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Acyl Histidines: New N-Acyl Amides from Legionella pneumophila.

ABSTRACT: Legionella pneumophila, the causative agent of Legionnaires' disease, is a Gram-negative gammaproteobacterial pathogen that infects and intracellularly replicates in human macrophages and a variety of protozoa. L.?pneumophila encodes an orphan biosynthetic gene cluster (BGC) that contains isocyanide-associated biosynthetic genes and is upregulated during infection. Because isocyanide-functionalized metabolites are known to harbor invertebrate innate immunosuppressive activities in bacterial pathogen-insect interactions, we used pathway-targeted molecular networking and tetrazine-based chemoseletive ligation chemistry to characterize the metabolites from the orphan pathway in L.?pneumophila. We also assessed their intracellular growth contributions in an amoeba and in murine bone-marrow-derived macrophages. Unexpectedly, two distinct groups of aromatic amino acid-derived metabolites were identified from the pathway, including a known tyrosine-derived isocyanide and a family of new N-acyl-l-histidine metabolites.

SUBMITTER: Torring T

PROVIDER: S-EPMC5546091 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Acyl Histidines: New N-Acyl Amides from Legionella pneumophila.

Tørring Thomas T Shames Stephanie R SR Cho Wooyoung W Roy Craig R CR Crawford Jason M JM

Chembiochem : a European journal of chemical biology 20170306 7

Legionella pneumophila, the causative agent of Legionnaires' disease, is a Gram-negative gammaproteobacterial pathogen that infects and intracellularly replicates in human macrophages and a variety of protozoa. L. pneumophila encodes an orphan biosynthetic gene cluster (BGC) that contains isocyanide-associated biosynthetic genes and is upregulated during infection. Because isocyanide-functionalized metabolites are known to harbor invertebrate innate immunosuppressive activities in bacterial path ...[more]

PMID: 28116768

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Project description:Legionnaires' disease is a potentially fatal pneumonia caused by Legionella pneumophila, an aquatic bacterium often found within the biofilm niche. In man-made water systems microbial biofilms increase the resistance of legionella to disinfection, posing a significant threat to public health. Disinfection methods currently used in water systems have been shown to be ineffective against legionella over the long-term, allowing recolonization by the biofilm-protected microorganisms. In this study, the anti-biofilm activity of previously fabricated polyamino-phenolic ligands and polyamidoamine dendrimers was investigated against legionella mono-species and multi-species biofilms formed by L. pneumophila in association with other bacteria that can be found in tap water (Aeromonas hydrophila, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae). Bacterial ability to form biofilms was verified using a crystal violet colorimetric assay and testing cell viability by real-time quantitative PCR and Plate Count assay. The concentration of the chemicals tested as anti-biofilm agents was chosen based on cytotoxicity assays: the highest non-cytotoxic chemical concentration was used for biofilm inhibition assays, with dendrimer concentration 10-fold higher than polyamino-phenolic ligands. While Macrophen and Double Macrophen were the most active substances among polyamino-phenolic ligands, dendrimers were overall twofold more effective than all other compounds with a reduction up to 85 and 73% of legionella and multi-species biofilms, respectively. Chemical interaction with matrix molecules is hypothesized, based on SEM images and considering the low or absent anti-microbial activity on planktonic bacteria showed by flow cytometry. These data suggest that the studied compounds, especially dendrimers, could be considered as novel molecules in the design of research projects aimed at the development of efficacious anti-biofilm disinfection treatments of water systems in order to minimize legionellosis outbreaks.

Project description:UnlabelledA total of 30 Legionella pneumophila serogroup 1 isolates representing 10 separate legionellosis laboratory investigations ("outbreaks") that occurred in New York State between 2004 and 2012 were selected for evaluation of whole-genome sequencing (WGS) approaches for molecular subtyping of this organism. Clinical and environmental isolates were available for each outbreak and were initially examined by pulsed-field gel electrophoresis (PFGE). Sequence-based typing alleles were extracted from WGS data yielding complete sequence types (ST) for isolates representing 8 out of the 10 outbreaks evaluated in this study. Isolates from separate outbreaks sharing the same ST also contained the fewest differences in core genome single nucleotide polymorphisms (SNPs) and the greatest proportion of identical allele sequences in a whole-genome multilocus sequence typing (wgMLST) scheme. Both core SNP and wgMLST analyses distinguished isolates from separate outbreaks, including those from two outbreaks sharing indistinguishable PFGE profiles. Isolates from a hospital-associated outbreak spanning multiple years shared indistinguishable PFGE profiles but displayed differences in their genome sequences, suggesting the presence of multiple environmental sources. Finally, the rtx gene demonstrated differences in the repeat region sequence among ST1 isolates from different outbreaks, suggesting that variation in this gene may be useful for targeted molecular subtyping approaches for L. pneumophila This study demonstrates the utility of various genome sequence analysis approaches for L. pneumophila for environmental source attribution studies while furthering the understanding of Legionella ecology.ImportanceWe demonstrate that whole-genome sequencing helps to improve resolution of Legionella pneumophila isolated during laboratory investigations of legionellosis compared to traditional subtyping methods. These data can be important in confirming the environmental sources of legionellosis outbreaks. Moreover, we evaluated various methods to analyze genome sequence data to help resolve outbreak-related isolates.

Dataset Information

Acyl Histidines: New N-Acyl Amides from Legionella pneumophila.

Publications

Acyl Histidines: New N-Acyl Amides from Legionella pneumophila.

Similar Datasets

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