Linearmycins are lytic membrane-targeting antibiotics

Stubbendieck, Reed M.; Brock, Dakota J.; Pellois, Jean‐Philippe; Gill, Jason J.; Straight, Paul D.

doi:10.1038/s41429-017-0005-z

Cited by 19 publications

(12 citation statements)

References 53 publications

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“…Linearmycins and ECO-02301 lyse B. subtilis cells, whereas amphotericin B and nystatin do not (Stubbendieck and Straight, 2017). The activity of linearmycins on B. subtilis cells is due to cytoplasmic membrane depolarization (Stubbendieck et al, 2018). Our experimental results [following established protocols described in te Winkel et al (2016)] showed that amphotericin B at a concentration of 10 µg ml −1 and nystatin at 83 µg ml −1 do not depolarize the B. subtilis cytoplasmic membrane (data not shown).…”

Section: Investigation Of the Whole-cell Biosensor Specificitymentioning

confidence: 65%

Amphotericin B Specifically Induces the Two-Component System LnrJK: Development of a Novel Whole-Cell Biosensor for the Detection of Amphotericin-Like Polyenes

et al. 2020

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The rise of drug-resistant fungal pathogens urges for the development of new tools for the discovery of novel antifungal compounds. Polyene antibiotics are potent agents against fungal infections in humans and animals. They inhibit the growth of fungal cells by binding to sterols in the cytoplasmic membrane that subsequently causes pore formation and eventually results in cell death. Many polyenes are produced by Streptomycetes and released into the soil environment, where they can then target fungal hyphae. While not antibacterial, these compounds could nevertheless be also perceived by bacteria sharing the same habitat and serve as signaling molecules. We therefore addressed the question of how polyenes such as amphotericin B are perceived by the soil bacterium, Bacillus subtilis. Global transcriptional profiling identified a very narrow and specific response, primarily resulting in strong upregulation of the lnrLMN operon, encoding an ABC transporter previously associated with linearmycin resistance. Its strong and specific induction prompted a detailed analysis of the lnrL promoter element and its regulation. We demonstrate that the amphotericin response strictly depends on the two-component system LnrJK and that the target of LnrKdependent gene regulation, the lnrLMN operon, negatively affects LnrJK-dependent signal transduction. Based on this knowledge, we developed a novel whole-cell biosensor, based on a P lnrL-lux fusion reporter construct in a lnrLMN deletion mutant background. This highly sensitive and dynamic biosensor is ready to be applied for the discovery or characterization of novel amphotericin-like polyenes, hopefully helping to increase the repertoire of antimycotic and antiparasitic polyenes available to treat human and animal infections.

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Section: Investigation Of the Whole-cell Biosensor Specificitymentioning

confidence: 65%

Amphotericin B Specifically Induces the Two-Component System LnrJK: Development of a Novel Whole-Cell Biosensor for the Detection of Amphotericin-Like Polyenes

et al. 2020

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“…This class of natural products commonly exhibits antibiotic and/or antifungal activity. The linearmycins were found to inhibit the growth of several Gram-positive bacteria and lyse Bacillus species by directly targeting the cytoplasmic membrane (64). A role in vesicle biogenesis within producing Streptomyces spp.…”

Section: Discussionmentioning

confidence: 99%

Response of Secondary Metabolism of Hypogean Actinobacterial Genera to Chemical and Biological Stimuli

Covington

Spraggins

Yñigez-Gutierrez

et al. 2018

Appl Environ Microbiol

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Microorganisms within microbial communities respond to environmental challenges by producing biologically active secondary metabolites, yet the majority of these small molecules remain unidentified. We have previously demonstrated that secondary metabolite biosynthesis in actinomycetes can be activated by model environmental chemical and biological stimuli, and metabolites can be identified by comparative metabolomics analyses between stimuli conditions. Herein, we survey the secondary metabolite productivity of a group of 20 phylogenetically diverse actinobacteria isolated from hypogean (cave) environments by applying a battery of stimuli consisting of exposure to antibiotics, metals, and mixed microbial culture. Comparative metabolomics was used to reveal secondary metabolite responses from stimuli. These analyses revealed substantial changes in global metabolomic dynamics with over 30 % of metabolomic features increasing more than 10-fold under at least one stimulus condition. Selected features were isolated and identified via NMR, revealing several known secondary metabolite families including the tetarimycins, aloesaponarins, hypogeamicins, actinomycins, and propeptins. One prioritized metabolite was identified to be a previously unreported aminopolyol polyketide, funisamine, produced by a cave isolate when exposed to mixed culture. The production of funisamine was most significantly increased in mixed culture with sp. The biosynthetic gene cluster responsible for the production of funisamine was identified via genomic sequencing of the producing strain, sp. KDCAGE35, which facilitated deduction of its biosynthesis. Together, these data demonstrate that comparative metabolomics can reveal the stimulus-induced production of natural products from diverse microbial phylogenies. Microbial secondary metabolites are an important source of biologically active and therapeutically relevant small molecules. However, much of this active molecular diversity is challenging to access due to low production levels or difficulty in discerning secondary metabolites within complex microbial extracts prior to isolation. Herein we demonstrate that ecological stimuli increase secondary metabolite production in phylogenetically diverse actinobacteria isolated from understudied hypogean environments. Additionally, we show that comparative metabolomics linking stimuli to metabolite response data can effectively reveal secondary metabolites within complex biological extracts. This approach highlighted secondary metabolites in almost all observed natural product classes, including low abundance analogs of biologically relevant metabolites, as well as a new linear aminopolyol polyketide, funisamine. This study demonstrates the generality of activating stimuli to potentiate secondary metabolite production across diverse actinobacterial genera.

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“…For example, Streptomyces spp. produce linear polyketides (linearmycins) that depolarize the membrane ( Stubbendieck and Straight, 2015 , 2017 ; Stubbendieck et al, 2018 ). Linearmycins strongly activate the LnrJK TCS that regulates an ABC transporter, LnrLMN ( Stubbendieck and Straight, 2017 ; Revilla-Guarinos et al, 2020 ).…”

Section: Cell Envelope Stress Responses That Function Through Membrane Proteinsmentioning

confidence: 99%

Mini Review: Bacterial Membrane Composition and Its Modulation in Response to Stress

Willdigg

Helmann

2021

Front. Mol. Biosci.

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Antibiotics and other agents that perturb the synthesis or integrity of the bacterial cell envelope trigger compensatory stress responses. Focusing on Bacillus subtilis as a model system, this mini-review summarizes current views of membrane structure and insights into how cell envelope stress responses remodel and protect the membrane. Altering the composition and properties of the membrane and its associated proteome can protect cells against detergents, antimicrobial peptides, and pore-forming compounds while also, indirectly, contributing to resistance against compounds that affect cell wall synthesis. Many of these regulatory responses are broadly conserved, even where the details of regulation may differ, and can be important in the emergence of antibiotic resistance in clinical settings.

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Linearmycins are lytic membrane-targeting antibiotics

Cited by 19 publications

References 53 publications

Amphotericin B Specifically Induces the Two-Component System LnrJK: Development of a Novel Whole-Cell Biosensor for the Detection of Amphotericin-Like Polyenes

Amphotericin B Specifically Induces the Two-Component System LnrJK: Development of a Novel Whole-Cell Biosensor for the Detection of Amphotericin-Like Polyenes

Response of Secondary Metabolism of Hypogean Actinobacterial Genera to Chemical and Biological Stimuli

Mini Review: Bacterial Membrane Composition and Its Modulation in Response to Stress

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