources for researchers. We also address the perspective of using sRNAs as molecular targets in bacteria through current literature. This chapter synthesizes the discussed topics, offering a comprehensive overview of the genetic, regulatory, and functional dimensions of sRNAs in major bacterial pathogens. This exploration contributes to understanding bacterial regulatory networks and underscores the potential of sRNAs as molecular targets in the ongoing battle against antimicrobial resistance (AMR).