Biosynthesis of cervimycin C, an aromatic polyketide antibiotic bearing an unusual dimethylmalonyl moiety

Herold, Kerstin; Xu, Zhongli; Gollmick, Friedrich A.; Gräfe, U.; Hertweck, Christian

doi:10.1039/b409221j

Cited by 31 publications

(16 citation statements)

References 19 publications

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“…Labeling studies in our laboratory revealed that this novel dimethylmalonyl unit is derived from valine, and not from a malonate precursor, as one might assume. [37] The results of antimicrobial testing showed that all cervimycins A-D proved to be highly active against various Gram-positive bacteria, such as Bacillus subtilis ATCC 6633, Staphylococcus aureus SG511, and multi-drug-resistant S. aureus 134/93 (MRSA), and displayed potencies comparable to those of tetracycline, vancomycin, and ciprofloxacin (Table 1). More importantly, they are also highly active against efflux-resistant S. aureus EfS4 and vancomycin-resistant Enterococcus faecalis 1528 (VRE) within a MIC range of 1.6-12.5 mg mL À1 , in contrast to tetracycline, vancomycin, or ciprofloxacin, which are ineffective against VRE and EfS4, respectively.…”

Section: Resultsmentioning

confidence: 97%

Cervimycin A–D: A Polyketide Glycoside Complex from a Cave Bacterium Can Defeat Vancomycin Resistance

Herold

Gollmick

Groth

et al. 2005

Chemistry A European J

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Cervimycins A-D are novel polyketide glycosides with significant activity against multi-drug-resistant staphylococci and vancomycin-resistant enterococci. They are produced by a strain of Streptomyces tendae, isolated from an ancient cave. The structures of the cervimycins were determined by performing extensive NMR and chemical degradation studies. All cervimycins have a common tetracyclic polyketide core that is substituted with unusual di- and tetrasaccharide chains, composed exclusively of trideoxysugars; however, they differ in the acetyl and carbamoyl ring substituent and in the highly unusual terminal methylmalonyl and dimethylmalonyl residues.

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Section: Resultsmentioning

confidence: 97%

Cervimycin A–D: A Polyketide Glycoside Complex from a Cave Bacterium Can Defeat Vancomycin Resistance

Herold

Gollmick

Groth

et al. 2005

Chemistry A European J

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“…In the course of a screening program for novel antibiotics from strains obtained from Grotta dei Cervi, a cave in Italy, Herold et al ( 2004 ) identified a bioactive complex, Cervimycins A–D, from a strain of Streptomyces tendae . Cervimycins are potent antibiotics against multidrug resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE) strains (Herold et al, 2005 ).…”

Section: Discussionmentioning

confidence: 99%

Actinobacterial diversity in limestone deposit sites in Hundung, Manipur (India) and their antimicrobial activities

et al. 2015

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Studies on actinobacterial diversity in limestone habitats are scarce. This paper reports profiling of actinobacteria isolated from Hundung limestone samples in Manipur, India using ARDRA as the molecular tool for preliminary classification. A total of 137 actinobacteria were clustered into 31 phylotypic groups based on the ARDRA pattern generated and representative of each group was subjected to 16S rRNA gene sequencing. Generic diversity of the limestone isolates consisted of Streptomyces (15 phylotypic groups), Micromonospora (4), Amycolatopsis (3), Arthrobacter (3), Kitasatospora (2), Janibacter (1), Nocardia (1), Pseudonocardia (1) and Rhodococcus (1). Considering the antimicrobial potential of these actinobacteria, 19 showed antimicrobial activities against at least one of the bacterial and candidal test pathogens, while 45 exhibit biocontrol activities against at least one of the rice fungal pathogens. Out of the 137 actinobacterial isolates, 118 were found to have at least one of the three biosynthetic gene clusters (PKS-I, PKS-II, NRPS). The results indicate that 86% of the strains isolated from Hundung limestone deposit sites possessed biosynthetic gene clusters of which 40% exhibited antimicrobial activities. It can, therefore, be concluded that limestone habitat is a promising source for search of novel secondary metabolites.

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“…UPLC analysis and dereplication of the compounds present in five peaks against our in-house database ( Pérez-Victoria et al, 2016 ), and the Chapman & Hall Dictionary of Natural Products Compounds ( Buckingham, 2013 ) revealed that, based on the absorption spectrum and mass analysis, they contain compounds compatible with members of the cervimycins family ( Figure 3B ), a tetracycline-type compound with six 6DOHs attached. They were identified as antibiotic HKI 10311129 ( 15, m/z = 1113.4765 [M+H] + ), antibiotic A2121-1 ( 16, m/z = 1199.4794 [M+H] + ), cervimycin D ( 17, m/z = 1213.4939 [M+H] + ), cervimycin C ( 18 , m/z = 1227.5115 [M+H] + ) and cervimycin A ( 19 , m/z = 1226.5152 [M+H] + ) ( Herold et al, 2004 , 2005 ).…”

Section: Resultsmentioning

confidence: 99%

Searching for Glycosylated Natural Products in Actinomycetes and Identification of Novel Macrolactams and Angucyclines

et al. 2018

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Many bioactive natural products are glycosylated compounds in which the sugar components usually participate in interaction and molecular recognition of the cellular target. Therefore, the presence of sugar moieties is important, in some cases essential, for bioactivity. Searching for novel glycosylated bioactive compounds is an important aim in the field of the research for natural products from actinomycetes. A great majority of these sugar moieties belong to the 6-deoxyhexoses and share two common biosynthetic steps catalyzed by a NDP-D-glucose synthase (GS) and a NDP-D-glucose 4,6-dehydratase (DH). Based on this fact, seventy one Streptomyces strains isolated from the integument of ants of the Tribe Attini were screened for the presence of biosynthetic gene clusters (BGCs) for glycosylated compounds. Total DNAs were analyzed by PCR amplification using oligo primers for GSs and DHs and also for a NDP-D-glucose-2,3-dehydratases. Amplicons were used in gene disruption experiments to generate non-producing mutants in the corresponding clusters. Eleven mutants were obtained and comparative dereplication analyses between the wild type strains and the corresponding mutants allowed in some cases the identification of the compound coded by the corresponding cluster (lobophorins, vicenistatin, chromomycins and benzanthrins) and that of two novel macrolactams (sipanmycin A and B). Several strains did not show UPLC differential peaks between the wild type strain and mutant profiles. However, after genome sequencing of these strains, the activation of the expression of two clusters was achieved by using nutritional and genetic approaches leading to the identification of compounds of the cervimycins family and two novel members of the warkmycins family. Our work defines a useful strategy for the identification new glycosylated compounds by a combination of genome mining, gene inactivation experiments and the activation of silent biosynthetic clusters in Streptomyces strains.

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Biosynthesis of cervimycin C, an aromatic polyketide antibiotic bearing an unusual dimethylmalonyl moiety

Cited by 31 publications

References 19 publications

Cervimycin A–D: A Polyketide Glycoside Complex from a Cave Bacterium Can Defeat Vancomycin Resistance

Cervimycin A–D: A Polyketide Glycoside Complex from a Cave Bacterium Can Defeat Vancomycin Resistance

Actinobacterial diversity in limestone deposit sites in Hundung, Manipur (India) and their antimicrobial activities

Searching for Glycosylated Natural Products in Actinomycetes and Identification of Novel Macrolactams and Angucyclines

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