Dataset Information

Combination of gallium(iii) with acetate for combating antibiotic resistant Pseudomonas aeruginosa.

ABSTRACT: Gallium(iii) has been widely used as a diagnostic and therapeutic agent in clinics for the treatment of various diseases, in particular, Ga-based drugs have been exploited as antimicrobials to combat the crisis of antimicrobial resistance. The therapeutic properties of Ga(iii) are believed to be attributable to its chemical similarity to Fe(iii). However, the molecular mechanisms of action of gallium remain unclear. Herein, by integrating metalloproteomics with metabolomics and transcriptomics, we for the first time identified RpoB and RpoC, two subunits of RNA polymerase, as Ga-binding proteins in Pseudomonas aeruginosa. We show that Ga(iii) targets the essential transcription enzyme RNA polymerase to suppress RNA synthesis, resulting in reduced metabolic rates and energy utilization. Significantly, we show that exogenous supplementation of acetate could enhance the antimicrobial activity of Ga(iii), evidenced by the inhibited growth of persister cells and attenuated bacterial virulence. The effectiveness of co-therapy of Ga(iii) and acetate was further validated in mammalian cell and murine skin infection models, which is attributable to enhanced uptake of Ga(iii), and reduced TCA cycle flow and bacterial respiration. Our study provides novel insights into the mechanistic understanding of the antimicrobial activity of Ga(iii) and offers a safe and practical strategy of using metabolites to enhance the efficacy of Ga(iii)-based antimicrobials to fight drug resistance.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6585600 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Combination of gallium(iii) with acetate for combating antibiotic resistant <i>Pseudomonas aeruginosa</i>.

Wang Yuchuan Y Han Bingjie B Xie Yanxuan Y Wang Haibo H Wang Runming R Xia Wei W Li Hongyan H Sun Hongzhe H

Chemical science 20190502 24

Gallium(iii) has been widely used as a diagnostic and therapeutic agent in clinics for the treatment of various diseases, in particular, Ga-based drugs have been exploited as antimicrobials to combat the crisis of antimicrobial resistance. The therapeutic properties of Ga(iii) are believed to be attributable to its chemical similarity to Fe(iii). However, the molecular mechanisms of action of gallium remain unclear. Herein, by integrating metalloproteomics with metabolomics and transcriptomics, ...[more]

PMID: 31360415

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Project description:BackgroundPseudomonas aeruginosa is a ubiquitous environmental microorganism and also a common cause of infection. Its ability to survive in many different environments and persistently colonize humans is linked to its presence in biofilms formed on indwelling device surfaces. Biofilm promotes adhesion to, and survival on surfaces, protects from desiccation and the actions of antibiotics and disinfectants.ResultsWe examined the genetic basis for biofilm production on polystyrene at room (22 °C) and body temperature (37 °C) within 280 P. aeruginosa. 193 isolates (69 %) produced more biofilm at 22 °C than at 37 °C. Using GWAS and pan-GWAS, we found a number of accessory genes significantly associated with greater biofilm production at 22 °C. Many of these are present on a 165 kb region containing genes for heavy metal resistance (arsenic, copper, mercury and cadmium), transcriptional regulators and methytransferases. We also discovered multiple core genome SNPs in the A-type flagellin gene and Type II secretion system gene xpsD. Analysis of biofilm production of isolates of the MDR ST111 and ST235 lineages on stainless-steel revealed several accessory genes associated with enhanced biofilm production. These include a putative translocase with homology to a Helicobacter pylori type IV secretion system protein, a TA system II toxin gene and the alginate biosynthesis gene algA, several transcriptional regulators and methytransferases as well as core SNPs in genes involved in quorum sensing and protein translocation.ConclusionsUsing genetic association approaches we discovered a number of accessory genes and core-genome SNPs that were associated with enhanced early biofilm formation at 22 °C compared to 37 °C. These included a 165 kb genomic island containing multiple heavy metal resistance genes, transcriptional regulators and methyltransferases. We hypothesize that this genomic island may be associated with overall genotypes that are environmentally adapted to survive at lower temperatures. Further work to examine their importance in, for example gene-knockout studies, are required to confirm their relevance. GWAS and pan-GWAS approaches have great potential as a first step in examining the genetic basis of novel bacterial phenotypes.

Project description:UnlabelledPseudomonas aeruginosa is an antibiotic-refractory pathogen with a large genome and extensive genotypic diversity. Historically, P. aeruginosa has been a major model system for understanding the molecular mechanisms underlying type I clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated protein (CRISPR-Cas)-based bacterial immune system function. However, little information on the phylogenetic distribution and potential role of these CRISPR-Cas systems in molding the P. aeruginosa accessory genome and antibiotic resistance elements is known. Computational approaches were used to identify and characterize CRISPR-Cas systems within 672 genomes, and in the process, we identified a previously unreported and putatively mobile type I-C P. aeruginosa CRISPR-Cas system. Furthermore, genomes harboring noninhibited type I-F and I-E CRISPR-Cas systems were on average ~300 kb smaller than those without a CRISPR-Cas system. In silico analysis demonstrated that the accessory genome (n = 22,036 genes) harbored the majority of identified CRISPR-Cas targets. We also assembled a global spacer library that aided the identification of difficult-to-characterize mobile genetic elements within next-generation sequencing (NGS) data and allowed CRISPR typing of a majority of P. aeruginosa strains. In summary, our analysis demonstrated that CRISPR-Cas systems play an important role in shaping the accessory genomes of globally distributed P. aeruginosa isolates.ImportanceP. aeruginosa is both an antibiotic-refractory pathogen and an important model system for type I CRISPR-Cas bacterial immune systems. By combining the genome sequences of 672 newly and previously sequenced genomes, we were able to provide a global view of the phylogenetic distribution, conservation, and potential targets of these systems. This analysis identified a new and putatively mobile P. aeruginosa CRISPR-Cas subtype, characterized the diverse distribution of known CRISPR-inhibiting genes, and provided a potential new use for CRISPR spacer libraries in accessory genome analysis. Our data demonstrated the importance of CRISPR-Cas systems in modulating the accessory genomes of globally distributed strains while also providing substantial data for subsequent genomic and experimental studies in multiple fields. Understanding why certain genotypes of P. aeruginosa are clinically prevalent and adept at horizontally acquiring virulence and antibiotic resistance elements is of major clinical and economic importance.

Dataset Information

Combination of gallium(iii) with acetate for combating antibiotic resistant Pseudomonas aeruginosa.

Publications

Combination of gallium(iii) with acetate for combating antibiotic resistant <i>Pseudomonas aeruginosa</i>.

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