Shipworm symbiosis ecology-guided discovery of an antibiotic that kills colistin-resistant Acinetobacter

Miller, Bailey W.; Lim, Albebson L.; Lin, Zhenjian; Bailey, Jeannie F.; Aoyagi, Kari L.; Fisher, Mark A.; Barrows, Louis R.; Manoil, Colin; Schmidt, Eric W.; Haygood, Margo G.

doi:10.1016/j.chembiol.2021.05.003

Cited by 16 publications

(18 citation statements)

References 43 publications

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“…In previous work with A. baylyi and A. baumannii , we and others found that lethal mutations affecting outer membrane biogenesis, including LOS and protein localization, led to a distinctive terminal morphology in which bacteria accumulated as chains of rounded cells ( 55 , 56 ). The phenotype suggests defects in lateral peptidoglycan synthesis and cell separation.…”

Section: Resultsmentioning

confidence: 90%

Genetic Dissection of Antibiotic Adjuvant Activity

Bailey

Gallagher

Barker

et al. 2022

mBio

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Section: Resultsmentioning

confidence: 90%

Genetic Dissection of Antibiotic Adjuvant Activity

Bailey

Gallagher

Barker

et al. 2022

mBio

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“…In contrast to most of the cases exposed until now, Teredinibacter turnerae , the γ-proteobacterial endosymbiont responsible for the biosynthesis of the natural products isolated in several species of shipworms (as well as for the supply of the lignocellulosic enzymes required to sustain their host lifestyle) is culturable, a fact that has enormously facilitated its study. T. turnerae natural products show remarkable biological activities, as in the case of the turnercyclamycins ( Figure 3 ), cyclic lipopeptides displaying biological activity against the life-threatening ESKAPE pathogen Acinetobacter baumannii [ 67 ]. T. turnerae is also able to produce boronated polyketides belonging to the tartrolon class [ 68 , 69 ], with tartrolon E displaying a antibiotic activity in the nanomolar range against a wide diversity of apicomplexan parasites [ 70 ].…”

Section: Bacterial Symbionts Of Marine Invertebratesmentioning

confidence: 99%

Beyond Soil-Dwelling Actinobacteria: Fantastic Antibiotics and Where to Find Them

Santos‐Aberturas

Vior

2022

Antibiotics

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Bacterial secondary metabolites represent an invaluable source of bioactive molecules for the pharmaceutical and agrochemical industries. Although screening campaigns for the discovery of new compounds have traditionally been strongly biased towards the study of soil-dwelling Actinobacteria, the current antibiotic resistance and discovery crisis has brought a considerable amount of attention to the study of previously neglected bacterial sources of secondary metabolites. The development and application of new screening, sequencing, genetic manipulation, cultivation and bioinformatic techniques have revealed several other groups of bacteria as producers of striking chemical novelty. Biosynthetic machineries evolved from independent taxonomic origins and under completely different ecological requirements and selective pressures are responsible for these structural innovations. In this review, we summarize the most important discoveries related to secondary metabolites from alternative bacterial sources, trying to provide the reader with a broad perspective on how technical novelties have facilitated the access to the bacterial metabolic dark matter.

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“…Because of the polyphyletic nature of these hydroxylases, well-performing pHMMs could not be made using the standard workflow used for other pathways (Figure S1); even after many iterations, non-metallophore NRPs were captured as false positives, such as the β-OHAsp-containing lipopeptide turnercyclamycin. 28 Instead, pHMM construction was guided by a phylogenetic tree of β-hydroxylases from NRPS BGCs (Figure S2). Clades likely to be involved in metallophore biosyntheses were located using known genes from reported BGCs, 26,27 and by the presence of nearby metallophore-specific transporter families (vide infra).…”

Section: Detection Of β-Hydroxyamino Acidsmentioning

confidence: 99%

Automated genome mining predicts combinatorial diversity and taxonomic distribution of peptide metallophore structures

Reitz

Butler

Medema

2022

Preprint

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Microbial competition for trace metals shapes their communities and interactions with humans and plants. Many bacteria scavenge trace metals with metallophores, small molecules that chelate environmental metal ions and transport them back into the cell. Our incomplete knowledge of metallophores diversity stymies our ability to fight infectious diseases and harness beneficial microbiome interactions. The majority of known metallophores are non-ribosomal peptides (NRPs), which feature metal-chelating moieties rarely found in other classes of natural products. NRP metallophore production may be predicted by genome mining, where genomes are scanned for homologs of known biosynthetic gene clusters (BGCs). However, accurately detecting NRP metallophore biosynthesis currently requires expert manual inspection. Here, we introduce automated identification of NRP metallophore BGCs through a comprehensive detection algorithm, newly implemented in antiSMASH. Custom-designed profile hidden Markov models detect genes encoding the biosynthesis of most known NRP metallophore chelating moieties (2,3-dihydroxybenzoate, hydroxamates, salicylate, β-hydroxyamino acids, graminine, Dmaq, and the pyoverdine chromophore), achieving 97% precision and 78% recall against manual curation. We leveraged the algorithm, in combination with transporter gene detection, to detect NRP metallophore BGCs in 15,562 representative bacterial genomes and predict that 25% of all non-ribosomal peptide synthetases encode metallophore production. BiG-SCAPE clustering of 2,562 NRP metallophore BGCs revealed that significant diversity remains unexplored, including new combinations of chelating groups. Additionally, we find that Cyanobacteria are severely understudied and should be the focus of more metallophore isolation efforts. The inclusion of NRP metallophore detection in antiSMASH version 7 will aid non-expert researchers and facilitate large-scale investigations into metallophore biology.

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Shipworm symbiosis ecology-guided discovery of an antibiotic that kills colistin-resistant Acinetobacter

Cited by 16 publications

References 43 publications

Genetic Dissection of Antibiotic Adjuvant Activity

Genetic Dissection of Antibiotic Adjuvant Activity

Beyond Soil-Dwelling Actinobacteria: Fantastic Antibiotics and Where to Find Them

Automated genome mining predicts combinatorial diversity and taxonomic distribution of peptide metallophore structures

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