Genetic Analysis and Manipulation of Polyene Antibiotic Gene Clusters as a Way to Produce More Effective Antifungal Compounds

Letek, Michal; Mateos, Luís M.; Gil, José A.

doi:10.1007/978-3-642-40444-3_7

Cited by 3 publications

(5 citation statements)

References 161 publications

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“…To identify the active molecule, we analyzed the HPLC-purified sample by UV absorbance and ESI-mass spectrometry. The molecule showed strong UV absorbances at 319, 333, and 351 nm, indicative of a conjugated pentaene moiety [ 33 ]. We found that the observed mass, 1166.7 [M+H] + ( S1A Fig ) and the UV absorbance profile are consistent with linearmycin B ( Fig 1D ), a linear polyene antibiotic produced by Streptomyces sp.…”

Section: Resultsmentioning

confidence: 99%

Escape from Lethal Bacterial Competition through Coupled Activation of Antibiotic Resistance and a Mobilized Subpopulation

Stubbendieck

Straight

2015

PLoS Genet

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Bacteria have diverse mechanisms for competition that include biosynthesis of extracellular enzymes and antibiotic metabolites, as well as changes in community physiology, such as biofilm formation or motility. Considered collectively, networks of competitive functions for any organism determine success or failure in competition. How bacteria integrate different mechanisms to optimize competitive fitness is not well studied. Here we study a model competitive interaction between two soil bacteria: Bacillus subtilis and Streptomyces sp. Mg1 (S. Mg1). On an agar surface, colonies of B. subtilis suffer cellular lysis and progressive degradation caused by S. Mg1 cultured at a distance. We identify the lytic and degradative activity (LDA) as linearmycins, which are produced by S. Mg1 and are sufficient to cause lysis of B. subtilis. We obtained B. subtilis mutants spontaneously resistant to LDA (LDAR) that have visibly distinctive morphology and spread across the agar surface. Every LDAR mutant identified had a missense mutation in yfiJK, which encodes a previously uncharacterized two-component signaling system. We confirmed that gain-of-function alleles in yfiJK cause a combination of LDAR, changes in colony morphology, and motility. Downstream of yfiJK are the yfiLMN genes, which encode an ATP-binding cassette transporter. We show that yfiLMN genes are necessary for LDA resistance. The developmental phenotypes of LDAR mutants are genetically separable from LDA resistance, suggesting that the two competitive functions are distinct, but regulated by a single two-component system. Our findings suggest that a subpopulation of B. subtilis activate an array of defensive responses to counter lytic stress imposed by competition. Coordinated regulation of development and antibiotic resistance is a streamlined mechanism to promote competitive fitness of bacteria.

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Section: Resultsmentioning

confidence: 99%

Escape from Lethal Bacterial Competition through Coupled Activation of Antibiotic Resistance and a Mobilized Subpopulation

Stubbendieck

Straight

2015

PLoS Genet

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“…mainly synthesized by Streptomycetes and related Actinobacteria. These compounds have been a focus of scientific interest since their discovery in the 1950s, and, thus far, more than 200 members have been discovered (3). Some polyene macrolides, such as amphotericin B (4), nystatin (5), candicidin (6,7), and natamycin (8), have been used as antifungal drugs or preservative agents.…”

mentioning

confidence: 99%

Identification and Predictions Regarding the Biosynthesis Pathway of Polyene Macrolides Produced by Streptomyces roseoflavus Men-myco-93-63

Han

Wang

Liu

et al. 2021

Appl Environ Microbiol

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A group of polyene macrolides mainly composed of two constituents was isolated from the fermentation broth of Streptomyces roseoflavus Men-myco-93-63, which was isolated from soil where potato scabs were repressed naturally. One of this macrolides was roflamycoin, which was first reported in 1968, and the other was a novel compound named Men-myco-A, which had one methylene unit more than roflamycoin. Together, they were designated RM. This group of antibiotics exhibited broad-spectrum antifungal activities in vitro against 17 plant pathogenic fungi with 50% effective concentration (EC50) values of 2.05-7.09 μg/mL and 90% effective concentration (EC90) values of 4.32-54.45 μg/mL, which indicates their potential use in plant disease control. Furthermore, their biosynthetic gene cluster was identified, and the associated biosynthetic assembly line was proposed based on a module and domain analysis of polyketide synthases (PKSs) and supported by findings from gene inactivation experiments. Importance Streptomyces roseoflavus Men-myco-93-63 is a biocontrol strain that has been studied in our laboratory for many years and exhibits a good inhibitory effect in many crop diseases. Therefore, the identification of antimicrobial metabolites is necessary and our main objective. In this work, chemical, bioinformatic and molecular biological methods were combined to identify the structures and biosynthesis of the active metabolites. This work provides a new alternative agent for the biological control of plant diseases and is helpful for improving both the properties and yield of the antibiotics via genetic engineering.

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“…New and known polyenes have been isolated from previously unexplored sources, such as marine microorganisms and rare actinomycetes (Letek et al, 2014). Prolific producers have been found among symbionts of ants that culture and exploit fungal species (Haeder et al, 2009;Barke et al, 2010;Seipke et al, 2011a).…”

Section: Genes For Polyene Macrolide Biosynthesismentioning

confidence: 99%

“…Engineering of PKS and late genes has delivered several analogues of pimaricin, amphotericin B, nystatin, candicidin and rimocidin. Much of this work has been reviewed previously (Caffrey et al, 2008;Kong et al, 2013;Letek et al, 2014;Aparicio, 2016). Of the biosynthetically engineered polyene analogues, the most promising are those in which the free carboxyl group is replaced by a methyl group.…”

Section: Production Of Polyene Analogues By Chemical and Biological Mmentioning

confidence: 99%

“…Improved analogues have been made by chemical methods and by genetic manipulation of producer micro-organisms (Cereghetti and Carreira, 2006). There have been several comprehensive reviews on polyene biosynthesis over the past few years (Caffrey et al, 2008;Kong et al, 2013;Letek et al, 2014;Aparicio et al, 2016). The field advances rapidly and genome sequences of many polyene producers are now available.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Polyene macrolide biosynthesis in streptomycetes and related bacteria: recent advances from genome sequencing and experimental studies

Caffrey

Poire

Sheehan

et al. 2016

Appl Microbiol Biotechnol

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Genetic Analysis and Manipulation of Polyene Antibiotic Gene Clusters as a Way to Produce More Effective Antifungal Compounds

Cited by 3 publications

References 161 publications

Escape from Lethal Bacterial Competition through Coupled Activation of Antibiotic Resistance and a Mobilized Subpopulation

Escape from Lethal Bacterial Competition through Coupled Activation of Antibiotic Resistance and a Mobilized Subpopulation

Identification and Predictions Regarding the Biosynthesis Pathway of Polyene Macrolides Produced by Streptomyces roseoflavus Men-myco-93-63

Polyene macrolide biosynthesis in streptomycetes and related bacteria: recent advances from genome sequencing and experimental studies

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