COLRAcinetobacter baumannii sRNA Signatures: Computational Comparative Identification and Biological Targets

Cafiso, Viviana; Stracquadanio, Stefano; Verde, Flavia Lo; Dovere, Veronica; Zega, Alessandra; Pigola, Giuseppe; Aranda, Jesús; Stefani, Stefania

doi:10.3389/fmicb.2019.03075

Cited by 7 publications

(8 citation statements)

References 47 publications

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“…The unstable COL-R phenotype was related by our group to two different onset strategies, i.e., a "COL-inducible" onset phenotype, considered as an "Adaptive Resistance" -in agreement to prior observations [25,26]-and a "Subpopulation" onset phenotype considered as "Heteroresistance" previously described by another group [27]. In our A. baumannii, the "COL-inducible" onset-phenotype emerged via an induction mechanism related to a constant long term colistin exposure, whilst the "Subpopulation" onset-phenotype emerged spontaneously in a subset of populations with higher COL-R levels, detectable as morphological variants with different COL MICs, exclusively in the presence of high COL concentrations (i.e., ≥COL 32/128 mg/L agar plates).…”

Section: Discussionsupporting

confidence: 89%

Colistin Resistance Onset Strategies and Genomic Mosaicism in Clinical Acinetobacter baumannii Lineages

et al. 2021

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The treatment of multidrug-resistant Gram-negative infections is based on colistin. As result, COL-resistance (COL-R) can develop and spread. In Acinetobacter baumannii, a crucial step is to understand COL-R onset and stability, still far to be elucidated. COL-R phenotypic stability, onset modalities, and phylogenomics were investigated in a clinical A. baumannii sample showing a COL resistant (COLR) phenotype at first isolation. COL-R was confirmed by Minimum-Inhibitory-Concentrations as well as investigated by Resistance-Induction assays and Population-Analysis-Profiles (PAPs) to determine: (i) stability; (ii) inducibility; (iii) heteroresistance. Genomics was performed by Mi-Seq Whole-Genome-Sequencing, Phylogenesis, and Genomic Epidemiology by bioinformatics. COLRA. baumannii were subdivided as follows: (i) 3 A. baumannii with stable and high COL MICs defining the “homogeneous-resistant” onset phenotype; (ii) 6 A. baumannii with variable and lower COL MICs displaying a “COL-inducible” onset phenotype responsible for adaptive-resistance or a “subpopulation” onset phenotype responsible for COL-heteroresistance. COL-R stability and onset strategies were not uniquely linked to the amount of LPS and cell envelope charge. Phylogenomics categorized 3 lineages clustering stable and/or unstable COL-R phenotypes with increasing genomic complexity. Likewise, different nsSNP profiling in genes already associated with COL-R marked the stable and/or unstable COL-R phenotypes. Our investigation finds out that A. baumannii can range through unstable or stable COLR phenotypes emerging via different “onset strategies” within phylogenetic lineages displaying increasing genomic mosaicism.

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Section: Discussionsupporting

confidence: 89%

Colistin Resistance Onset Strategies and Genomic Mosaicism in Clinical Acinetobacter baumannii Lineages

et al. 2021

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“…As described in previous studies [ 31 , 32 ], we analyzed the length and secondary structure of genes that could not be aligned with the reference genome and Non-Redundant Protein (NR) database, and obtained 115 candidate sRNAs. We annotated candidate sRNAs using the sRNAMap database and Rfam databases, and identified three known sRNAs, while the remaining 112 were newly discovered sRNAs ( S6 Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Referring to methods described in previous studies [ 32 , 40 ], we first compared the available reads obtained from RNA-seq with a reference genome to obtain known genes using Bowtie2 (version 2.2.8). RNA-seq has been widely used in bacterial transcriptome sequencing owing to its ability for comprehensive and in-depth mining of transcriptome information and functionality [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

sRNA expression profile of KPC-2-producing carbapenem-resistant Klebsiella pneumoniae: Functional role of sRNA51

Bai,

Xie,

Zhang

et al. 2024

PLoS Pathog

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The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) has significant challenges to human health and clinical treatment, with KPC-2-producing CRKP being the predominant epidemic strain. Therefore, there is an urgent need to identify new therapeutic targets and strategies. Non-coding small RNA (sRNA) is a post-transcriptional regulator of genes involved in important biological processes in bacteria and represents an emerging therapeutic strategy for antibiotic-resistant bacteria. In this study, we analyzed the transcription profile of KPC-2-producing CRKP using RNA-seq. Of the 4693 known genes detected, the expression of 307 genes was significantly different from that of carbapenem-sensitive Klebsiella pneumoniae (CSKP), including 133 up-regulated and 174 down-regulated genes. Both the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) analysis showed that these differentially expressed genes (DEGs) were mainly related to metabolism. In addition, we identified the sRNA expression profile of KPC-2-producing CRKP for the first time and detected 115 sRNAs, including 112 newly discovered sRNAs. Compared to CSKP, 43 sRNAs were differentially expressed in KPC-2-producing CRKP, including 39 up-regulated and 4 down-regulated sRNAs. We chose sRNA51, the most significantly differentially expressed sRNA in KPC-2-producing CRKP, as our research subject. By constructing sRNA51-overexpressing KPC-2-producing CRKP strains, we found that sRNA51 overexpression down-regulated the expression of acrA and alleviated resistance to meropenem and ertapenem in KPC-2-producing CRKP, while overexpression of acrA in sRNA51-overexpressing strains restored the reduction of resistance. Therefore, we speculated that sRNA51 could affect the resistance of KPC-2-producing CRKP by inhibiting acrA expression and affecting the formation of efflux pumps. This provides a new approach for developing antibiotic adjuvants to restore the sensitivity of CRKP.

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“…For validation of the expression of sRNA, MW1303 asRNA ( suc A), encoding the alpha-ketoglutarate dehydrogenase, was an essential metabolic gene that was selected for validation because of its high level of overexpression in 1-R versus 1-S [ 66 ]. The genome position and orientation of the MW1303 asRNA is reported in Table 2 .…”

Section: Methodsmentioning

confidence: 99%

New Antimicrobial Resistance Strategies: An Adaptive Resistance Network Conferring Reduced Glycopeptide Susceptibility in VISA

et al. 2023

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Background: Vancomycin-intermediate Staphylococcus aureus (VISA) emerges typically in the healthcare-associated methicillin-resistant S. aureus and more rarely in community-acquired S. aureus (CA-MRSA). VISA is a serious concern for public health due to its association with persistent infections, the failure of vancomycin treatment, and poor clinical outcomes. Currently, the burden of VISA is somewhat high, even though vancomycin is the mainstay treatment for severe MRSA infections. The molecular mechanisms of reduced glycopeptide susceptibility in S. aureus are constantly under investigation but have still not yet been fully characterized. Methods: Our goal was to investigate the reduced glycopeptide susceptibility mechanisms emerging in a VISA CA-MRSA versus its vancomycin-susceptible (VSSA) CA-MRSA parents in a hospitalized patient undergoing glycopeptide treatment. Comparative integrated omics, Illumina MiSeq whole-genome sequencing (WGS), RNA-Seq, and bioinformatics were performed. Results: Through a comparison of VISA CA-MRSA vs. its VSSA CA-MRSA parent, mutational and transcriptomic adaptations were found in a pool of genes involved, directly or indirectly, in the biosynthesis of the glycopeptide target conferring or supporting the VISA phenotype, and its cross-resistance with daptomycin. This pool included key genes responsible for the biosynthesis of the peptidoglycan precursors, i.e., D-Ala, the D-Ala-D-Ala dipeptide termini of the pentapeptide, and its incorporation in the nascent pentapeptide, as key targets of the glycopeptide resistance. Furthermore, accessory glycopeptide-target genes involved in the pathways corroborating the key adaptations, and thus, supporting the acquisition of the VISA phenotype i.e., transporters, nucleotide metabolism genes, and transcriptional regulators. Finally, transcriptional changes were also found in computationally predicted cis-acting small antisense RNA triggering genes related both to the key or accessory adaptive pathways. Conclusion: Our investigation describes an adaptive resistance pathway acquired under antimicrobial therapy conferring reduced glycopeptide susceptibility in a VISA CA-MRSA due to a comprehensive network of mutational and transcriptional adaptations in genes involved in pathways responsible for the biosynthesis of glycopeptide’s target or supporters of the key resistance path.

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COLRAcinetobacter baumannii sRNA Signatures: Computational Comparative Identification and Biological Targets

Cited by 7 publications

References 47 publications

Colistin Resistance Onset Strategies and Genomic Mosaicism in Clinical Acinetobacter baumannii Lineages

Colistin Resistance Onset Strategies and Genomic Mosaicism in Clinical Acinetobacter baumannii Lineages

sRNA expression profile of KPC-2-producing carbapenem-resistant Klebsiella pneumoniae: Functional role of sRNA51

New Antimicrobial Resistance Strategies: An Adaptive Resistance Network Conferring Reduced Glycopeptide Susceptibility in VISA

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