Synergistic activity of an OmpA inhibitor and colistin against colistin-resistant Acinetobacter baumannii: mechanistic analysis and in vivo efficacy

Parra-Millán, Raquel; Vila-Farrés, Xavier; Ayerbe-Algaba, Rafael; Varese, Monica; Sánchez-Encinales, Viviana; Bayó‐Puxán, Núria; Pachón-Ibáñez, María Eugenia; Teixidó, Meritxell; Vilà, Jordi; Pachón, Jerónimo; Giralt, Ernest; Smani, Younes

doi:10.1093/jac/dky343

Cited by 20 publications

(21 citation statements)

References 31 publications

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“…Few mechanisms have been proposed to the underlying colistin resistance in Ab (Li et al, 2006;Adams et al, 2009;Falagas et al, 2010;Moffatt et al, 2010;Arroyo et al, 2011;Cai et al, 2012;Hood et al, 2013;Parra-Millán et al, 2018;Cafiso et al, 2019), however, no investigations have been conducted so far on the role that sRNAs exert on the biological adaptations of colistin resistance acquisition. Few studies have analyzed the sRNA contribution to the A. baumannii biology and antimicrobial resistance.…”

Section: Introductionmentioning

confidence: 99%

COLRAcinetobacter baumannii sRNA Signatures: Computational Comparative Identification and Biological Targets

et al. 2020

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Multidrug-Resistant (MDR) and Extensively Drug Resistant (XDR) Acinetobacter baumannii (Ab) represent a serious cause of healthcare-associated infections worldwide. Currently, the available treatment options are very restricted and colistin-based therapies are last-line treatments of these infections, even though colistin resistant (COL R) Ab have rarely been isolated yet. In bacteria, small non-coding RNAs (sRNAs) have been implicated in regulatory pathways of different biological functions, however, no knowledge exists about the sRNA role on the biological adaptation in COL R Ab. Our study investigated two Italian XDR isogenic colistin-susceptible/resistant (COL S/R) Ab strain-pairs to discover new sRNA signatures. Comparative sRNA transcriptome (sRNAome) analyses were carried out by Illumina RNA-seq using both a Tru-Seq and a Short Insert library, whilst Ab ATCC 17978 and ACICU Reference Genome assembly, mapping, annotation and statistically significant differential expression (qvalue ≤ 0.01) of the raw reads were performed by the Rockhopper tool. A computational filtering, sorting only similarly statistically significant differentially expressed (DE) sRNAs mapping on the same gene in both COL R Ab isolates was conducted. COL R vs. COL S sRNAome, analyzed integrating the DE sRNAs obtained from the two different libraries, revealed some statistically significant DE sRNAs in COL R Ab. In detail, we found: (i) two different under-expressed cis-acting sRNAs (AbsRNA 1 and AbsRNA 2) mapping in antisense orientation the 16S rRNA gene A1S_r01, (ii) one under-expressed cis-acting sRNA (AbsRNA 3) targeting the A1S_2505 gene (hypothetical protein), (iii) one underexpressed microRNA-size small RNA fragment (AbsRNA 4) and its pre-microAbsRNA 4 targeting the A1S_0501 gene (hypothetical protein), (iv) as well as an over-expressed microRNA-size small RNA fragment (AbsRNA 5) and its pre-microAbsRNA 5 targeting the A1S_3097 gene (signal peptide). Custom TaqMan R probe-based real-time qPCRs validated the expression pattern of the selected sRNA candidates shown by RNA-seq. Furthermore, analysis on sRNA A1S_r01, A1S_2505 as well as the over-expressed A1S_3097 mutants revealed no effects on colistin resistance. Our study, for the

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Section: Introductionmentioning

confidence: 99%

COLRAcinetobacter baumannii sRNA Signatures: Computational Comparative Identification and Biological Targets

et al. 2020

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“…One of these peptides, a cyclic hexapeptide (AOA-2) lacking bactericidal or cytotoxic activities, was able to inhibit GNB adherence to host cells and biofilm formation, thereby preventing the development of infection in vitro and in a murine model of peritoneal sepsis [40]. A further study indicated that this OmpA inhibitor was effective in combination with colistin in an experimental model of severe infection with colistin-resistant A. baumannii strains [43]. This drug discovery program is considered as an initial stage of the development of a novel class of antimicrobial agents, and in this context, CarO emerges as an attractive target for drug design.…”

Section: Discussionmentioning

confidence: 99%

Virulence role of the outer membrane protein CarO in carbapenem-resistant Acinetobacter baumannii

et al. 2020

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“…AOA-2, a cyclic hexapeptide as a blocking agent of AbOmpA without bactericidal activity decreases the adhesion of A. baumannii, Pseudomonas aeruginosa and E. coli to the surfaces of biotic and abiotic, and significantly enhances the sensitivity of A. baumannii to CST at the concentration of 125 μg/ mL. In vivo, the intraperitoneal injection of AOA-2 (10 mg/kg) in combination with CST (10 mg/kg) improved the survival rate of mice with bacteraemia by 20% [72,73]. In addition, some classic antimicrobial peptides (AMPs) interacting with AbOmpA have been gradually discovered, which are a series of endogenous defense peptides to kill bacteria and fungus [74][75][76].…”

Section: Therapeutic Strategies Targeting Abompa Polypeptidementioning

confidence: 99%

Outer membrane protein A (OmpA) as a potential therapeutic target for Acinetobacter baumannii infection

et al. 2020

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Acinetobacter baumannii (A. baumannii) is an important opportunistic pathogen causing serious nosocomial infections, which is considered as the most threatening Gram-negative bacteria (GNB). Outer membrane protein A (OmpA), a major component of outer membrane proteins (OMPs) in GNB, is a key virulence factor which mediates bacterial biofilm formation, eukaryotic cell infection, antibiotic resistance and immunomodulation. The characteristics of OmpA in Escherichia coli (E. coli) have been extensively studied since 1974, but only in recent years researchers started to clarify the functions of OmpA in A. baumannii. In this review, we summarized the structure and functions of OmpA in A. baumannii (AbOmpA), collected novel therapeutic strategies against it for treating A. baumannii infection, and emphasized the feasibility of using AbOmpA as a potential therapeutic target.

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Synergistic activity of an OmpA inhibitor and colistin against colistin-resistant Acinetobacter baumannii: mechanistic analysis and in vivo efficacy

Abstract: We identified a novel class of antimicrobial agents that has proven to be effective in combination with colistin in an experimental model of severe infection by CST-R A. baumannii.

Cited by 20 publications

References 31 publications

COLRAcinetobacter baumannii sRNA Signatures: Computational Comparative Identification and Biological Targets

COLRAcinetobacter baumannii sRNA Signatures: Computational Comparative Identification and Biological Targets

Virulence role of the outer membrane protein CarO in carbapenem-resistant Acinetobacter baumannii

Outer membrane protein A (OmpA) as a potential therapeutic target for Acinetobacter baumannii infection

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