A new antibiotic selectively kills Gram-negative pathogens

Imai, Yu; Meyer, Kirsten J.; Iinishi, Akira; Favre-Godal, Quentin; Green, Robert; Manuse, Sylvie; Caboni, Mariaelena; Mori, Miho; Niles, Samantha; Ghiglieri, Meghan; Honrao, Chandrashekhar; Ma, Xiaoyu; Guo, Jason; Makriyannis, Alexandros; Linares-Otoya, Luis; Böhringer, Nils; Wuisan, Zerlina G.; Kaur, Hundeep; Wu, Runrun; Mateus, André; Typas, Athanasios; Savitski, Mikhail M.; Espinoza, Josh L.; O’Rourke, Aubrie; Nelson, Karen E.; Hiller, Sebastian; Noinaj, Nicholas; Schäberle, Till F.; D’Onofrio, Anthony; Lewis, Kim

doi:10.1038/s41586-019-1791-1

Cited by 500 publications

(631 citation statements)

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“…A considerable proportion of matches to biosynthetic genes comes from rare and/or genera only recently described and that are usually recalcitrant to laboratory cultivation. Thus, new approaches to microbial cultivation [93] together with metagenomic strategies involving capture/heterologous expression of cryptic BGCs [94] will be useful to recover this hidden chemistry.…”

Section: Discussionmentioning

confidence: 99%

Diversity of Bacterial Biosynthetic Genes in Maritime Antarctica

et al. 2020

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Bacterial natural products (NPs) are still a major source of new drug leads. Polyketides (PKs) and non-ribosomal peptides (NRP) are two pharmaceutically important families of NPs and recent studies have revealed Antarctica to harbor endemic polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) genes, likely to be involved in the production of novel metabolites. Despite this, the diversity of secondary metabolites genes in Antarctica is still poorly explored. In this study, a computational bioprospection approach was employed to study the diversity and identity of PKS and NRPS genes to one of the most biodiverse areas in maritime Antarctica-Maxwell Bay. Amplicon sequencing of soil samples targeting ketosynthase (KS) and adenylation (AD) domains of PKS and NRPS genes, respectively, revealed abundant and unexplored chemical diversity in this peninsula. About 20% of AD domain sequences were only distantly related to characterized biosynthetic genes. Several PKS and NRPS genes were found to be closely associated to recently described metabolites including those from uncultured and candidate phyla. The combination of new approaches in computational biology and new culture-dependent and -independent strategies is thus critical for the recovery of the potential novel chemistry encoded in Antarctica microorganisms. target the highly conserved ketosynthase (KS) and adenylation (AD) domains of PKS and NRPS genes, respectively. A growing number of studies have employed the PCR-based sequence tag approach to uncover PKS and NRPS gene diversity across different environmental microbiomes [7][8][9].Extreme environments, such as Antarctica, have the potential to reveal novel molecules since they are still a poorly explored source of chemical scaffolds and novel chemical diversity [10,11]. As such, metabarcoding approaches to study PKS and NRPS diversity in Antarctic ecosystems represent a simple and effective strategy to understand the biosynthetic potential of a large number of sampling sites [7]. A couple of such studies have been carried out very recently in Antarctica [12,13] revealing that soils at different Antarctica locations harbor multiple endemic PKS and NRPS genes, likely to be involved in the synthesis of new chemical diversity. In Antarctic soils, the percentage of yet-uncultured genera is expected to be much higher [14] than the 82% described for general soils [15]. A considerable fraction of such uncultured bacteria corresponds to members of the NP-rich Actinobacteria [16,17] and Cyanobacteria [18,19] phyla.King George Island is one of the largest ice-free and biodiverse areas in maritime Antarctica [20]. It harbors a high density of scientific stations, particularly in Maxwell Bay [21], where most of terrestrial biology research takes place. Although bacterial diversity studies have been conducted in this area [22,23], the diversity of bacterial biosynthetic genes has not been a target of study. Here, we perform a detailed study on soil samples from Maxwell Bay, with the main goal of assessing the...

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Section: Discussionmentioning

confidence: 99%

Diversity of Bacterial Biosynthetic Genes in Maritime Antarctica

et al. 2020

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“…In addition, the crude extract containing ADC56 was assigned to CW instead of CM, a common problem with the existing model. ADC56, also known as darobactin, has recently been described as a BamA inhibiter, where BamA is an essential outer membrane protein (18). However, the crude extract containing desota- mide was accurately predicted to be an RS inhibitor, albeit with a low correlation coefficient (0.54) ( Table 2).…”

Section: Antibiotic Classification By Transcriptomic Profilingmentioning

confidence: 99%

Mechanism-of-Action Classification of Antibiotics by Global Transcriptome Profiling

O’Rourke

Beyhan

Choi

et al. 2020

Antimicrob Agents Chemother

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Antimicrobial resistance (AMR) is an ever-growing public health problem worldwide. The low rate of antibiotic discovery coupled with the rapid spread of drug-resistant bacterial pathogens is causing a global health crisis. To facilitate the drug discovery processes, we present a large-scale study of reference antibiotic challenge bacterial transcriptome profiles, which included 37 antibiotics across 6 mechanisms of actions (MOAs) and provide an economical approach to aid in antimicrobial dereplication in the discovery process. We demonstrate that classical MOAs can be sorted based upon the magnitude of gene expression profiles despite some overlap in the secondary effects of antibiotic exposures across MOAs. Additionally, using gene subsets, we were able to subdivide broad MOA classes into subMOAs. Furthermore, we provide a biomarker gene set that can be used to classify most antimicrobial challenges according to their canonical MOA. We also demonstrate the ability of this rapid MOA diagnostic tool to predict and classify the expression profiles of pure compounds and crude extracts to their expression profile-associated MOA class.

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“…Following the logic that antimicrobial compounds could be found in bacteria that share similar requirements for antibiotics with humans, the group of Kim Lewis has discovered darobactin, the first member of a new class of antibiotics that selectively kills Gram-negative bacteria (GNB) [71]. GNB that are common opportunistic pathogens of humans are abundant in the gut microbiome of entomopathogenic nematodes, where GNB are competitors of nematophilic symbiotic bacteria.…”

Section: Highlighted By Diego Muñoz-torreromentioning

confidence: 99%