The Antibiotic Resistant Target Seeker (ARTS), an exploration engine for antibiotic cluster prioritization and novel drug target discovery

Abstract

With the rise of multi-drug resistant pathogens and the decline in number of potential new antibiotics in development there is a fervent need to reinvigorate the natural products discovery pipeline. Most antibiotics are derived from secondary metabolites produced by microorganisms and plants. To avoid suicide, an antibiotic producer harbors resistance genes often found within the same biosynthetic gene cluster (BGC) responsible for manufacturing the antibiotic. Existing mining tools are excellent at detecting BGCs or resistant genes in general, but provide little help in prioritizing and identifying gene clusters for compounds active against specific and novel targets. Here we introduce the ‘Antibiotic Resistant Target Seeker’ (ARTS) available at https://arts.ziemertlab.com. ARTS allows for specific and efficient genome mining for antibiotics with interesting and novel targets. The aim of this web server is to automate the screening of large amounts of sequence data and to focus on the most promising strains that produce antibiotics with new modes of action. ARTS integrates target directed genome mining methods, antibiotic gene cluster predictions and ‘essential gene screening’ to provide an interactive page for rapid identification of known and putative targets in BGCs.

Genomics‐driven discovery of a novel self‐resistance mechanism in the echinocandin‐producing fungus Pezicula radicicola

“…Many secondary metabolites are assumed to be agents of chemical defense or offense. These hypotheses are supported by observations that antibiotic resistance genes are common in nature and that the producing‐organisms often have complex self‐resistance mechanisms (Perry et al ., ; Alanjary et al ., ). Evidence that fungal secondary metabolite gene clusters can encode auxiliary target proteins to evade self‐toxicity from their own metabolites is accumulating.…”

Self-immunity guided identification of threonyl-tRNA synthetase as the molecular target of obafluorin, a β-lactone antibiotic

“…Genes encoding immunity determinants commonly co-occur with the biosynthetic loci required for the production of natural product antibiotics, 14 a phenomenon that has inspired recent genome-mining efforts to identify novel scaffolds with known targets. [15][16][17] Comparative genomic analysis of the oba BGC characterized in P. fluorescens ATCC 39502 with other putative 1 BGCs present in the genomes of two P. fluorescens soil isolates, several Burkholderia species and Chitiniphilus shinanonensis DSM Table 1) allowed the identification of a minimal set of genes conserved across all clusters (Fig. 2).…”

“…Using a combination of bioinformatics, mutational analyses, bioassays, and in vitro enzyme assays we identified the gene product ObaO as the immunity determinant of 1, which functions as a resistant isoform of the 1 target ThrRS. Self-immunity guided natural product target discovery has been the subject of much interest in recent years, 16,29 however there are still relatively few examples in which a hitherto unknown target has been identified de novo from its self-immunity determinant. 30,31 Our data demonstrate the utility of this approach, especially in cases such as ours, when the inherent lability of the compound in aqueous solution precludes the generation of spontaneous mutants.…”

Toward Systems Metabolic Engineering of Streptomycetes for Secondary Metabolites Production

“…[26] In addition, an alternative way of mining BGCs is found in the Antibiotics Resistant Target Seeker (ARTS) (https://arts2.ziemertlab.com), which evaluates BGCs based on self-resistance mechanisms of antibiotic producers. [27] ARTS scans genomes for promising BGCs based on known resistances and the presence of duplicated, co-localized housekeeping genes that display an evidence of horizontal gene transfer. In the context of systems metabolic engineering, the identified resistance genes can be used as probes to find novel BGCs without requiring detailed information on the BGC.…”