Thirty Years of sRNA-Mediated Regulation in Staphylococcus aureus: From Initial Discoveries to In Vivo Biological Implications

Ménard, Guillaume; Silard, Chloé; Suriray, Marie; Rouillon, Astrid; Augagneur, Yoann

doi:10.3390/ijms23137346

Cited by 17 publications

(7 citation statements)

References 202 publications

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“…They are major regulators or contributors to fine-tune processes including metabolism, virulence, and antibiotic resistance; however, the function of most of them remains unknown (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

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StaphylococcalsRNA IsrR down-regulates methylthiotransferase MiaB under iron-deficient conditions

Barrault,

Leclair,

Kumeko

et al. 2023

Preprint

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Staphylococcus aureusis a major contributor to bacterial-associated mortality, owing to its exceptional adaptability across diverse environments. Iron, vital for most organisms, poses toxicity risks in excess. To manage iron,S. aureus, like many pathogens, employs intricate systems. We have recently identified IsrR as a key regulatory RNA induced during iron starvation. Its role is to curtail the synthesis of non-essential iron-containing proteins under iron-depleted conditions. In this study, we unveil IsrR’s regulatory action on MiaB, an enzyme responsible for methylthio group addition to specific sites on transfer RNAs (tRNAs). We use predictive tools and reporter fusion assays to demonstrate IsrR’s binding to the Shine-Dalgarno sequence ofmiaBRNA, thereby impeding its translation. The effectiveness of IsrR hinges on the integrity of a specific C-rich region. As MiaB is non-essential and contains two [4Fe-4S] clusters, IsrR induction spares iron by downregulatingmiaB. This likely enhancesS. aureusfitness and aids in navigating the host’s nutritional immune defenses.IMPORTANCEIn numerous biotopes, including those found within an infected host, bacteria confront the challenge of iron deficiency. They employ various strategies to adapt to this scarcity of nutrients, one of which involves the regulation of iron-containing proteins through the action of small regulatory RNAs. In our study, we demonstrate how IsrR, a small RNA fromS. aureus, inhibits the translation of MiaB, a tRNA-modifying enzyme containing [Fe-S] clusters. Through this illustration, we shed light on a novel substrate for a small RNA sparing iron, thereby unveiling a way by which bacteria conserve their iron resource.

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Section: Introductionmentioning

confidence: 99%

“…Their estimated number in S. aureus varies from around 50 to a few hundred according to studies. They are major regulators or contributors to fine-tune processes including metabolism, virulence, and antibiotic resistance; however, the function of most of them remains unknown (5–7).…”

Section: Introductionmentioning

confidence: 99%

StaphylococcalsRNA IsrR down-regulates methylthiotransferase MiaB under iron-deficient conditions

Barrault,

Leclair,

Kumeko

et al. 2023

Preprint

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“…Several other sRNAs have been described as pleiotropic modulators of bacterial virulence, such as P. aeruginosa RsmZ, ReaL, ErsA, and SrbA (Liu et al 2022); Staphylococcus aureus RsaA and Teg49 (Menard et al 2022); and E. coli and Salmonella enterica McaS, OmrA, and OxyS (Mitra and Mukhopadhyay 2023). Therefore, whilst most of these sRNAs positively modulate bacterial virulence and biofilm formation, RIT11b was downregulated when B. cenocepacia was infecting C. elegans and its overexpression reduced bacterial virulence and biofilm formation.…”

Section: Discussionmentioning

confidence: 99%

Identification of Burkholderia cenocepacia non-coding RNAs expressed during Caenorhabditis elegans infection

Pita

Feliciano

Leitão

2023

Appl Microbiol Biotechnol

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Small non-coding RNAs (sRNAs) are key regulators of post-transcriptional gene expression in bacteria. Despite the identification of hundreds of bacterial sRNAs, their roles on bacterial physiology and virulence remain largely unknown, as is the case of bacteria of the Burkholderia cepacia complex (Bcc). Bcc is a group of opportunistic pathogens with relatively large genomes that can cause lethal lung infections amongst cystic fibrosis (CF) patients. To characterise sRNAs expressed by Bcc bacteria when infecting a host, the nematode Caenorhabditis elegans was used as an infection model by the epidemic CF strain B. cenocepacia J2315. A total of 108 new and 31 previously described sRNAs with a predicted Rho independent terminator were identified, most of them located on chromosome 1. RIT11b, a sRNA downregulated under C. elegans infection conditions, was shown to directly affect B. cenocepacia virulence, biofilm formation, and swimming motility. RIT11b overexpression reduced the expression of the direct targets dusA and pyrC, involved in biofilm formation, epithelial cell adherence, and chronic infections in other organisms. The in vitro direct interaction of RIT11b with the dusA and pyrC messengers was demonstrated by electrophoretic mobility shift assays. To the best of our knowledge this is the first report on the functional characterization of a sRNA directly involved in B. cenocepacia virulence. Key points • 139 sRNAs expressed by B. cenocepacia during C. elegans infection were identified • The sRNA RIT11b affects B. cenocepacia virulence, biofilm formation, and motility • RIT11b directly binds to and regulates dusA and pyrC mRNAs

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“…The need for novel antimicrobial agents with unique mechanisms of action is particularly evident in the case of Gram-positive pathogens, especially multidrug-resistant (MDR) Staphylococcus aureus (S. aureus) [5,6]. This becomes more evident in infections caused by methicillin-resistant S. aureus (MRSA) or vancomycin-resistant (VRSA) S. aureus, particularly those cases with surgically implanted medical devices like prostheses or catheters, which require assertive treatment strategies often involving surgical removal [7,8]. Additionally, the ability of S. aureus to form biofilms is associated with prolonged and persistent infections, demanding extended treatment durations [8,9].…”

Section: Introductionmentioning

confidence: 99%

Exploring the potential of bis(thiazol-5-yl)phenylmethane derivatives as novel candidates against genetically defined multidrug-resistant Staphylococcus aureus

Kavaliauskas,

Acevedo,

Garcia

et al. 2024

PLoS ONE

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Antimicrobial resistance (AMR) represents an alarming global challenge to public health. Infections caused by multidrug-resistant Staphylococcus aureus (S. aureus) pose an emerging global threat. Therefore, it is crucial to develop novel compounds with promising antimicrobial activity against S. aureus especially those with challenging resistance mechanisms and biofilm formation. Series of bis(thiazol-5-yl)phenylmethane derivatives were evaluated against drug-resistant Gram-positive bacteria. The screening revealed an S. aureus-selective mechanism of bis(thiazol-5-yl)phenylmethane derivatives (MIC 2–64 μg/mL), while significantly lower activity was observed with vancomycin-resistant Enterococcus faecalis (MIC 64 μg/mL) (p<0.05). The most active phenylmethane-based (p-tolyl) derivative, 23a, containing nitro and dimethylamine substituents, and the naphthalene-based derivative, 28b, harboring fluorine and nitro substituents, exhibited strong, near MIC bactericidal activity against S. aureus with genetically defined resistance phenotypes such as MSSA, MRSA, and VRSA and their biofilms. The in silico modeling revealed that most promising compounds 23a and 28b were predicted to bind S. aureus MurC ligase. The 23a and 28b formed bonds with MurC residues at binding site, specifically Ser12 and Arg375, indicating consequential interactions essential for complex stability. The in vitro antimicrobial activity of compound 28b was not affected by the addition of 50% serum. Finally, all tested bis(thiazol-5-yl)phenylmethane derivatives showed favorable cytotoxicity profiles in A549 and THP-1-derived macrophage models. These results demonstrated that bis(thiazol-5-yl)phenylmethane derivatives 23a and 28b could be potentially explored as scaffolds for the development of novel candidates targeting drug-resistant S. aureus. Further studies are also warranted to understand in vivo safety, efficacy, and pharmacological bioavailability of bis(thiazol-5-yl)phenylmethane derivatives.

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Thirty Years of sRNA-Mediated Regulation in Staphylococcus aureus: From Initial Discoveries to In Vivo Biological Implications

Cited by 17 publications

References 202 publications

StaphylococcalsRNA IsrR down-regulates methylthiotransferase MiaB under iron-deficient conditions

StaphylococcalsRNA IsrR down-regulates methylthiotransferase MiaB under iron-deficient conditions

Identification of Burkholderia cenocepacia non-coding RNAs expressed during Caenorhabditis elegans infection

Exploring the potential of bis(thiazol-5-yl)phenylmethane derivatives as novel candidates against genetically defined multidrug-resistant Staphylococcus aureus

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