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Discovery of cationic nonribosomal peptides as Gram-negative antibiotics through global genome mining.

ABSTRACT: The worldwide prevalence of infections caused by antibiotic-resistant Gram-negative bacteria poses a serious threat to public health due to the limited therapeutic alternatives. Cationic peptides represent a large family of antibiotics and have attracted interest due to their diverse chemical structures and potential for combating drug-resistant Gram-negative pathogens. Here, we analyze 7395 bacterial genomes to investigate their capacity for biosynthesis of cationic nonribosomal peptides with activity against Gram-negative bacteria. Applying this approach, we identify two novel compounds (brevicidine and laterocidine) showing bactericidal activities against antibiotic-resistant Gram-negative pathogens, such as Pseudomonas aeruginosa and colistin-resistant Escherichia coli, and an apparently low risk of resistance. The two peptides show efficacy against E. coli in a mouse thigh infection model. These findings may contribute to the discovery and development of Gram-negative antibiotics.

SUBMITTER: Li YX

PROVIDER: S-EPMC6095874 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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Discovery of cationic nonribosomal peptides as Gram-negative antibiotics through global genome mining.

Li Yong-Xin YX Zhong Zheng Z Zhang Wei-Peng WP Qian Pei-Yuan PY

Nature communications 20180816 1

The worldwide prevalence of infections caused by antibiotic-resistant Gram-negative bacteria poses a serious threat to public health due to the limited therapeutic alternatives. Cationic peptides represent a large family of antibiotics and have attracted interest due to their diverse chemical structures and potential for combating drug-resistant Gram-negative pathogens. Here, we analyze 7395 bacterial genomes to investigate their capacity for biosynthesis of cationic nonribosomal peptides with a ...[more]

PMID: 30115920

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Project description:BackgroundAntibiotic resistance in bacteria spreads quickly, overtaking the pace at which new compounds are discovered and this emphasizes the immediate need to discover new compounds for control of infectious diseases. Terrestrial bacteria have for decades been investigated as a source of bioactive compounds leading to successful applications in pharmaceutical and biotech industries. Marine bacteria have so far not been exploited to the same extent; however, they are believed to harbor a multitude of novel bioactive chemistry. To explore this potential, genomes of 21 marine Alpha- and Gammaproteobacteria collected during the Galathea 3 expedition were sequenced and mined for natural product encoding gene clusters.ResultsIndependently of genome size, bacteria of all tested genera carried a large number of clusters encoding different potential bioactivities, especially within the Vibrionaceae and Pseudoalteromonadaceae families. A very high potential was identified in pigmented pseudoalteromonads with up to 20 clusters in a single strain, mostly NRPSs and NRPS-PKS hybrids. Furthermore, regulatory elements in bioactivity-related pathways including chitin metabolism, quorum sensing and iron scavenging systems were investigated both in silico and in vitro. Genes with siderophore function were identified in 50% of the strains, however, all but one harboured the ferric-uptake-regulator gene. Genes encoding the syntethase of acylated homoserine lactones were found in Roseobacter-clade bacteria, but not in the Vibrionaceae strains and only in one Pseudoalteromonas strains. The understanding and manipulation of these elements can help in the discovery and production of new compounds never identified under regular laboratory cultivation conditions. High chitinolytic potential was demonstrated and verified for Vibrio and Pseudoalteromonas species that commonly live in close association with eukaryotic organisms in the environment. Chitin regulation by the ChiS histidine-kinase seems to be a general trait of the Vibrionaceae family, however it is absent in the Pseudomonadaceae. Hence, the degree to which chitin influences secondary metabolism in marine bacteria is not known.ConclusionsUtilizing the rapidly developing sequencing technologies and software tools in combination with phenotypic in vitro assays, we demonstrated the high bioactive potential of marine bacteria in an efficient, straightforward manner - an approach that will facilitate natural product discovery in the future.

Dataset Information

Discovery of cationic nonribosomal peptides as Gram-negative antibiotics through global genome mining.

Publications

Discovery of cationic nonribosomal peptides as Gram-negative antibiotics through global genome mining.

Similar Datasets

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