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Review
Small regulatory RNAs as key modulators of antibiotic resistance in pathogenic bacteria
Yubin Yang, Hana Hyeon, Minju Joo, Kangseok Lee, Eunkyoung Shin
J. Microbiol. 2025;63(4):e2501027.   Published online April 2, 2025
DOI: https://doi.org/10.71150/jm.2501027
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  • 8 Download
AbstractAbstract PDF

The escalating antibiotic resistance crisis poses a significant challenge to global public health, threatening the efficacy of current treatments and driving the emergence of multidrug-resistant pathogens. Among the various factors associated with bacterial antibiotic resistance, small regulatory RNAs (sRNAs) have emerged as pivotal post-transcriptional regulators which orchestrate bacterial adaptation to antibiotic pressure via diverse mechanisms. This review consolidates the current knowledge on sRNA-mediated mechanisms, focusing on drug uptake, drug efflux systems, lipopolysaccharides, cell wall modification, biofilm formation, and mutagenesis. Recent advances in transcriptomics and functional analyses have revealed novel sRNAs and their regulatory networks, expanding our understanding of resistance mechanisms. These findings highlight the potential of targeting sRNA-mediated pathways as an innovative therapeutic strategy to combat antibiotic resistance, and offer promising avenues for managing challenging bacterial infections.

Journal Articles
Transcript-specific selective translation by specialized ribosomes bearing genome-encoded heterogeneous rRNAs in V. vulnificus CMCP6
Younkyung Choi , Minju Joo , Wooseok Song , Minho Lee , Hana Hyeon , Hyun-Lee Kim , Ji-Hyun Yeom , Kangseok Lee , Eunkyoung Shin
J. Microbiol. 2022;60(12):1162-1167.   Published online November 24, 2022
DOI: https://doi.org/10.1007/s12275-022-2437-9
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  • 2 Web of Science
  • 2 Crossref
AbstractAbstract
Ribosomes composed of genome-encoded heterogeneous rRNAs are implicated in the rapid adaptation of bacterial cells to environmental changes. A previous study showed that ribosomes bearing the most heterogeneous rRNAs expressed from the rrnI operon (I-ribosomes) are implicated in the preferential translation of a subset of mRNAs, including hspA and tpiA, in Vibrio vulnificus CMCP6. In this study, we show that HspA nascent peptides were predominantly bound to I-ribosomes. Specifically, I-ribosomes were enriched more than two-fold in ribosomes that were pulled down by immunoprecipitation of HspA peptides compared with the proportion of I-ribosomes in crude ribosomes and ribosomes pulled down by immunoprecipitation of RNA polymerase subunit ß peptides in the wild-type (WT) and rrnI-completed strains. Other methods that utilized the incorporation of an affinity tag in 23S rRNA or chimeric rRNA tethering 16S and 23S rRNAs, which generated specialized functional ribosomes in Escherichia coli, did not result in functional I-ribosomes in V. vulnificus CMCP6. This study provides direct evidence of the preferential translation of hspA mRNA by I-ribosomes.

Citations

Citations to this article as recorded by  
  • Functional conservation of specialized ribosomes bearing genome-encoded variant rRNAs in Vibrio species
    Younkyung Choi, Eunkyoung Shin, Minho Lee, Ji-Hyun Yeom, Kangseok Lee, Bashir Sajo Mienda
    PLOS ONE.2023; 18(12): e0289072.     CrossRef
  • Relaxed Cleavage Specificity of Hyperactive Variants of Escherichia coli RNase E on RNA I
    Dayeong Bae, Hana Hyeon, Eunkyoung Shin, Ji-Hyun Yeom, Kangseok Lee
    Journal of Microbiology.2023; 61(2): 211.     CrossRef
Gold nanoparticle-DNA aptamer-assisted delivery of antimicrobial peptide effectively inhibits Acinetobacter baumannii infection in mice
Jaeyeong Park , Eunkyoung Shin , Ji-Hyun Yeom , Younkyung Choi , Minju Joo , Minho Lee , Je Hyeong Kim , Jeehyeon Bae , Kangseok Lee
J. Microbiol. 2022;60(1):128-136.   Published online December 29, 2021
DOI: https://doi.org/10.1007/s12275-022-1620-3
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  • 0 Download
  • 14 Web of Science
  • 15 Crossref
AbstractAbstract
Acinetobacter baumannii causes multidrug resistance, leading to fatal infections in humans. In this study, we showed that Lys AB2 P3-His–a hexahistidine-tagged form of an antimicrobial peptide (AMP) loaded onto DNA aptamer-functionalized gold nanoparticles (AuNP-Apt)–can effectively inhibit A. baumannii infection in mice. When A. baumannii-infected mice were intraperitoneally injected with AuNP-Apt loaded with Lys AB2 P3-His, a marked reduction in A. baumannii colonization was observed in the mouse organs, leading to prominently increased survival time and rate of the mice compared to those of the control mice treated with AuNP-Apt or Lys AB2 P3-His only. This study shows that AMPs loaded onto AuNP-Apt could be an effective therapeutic tool against infections caused by multidrug-resistant pathogenic bacteria in humans.

Citations

Citations to this article as recorded by  
  • Challenges and Emerging Molecular Approaches in Combating Antimicrobial Resistance
    Gene Philip Levee Ynion, Christian Jay Rosal, Arvin Zulueta, Angelo Ordanel, Christopher Marlowe Caipang
    Journal of Bacteriology and Virology.2024; 54(1): 12.     CrossRef
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    Şule Balcı, Bengü Ergüden
    ChemistrySelect.2024;[Epub]     CrossRef
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    María Guadalupe Córdova-Espinoza, Rosa González-Vázquez, Rolando Rafik Barron-Fattel, Raquel Gónzalez-Vázquez, Marco Antonio Vargas-Hernández, Exsal Manuel Albores-Méndez, Ana Laura Esquivel-Campos, Felipe Mendoza-Pérez, Lino Mayorga-Reyes, María Angélica
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    Kamila Botelho Sampaio de Oliveira, Michel Lopes Leite, Nadielle Tamires Moreira Melo, Letícia Ferreira Lima, Talita Cristina Queiroz Barbosa, Nathalia Lira Carmo, Douglas Afonso Bittencourt Melo, Hugo Costa Paes, Octávio Luiz Franco
    Antibiotics.2024; 13(11): 1042.     CrossRef
  • Optimizing Treatment for Carbapenem-Resistant Acinetobacter baumannii Complex Infections: A Review of Current Evidence
    Seong Jin Choi, Eu Suk Kim
    Infection & Chemotherapy.2024; 56(2): 171.     CrossRef
  • Advances in skin gene therapy: utilizing innovative dressing scaffolds for wound healing, a comprehensive review
    Fatemeh Karimzadeh, Elahe Soltani Fard, Akram Nadi, Rahim Malekzadeh, Fatemeh Elahian, Seyed Abbas Mirzaei
    Journal of Materials Chemistry B.2024; 12(25): 6033.     CrossRef
  • Colistin Resistance Mechanism and Management Strategies of Colistin-Resistant Acinetobacter baumannii Infections
    Md Minarul Islam, Da Eun Jung, Woo Shik Shin, Man Hwan Oh
    Pathogens.2024; 13(12): 1049.     CrossRef
  • Progress in Programmable DNA-Aided Self-Assembly of the Master Frame of a Drug Delivery System
    Gary Q. Yang, Weibin Cai, Zhiwen Zhang, Yujun Wang
    ACS Applied Bio Materials.2023; 6(12): 5125.     CrossRef
  • Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas Disease
    Sara M. Robledo, Silvia Pérez-Silanes, Celia Fernández-Rubio, Ana Poveda, Lianet Monzote, Víctor M. González, Paloma Alonso-Collado, Javier Carrión
    Pathogens.2023; 12(7): 939.     CrossRef
  • Applications and Challenges of Bacteriostatic Aptamers in the Treatment of Common Pathogenic Bacteria Infections
    Diandian Li, Yuan Su, Jie Li, Rong Liu, Bing Fang, Jingjing He, Wentao Xu, Longjiao Zhu
    Biomacromolecules.2023; 24(11): 4568.     CrossRef
  • Promising Acinetobacter baumannii Vaccine Candidates and Drug Targets in Recent Years
    Yong Chiang Tan, Chandrajit Lahiri
    Frontiers in Immunology.2022;[Epub]     CrossRef
  • Advances and Perspective on Antimicrobial Nanomaterials for Biomedical Applications
    Preeti Garg, Prerna Attri, Rohit Sharma, Moondeep Chauhan, Ganga Ram Chaudhary
    Frontiers in Nanotechnology.2022;[Epub]     CrossRef
  • Aptamer Decorated Emodin Nanoparticles-Assisted Delivery of Dermcidin-Derived Peptide DCD-1L: Photoactive Bio-Theragnostic Agent for Enterococcus Faecalis Biofilm Destruction
    Maryam Pourhajibagher, Abbas Bahador
    SSRN Electronic Journal .2022;[Epub]     CrossRef
  • Development of DNA aptamers specific for small therapeutic peptides using a modified SELEX method
    Jaemin Lee, Minkyung Ryu, Dayeong Bae, Hong-Man Kim, Seong-il Eyun, Jeehyeon Bae, Kangseok Lee
    Journal of Microbiology.2022; 60(7): 659.     CrossRef
  • Aptamer decorated emodin nanoparticles-assisted delivery of dermcidin-derived peptide DCD-1L: Photoactive bio-theragnostic agent for Enterococcus faecalis biofilm destruction
    Maryam Pourhajibagher, Abbas Bahador
    Photodiagnosis and Photodynamic Therapy.2022; 39: 103020.     CrossRef
Review
Rediscovery of antimicrobial peptides as therapeutic agents
Minkyung Ryu , Jaeyeong Park , Ji-Hyun Yeom , Minju Joo , Kangseok Lee
J. Microbiol. 2021;59(2):113-123.   Published online February 1, 2021
DOI: https://doi.org/10.1007/s12275-021-0649-z
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  • 26 Web of Science
  • 28 Crossref
AbstractAbstract
In recent years, the occurrence of antibiotic-resistant pathogens is increasing rapidly. There is growing concern as the development of antibiotics is slower than the increase in the resistance of pathogenic bacteria. Antimicrobial peptides (AMPs) are promising alternatives to antibiotics. Despite their name, which implies their antimicrobial activity, AMPs have recently been rediscovered as compounds having antifungal, antiviral, anticancer, antioxidant, and insecticidal effects. Moreover, many AMPs are relatively safe from toxic side effects and the generation of resistant microorganisms due to their target specificity and complexity of the mechanisms underlying their action. In this review, we summarize the history, classification, and mechanisms of action of AMPs, and provide descriptions of AMPs undergoing clinical trials. We also discuss the obstacles associated with the development of AMPs as therapeutic agents and recent strategies formulated to circumvent these obstacles.

Citations

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    Muhammad Asif, Shuang Liang, Hu RenJian, Xin Xie, Zhibo Zhao
    Physiological and Molecular Plant Pathology.2025; 136: 102506.     CrossRef
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    Vitor M. de Andrade, Vitor D.M. de Oliveira, Uilla Barcick, Vasanthakumar G. Ramu, Montserrat Heras, Eduard R. Bardají, Miguel A.R.B. Castanho, André Zelanis, Aline Capella, Juliana C. Junqueira, Katia Conceição
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    Przemysław Gagat, Michał Ostrówka, Anna Duda-Madej, Paweł Mackiewicz
    International Journal of Molecular Sciences.2024; 25(19): 10821.     CrossRef
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    The Journal of Membrane Biology.2023; 256(4-6): 317.     CrossRef
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  • Gold nanoparticle-DNA aptamer-assisted delivery of antimicrobial peptide effectively inhibits Acinetobacter baumannii infection in mice
    Jaeyeong Park, Eunkyoung Shin, Ji-Hyun Yeom, Younkyung Choi, Minju Joo, Minho Lee, Je Hyeong Kim, Jeehyeon Bae, Kangseok Lee
    Journal of Microbiology.2022; 60(1): 128.     CrossRef
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    Journal of Microbiology.2022; 60(7): 659.     CrossRef
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Journal Articles
RraAS1 inhibits the ribonucleolytic activity of RNase ES by interacting with its catalytic domain in Streptomyces coelicolor
Sojin Seo , Daeyoung Kim , Wooseok Song , Jihune Heo , Minju Joo , Yeri Lim , Ji-Hyun Yeom , Kangseok Lee
J. Microbiol. 2017;55(1):37-43.   Published online December 30, 2016
DOI: https://doi.org/10.1007/s12275-017-6518-0
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AbstractAbstract
RraA is a protein inhibitor of RNase E, which degrades and processes numerous RNAs in Escherichia coli. Streptomyces coelicolor also contains homologs of RNase E and RraA, RNase ES and RraAS1/RraAS2, respectively. Here, we report that, unlike other RraA homologs, RraAS1 directly interacts with the catalytic domain of RNase ES to exert its inhibitory effect. We further show that rraAS1 gene deletion in S. coelicolor
results
in a higher growth rate and increased production of actinorhodin and undecylprodigiosin, compared with the wild-type strain, suggesting that RraAS1-mediated regulation of RNase ES activity contributes to modulating the cellular physiology of S. coelicolor.

Citations

Citations to this article as recorded by  
  • Identification of the global regulatory roles of RraA via the integrative transcriptome and proteome in Vibrio alginolyticus
    Huizhen Chen, Qian Gao, Bing Liu, Ying Zhang, Jianxiang Fang, Songbiao Wang, Youqi Chen, Chang Chen, Nicolas E. Buchler
    mSphere.2024;[Epub]     CrossRef
  • Streptomyces RNases – Function and impact on antibiotic synthesis
    George H. Jones
    Frontiers in Microbiology.2023;[Epub]     CrossRef
  • Regulator of RNase E activity modulates the pathogenicity of Salmonella Typhimurium
    Jaejin Lee, Eunkyoung Shin, Ji-Hyun Yeom, Jaeyoung Park, Sunwoo Kim, Minho Lee, Kangseok Lee
    Microbial Pathogenesis.2022; 165: 105460.     CrossRef
  • Regulator of ribonuclease activity modulates the pathogenicity of Vibrio vulnificus
    Jaejin Lee, Eunkyoung Shin, Jaeyeong Park, Minho Lee, Kangseok Lee
    Journal of Microbiology.2021; 59(12): 1133.     CrossRef
  • The coordinated action of RNase III and RNase G controls enolase expression in response to oxygen availability in Escherichia coli
    Minho Lee, Minju Joo, Minji Sim, Se-Hoon Sim, Hyun-Lee Kim, Jaejin Lee, Minkyung Ryu, Ji-Hyun Yeom, Yoonsoo Hahn, Nam-Chul Ha, Jang-Cheon Cho, Kangseok Lee
    Scientific Reports.2019;[Epub]     CrossRef
  • RNase G controls tpiA mRNA abundance in response to oxygen availability in Escherichia coli
    Jaejin Lee, Dong-Ho Lee, Che Ok Jeon, Kangseok Lee
    Journal of Microbiology.2019; 57(10): 910.     CrossRef
  • Functional implications of hexameric assembly of RraA proteins from Vibrio vulnificus
    Saemee Song, Seokho Hong, Jinyang Jang, Ji-Hyun Yeom, Nohra Park, Jaejin Lee, Yeri Lim, Jun-Yeong Jeon, Hyung-Kyoon Choi, Minho Lee, Nam-Chul Ha, Kangseok Lee, Eric Cascales
    PLOS ONE.2017; 12(12): e0190064.     CrossRef
  • Crystal structure of Streptomyces coelicolor RraAS2, an unusual member of the RNase E inhibitor RraA protein family
    Nohra Park, Jihune Heo, Saemee Song, Inseong Jo, Kangseok Lee, Nam-Chul Ha
    Journal of Microbiology.2017; 55(5): 388.     CrossRef
RraAS2 requires both scaffold domains of RNase ES for high-affinity binding and inhibitory action on the ribonucleolytic activity
Jihune Heo , Daeyoung Kim , Minju Joo , Boeun Lee , Sojin Seo , Jaejin Lee , Saemee Song , Ji-Hyun Yeom , Nam-Chul Ha , Kangseok Lee
J. Microbiol. 2016;54(10):660-666.   Published online September 30, 2016
DOI: https://doi.org/10.1007/s12275-016-6417-9
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AbstractAbstract
RraA is a protein inhibitor of RNase E (Rne), which catalyzes the endoribonucleolytic cleavage of a large proportion of RNAs in Escherichia coli. The antibiotic‐producing bacterium Streptomyces coelicolor also contains homologs of RNase E and RraA, designated as RNase ES (Rns), RraAS1, and RraAS2, respectively. Here, we report that RraAS2 requires both scaffold domains of RNase ES for high-affinity binding and inhibitory action on the ribonucleolytic activity. Analyses of the steady-state level of RNase E substrates indicated that coexpression of RraAS2 in E. coli cells overproducing Rns effectively inhibits the ribonucleolytic activity of full-length RNase ES, but its inhibitory effects were moderate or undetectable on other truncated forms of Rns, in which the N- or/and C-terminal scaffold domain was deleted. In addition, RraAS2 more efficiently inhibited the in vitro ribonucleolytic activity of RNase ES than that of a truncated form containing the catalytic domain only. Coimmunoprecipitation and in vivo cross-linking experiments further showed necessity of both scaffold domains of RNase ES for high-affinity binding of RraAS2 to the enzyme, resulting in decreased RNA-binding capacity of RNase ES. Our results indicate that RraAS2 is a protein inhibitor of RNase ES and provide clues to how this inhibitor affects the ribonucleolytic activity of RNase ES.

Citations

Citations to this article as recorded by  
  • Identification of the global regulatory roles of RraA via the integrative transcriptome and proteome in Vibrio alginolyticus
    Huizhen Chen, Qian Gao, Bing Liu, Ying Zhang, Jianxiang Fang, Songbiao Wang, Youqi Chen, Chang Chen, Nicolas E. Buchler
    mSphere.2024;[Epub]     CrossRef
  • Streptomyces RNases – Function and impact on antibiotic synthesis
    George H. Jones
    Frontiers in Microbiology.2023;[Epub]     CrossRef
  • Regulator of RNase E activity modulates the pathogenicity of Salmonella Typhimurium
    Jaejin Lee, Eunkyoung Shin, Ji-Hyun Yeom, Jaeyoung Park, Sunwoo Kim, Minho Lee, Kangseok Lee
    Microbial Pathogenesis.2022; 165: 105460.     CrossRef
  • Regulator of ribonuclease activity modulates the pathogenicity of Vibrio vulnificus
    Jaejin Lee, Eunkyoung Shin, Jaeyeong Park, Minho Lee, Kangseok Lee
    Journal of Microbiology.2021; 59(12): 1133.     CrossRef
  • Divergent rRNAs as regulators of gene expression at the ribosome level
    Wooseok Song, Minju Joo, Ji-Hyun Yeom, Eunkyoung Shin, Minho Lee, Hyung-Kyoon Choi, Jihwan Hwang, Yong-In Kim, Ramin Seo, J. Eugene Lee, Christopher J. Moore, Yong-Hak Kim, Seong-il Eyun, Yoonsoo Hahn, Jeehyeon Bae, Kangseok Lee
    Nature Microbiology.2019; 4(3): 515.     CrossRef
  • RraAS1 inhibits the ribonucleolytic activity of RNase ES by interacting with its catalytic domain in Streptomyces coelicolor
    Sojin Seo, Daeyoung Kim, Wooseok Song, Jihune Heo, Minju Joo, Yeri Lim, Ji-Hyun Yeom, Kangseok Lee
    Journal of Microbiology.2017; 55(1): 37.     CrossRef
  • Bdm-Mediated Regulation of Flagellar Biogenesis in Escherichia coli and Salmonella enterica Serovar Typhimurium
    Jaejin Lee, Dae-Jun Kim, Ji-Hyun Yeom, Kangseok Lee
    Current Microbiology.2017; 74(9): 1015.     CrossRef
  • Functional implications of hexameric assembly of RraA proteins from Vibrio vulnificus
    Saemee Song, Seokho Hong, Jinyang Jang, Ji-Hyun Yeom, Nohra Park, Jaejin Lee, Yeri Lim, Jun-Yeong Jeon, Hyung-Kyoon Choi, Minho Lee, Nam-Chul Ha, Kangseok Lee, Eric Cascales
    PLOS ONE.2017; 12(12): e0190064.     CrossRef
  • Crystal structure of Streptomyces coelicolor RraAS2, an unusual member of the RNase E inhibitor RraA protein family
    Nohra Park, Jihune Heo, Saemee Song, Inseong Jo, Kangseok Lee, Nam-Chul Ha
    Journal of Microbiology.2017; 55(5): 388.     CrossRef
Research Support, Non-U.S. Gov't
The α-Barrel Tip Region of Escherichia coli TolC Homologs of Vibrio vulnificus Interacts with the MacA Protein to Form the Functional Macrolide-Specific Efflux Pump MacAB-TolC
Minho Lee , Hyun-Lee Kim , Saemee Song , Minju Joo , Seunghwa Lee , Daeyoung Kim , Yoonsoo Hahn , Nam-Chul Ha , Kangseok Lee
J. Microbiol. 2013;51(2):154-159.   Published online April 27, 2013
DOI: https://doi.org/10.1007/s12275-013-2699-3
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  • 18 Scopus
AbstractAbstract
TolC and its homologous family of proteins are outer membrane factors that are essential for exporting small molecules and toxins across the outer membrane in Gram-negative bacteria. Two open reading frames in the Vibrio vulnificus genome that encode proteins homologous to Escherichia coli TolC, designated TolCV1 and TolCV2, have 51.3% and 29.6% amino acid identity to TolC, respectively. In this study, we show that TolCV1 and TolCV2 functionally and physically interacted with the membrane fusion protein, MacA, a component of the macrolide-specific MacAB-TolC pump of E. coli. We further show that the conserved residues located at the aperture tip region of the α-hairpin of TolCV1 and TolCV2 played an essential role in the formation of the functional MacAB-TolC pump using site-directed mutational analyses. Our findings suggest that these outer membrane factors have conserved tip-to-tip interaction with the MacA membrane fusion protein for action of the drug efflux pump in Gramnegative bacteria.

Journal of Microbiology : Journal of Microbiology
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