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Grant
Agency: European Commission | Branch: H2020 | Program: RIA | Phase: BG-03-2014 | Award Amount: 7.65M | Year: 2015

Microalgae are a source of secondary metabolites useful as new bioactive compounds. Activity of these compounds against bacterial pathogens and biofilm formation has not been determined yet. Biofilm formation is especially important in infections and tissue inflammation related to implants and catheters. These problems finally cause a release of the implant, which must be removed and replaced by a new one, entailing an increase in antibiotic consumption, together with a health costs of about 50,000-90,000 per infection episode. Taking both problems in account, the search of new antimicrobial agents that will be effective against the bacteria in their two ways of life, planktonic and biofilm stage, is a priority need in the clinical practice. For this reason, the overall objective of NOMORFILM project is to search for antibiofilm compounds isolated from microalgae that will be useful in the treatment of this kind of infections and could be incorporated in the manufacturing of medical prosthetic devices. For this purpose, 4,000 microalgae species will be deeply screened specifically for new antibacterial and antibiofilm molecules. Structural elucidation of bioactive compounds from these extracts will assure that only new chemical entities, therefore with anticipated new mechanisms of action, will arise to further project stages, those including toxicity tests and animal models. This project also addresses the biosynthesis of the targeted bioactive compounds in sustainable microalgae co-cultures, diminishing cultivation costs by mimicking natural aquatic ecosystems. Most industrially interesting antibiofilm molecules will be incorporated into nanoparticles in order to develop manufacturing methodologies able to incorporate these compounds into real prosthetic devices matrixes. Marketing of results are assured by the presence of diverse SMEs along the manufacture and distribution of prosthetic devices, and the corresponding consortium agreements with respect to IPRs


Maffioli S.I.,Naicons Srl | Maffioli S.I.,KtedoGen Srl | Monciardini P.,Naicons Srl | Monciardini P.,KtedoGen Srl | And 9 more authors.
ACS Chemical Biology | Year: 2015

Lantibiotics, an abbreviation for "lanthionine-containing antibiotics", interfere with bacterial metabolism by a mechanism not exploited by the antibiotics currently in clinical use. Thus, they have aroused interest as a source for new therapeutic agents because they can overcome existing resistance mechanisms. Starting from fermentation broth extracts preselected from a high-throughput screening program for discovering cell-wall inhibitors, we isolated a series of related class I lantibiotics produced by different genera of actinomycetes. Analytical techniques together with explorative chemistry have been used to establish their structures: the newly described compounds share a common 24 aa sequence with the previously reported lantibiotic planosporicin (aka 97518), differing at positions 4, 6, and 14. All of these compounds maintain an overall -1 charge at physiological pH. While all of these lantibiotics display modest antibacterial activity, their potency can be substantially modulated by progressively eliminating the negative charges, with the most active compounds carrying basic amide derivatives of the two carboxylates originally present in the natural compounds. Interestingly, both natural and chemically modified lantibiotics target the key biosynthetic intermediate lipid II, but the former compounds do not bind as effectively as the latter in vivo. Remarkably, the basic derivatives display an antibacterial potency and a killing effect similar to those of NAI-107, a distantly related actinomycete-produced class I lantibiotic which lacks altogether carboxyl groups and which is a promising clinical candidate for treating Gram-positive infections caused by multi-drug-resistant pathogens. © 2015 American Chemical Society.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2011-ITN | Award Amount: 3.52M | Year: 2012

TRAIN-ASAP addresses a very urgent public health issue. The lack of effective antibacterial drugs against resistant bacteria poses a serious threat to human health and has huge economical consequences to the healthcare system. The objective of this ITN is to fill the current gap between the burden of infections due to resistant bacteria and the strong need for alternative solutions to combat antibiotic resistance in both humans and animals. Young researchers will be trained in the scientific and complementary skills needed to implement a broad range of antibacterial approaches including discovery of new antibiotics, synthesis of antimicrobial peptides with improved pharmacological properties, improvement of the clinical efficacy of currently known drugs, and alternative strategies based on phages and bacteriocin-producing organisms. TRAIN-ASAP is a multidisciplinary and intersectorial ITN dedicated to the scientific and professional training of 14 early-stage researchers, including 2 financed by the University of Copenhagen, with the aim to develop novel antibacterial solutions for humans and animals. The consortium includes 7 academic institutions, 9 private enterprises and 2 national research centres representing 9 countries. The training programme is characterized by a unique innovative and multidisciplinary approach based on the use of front line research tools in molecular biology, combinatorial chemistry and in vivo pharmacology, an appropriate balance between scientific and generic skills training, and a strong contribution by the private partners in the form of mentoring, courses and secondments. Considering the urgent need for new drugs to combat antibiotic resistance and the growing demand for skilled scientists specialised in antibacterial drug discovery, TRAIN-ASAP is expected to have a strong impact on the careers of the trainees and result in a lasting collaboration between the partners and political, societal and economical benefits to Europe.


PubMed | KtedoGen Srl, Naicons Srl and University of Warwick
Type: Journal Article | Journal: Journal of natural products | Year: 2015

We identified an Actinoallomurus strain producing NAI-107, a chlorinated lantibiotic effective against multidrug-resistant Gram-positive pathogens and previously reported from the distantly related genus Microbispora. Inclusion of KBr in the production medium of either the Actinoallomurus or the Microbispora producer readily afforded brominated variants of NAI-107, which were designated as NAI-108. The other post-translational modifications naturally occurring in this lantibiotic family (i.e., hydroxylation of Pro-14 and C-terminal decarboxylation) were unaffected by the presence of a brominated tryptophan. In addition to being the first example of a bromine-containing lantibiotic, NAI-108 displayed a small but consistent improvement in antibacterial activity against all tested strains. The brominated lantibiotic maintained the same rapid bactericidal activity as NAI-107 but at reduced concentrations, consistent with its increased potency and with the role played by the hydrophobicity of the first lanthionine ring. NAI-108 thus represents an interesting addition to a promising family of potent and effective lantibiotics.


PubMed | Ktedogen Srl, NAICONS Srl and University of Warwick
Type: Journal Article | Journal: The Journal of antibiotics | Year: 2016

A screening program on a limited number of strains belonging to the Actinoallomurus genus yielded a series of new angucyclinones. NMR and MS analyses established that these compounds are characterized by an unusual lactone ring and present up to four halogens per molecule, with one congener representing the first natural product containing a trichloromethyl substitution on an aromatic system. Remarkably, this family of metabolites seems to be produced by phylogenetically distinct Actinoallomurus isolates. Because of the unique structural features and wide distribution among Actinoallomurus, we have designated these angucyclinones as allocyclinones. Allocyclinones possess interesting activity against different Gram-positive bacteria, including antibiotic-resistant strains, with antibacterial potency increasing with the number of chlorine substituents. The tetrachlorinated compound is the most abundant congener in the allocyclinone complex.


Furness D.N.,Keele University | Johnson S.L.,University of Sheffield | Manor U.,U.S. National Institutes of Health | Ruttiger L.,University of Tübingen | And 19 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2013

Mechanotransduction in the mammalian auditory system depends on mechanosensitive channels in the hair bundles that project from the apical surface of the sensory hair cells. Individual stereocilia within each bundle contain a core of tightly packed actin filaments, whose length is dynamically regulated during development and in the adult. We show that the actin-binding protein epidermal growth factor receptor pathway substrate 8 (Eps8)L2, a member of the Eps8-like protein family, is a newly identified hair bundle protein that is localized at the tips of stereocilia of both cochlear and vestibular hair cells. It has a spatiotemporal expression pattern that complements that of Eps8. In the cochlea, whereas Eps8 is essential for the initial elongation of stereocilia, Eps8L2 is required for their maintenance in adult hair cells. In the absence of both proteins, the ordered staircase structure of the hair bundle in the cochlea decays. In contrast to the early profound hearing loss associated with an absence of Eps8, Eps8L2 nullmutant mice exhibit a late-onset, progressive hearing loss that is directly linked to a gradual deterioration in hair bundle morphology. We conclude that Eps8L2 is required for the long-term maintenance of the staircase structure and mechanosensory function of auditory hair bundles. It complements the developmental role of Eps8 and is a candidate gene for progressive age-related hearing loss.


Sosio M.,Vicuron Pharmaceuticals | Sosio M.,KtedoGen Srl | Canavesi A.,Vicuron Pharmaceuticals | Canavesi A.,Sicor Srl | And 3 more authors.
Applied Microbiology and Biotechnology | Year: 2010

Nonomuraea strain ATCC 39727 produces the glycopeptide A40926, used for manufacturing dalbavancin, currently in advanced clinical trials. From the gene cluster involved in A40926 biosynthesis, a strain deleted in dbv23 was constructed. This mutant can produce only the glycopeptides lacking the O-linked acetyl residue at position 6 of the mannose moiety, while, under identical fermentation conditions, the wild-type strain produces mostly glycopeptides carrying an acetylated mannose. Furthermore, the total amount of glycopeptides produced by the mutant strain was found to be approximately twice that of the wild type. The reduced level of glycopeptides observed in the wild-type strain may be due to an inhibitory effect exerted by the acetylated compound on the biosynthesis of A40926. Indeed, spiking production cultures with ≥1 μg/ml of the acetylated glycopeptide inhibited A40926 production in the mutant strain. © 2010 Springer-Verlag.


Flinspach K.,University of Tübingen | Flinspach K.,German Center for Infection Research | Kapitzke C.,University of Tübingen | Tocchetti A.,KtedoGen Srl | And 4 more authors.
PLoS ONE | Year: 2014

GE2270 is a thiopeptide antibiotic generated by extensive posttranslational modifications of a ribosomally generated precursor peptide. Thiopeptides are especially active against Gram-positive bacteria, including methicillin resistant Staphylococcus aureus (MRSA). In this study the GE2270 biosynthetic gene cluster (pbt) from Planobispora rosea ATCC 53733 was successfully expressed in the heterologous host strain Streptomyces coelicolor M1146. Notably, exconjugants containing the pbt gene cluster could only be obtained after deletion of the major part of the ribosomal genes flanking the gene cluster. This is a striking example that genes belonging to primary metabolism can prevent the successful conjugative transfer of DNA from phylogenetic distant species and thus complicate heterologous expression of secondary metabolite gene clusters. GE2270 production in the heterologous producer strain increased after introduction of the constitutive ermE*promoter upstream of the GE2270 resistance gene tuf from P. rosea. Insertion of the inducible tcp830 promoter resulted in inducible GE2270 production. When the regulatory gene pbtR was deleted, the resulting strain ceased to produce GE2270, suggesting an essential role of PbtR as a putative transcriptional activator of GE2270 expression. © 2014 Flinspach et al.


Tocchetti A.,KtedoGen Srl | Maffioli S.,Naicons Scrl | Iorio M.,Naicons Scrl | Alt S.,Naicons Scrl | And 4 more authors.
Chemistry and Biology | Year: 2013

Thiopeptides are ribosomally synthesized, posttranslationally modified peptides with potent activity against Gram-positives. However, only GE2270 has yielded semisynthetic derivatives under clinical investigations. The pbt gene cluster from the GE2270 producer Planobispora rosea was successfully expressed in the genetically tractable Nonomuraea ATCC39727. Gene deletions established that PbtO, PbtM1, PbtM2, PbtM3, and PbtM4 are involved in regiospecific hydroxylation and methylations of GE2270, leading to the generation of various derivatives with altered decorations. Further deletions established that PbtH and PbtG1 are involved in C-terminal amide and oxazoline formation, respectively. Surprisingly, preventing either step resulted in the accumulation of linear precursors in which the pyridine-generated macrocycle failed to form, and only one of the pyridine-forming serine residues had been dehydrated. Often, these linear precursors present a shortened C terminus but retain the full set of methylation and hydroxylation decorations. © 2013 Elsevier Ltd.


PubMed | KtedoGen Srl
Type: Journal Article | Journal: Journal of industrial microbiology & biotechnology | Year: 2016

Natural products represent a major source of approved drugs and still play an important role in supplying chemical diversity. Consistently, 2014 has seen new, natural product-derived antibiotics approved for human use by the US Food and Drug Administration. One of the recently approved second-generation glycopeptides is dalbavancin, a semi-synthetic derivative of the natural product A40,926. This compound inhibits bacterial growth by binding to lipid intermediate II (Lipid II), a key intermediate in peptidoglycan biosynthesis. Like other recently approved antibiotics, dalbavancin has a complex history of preclinical and clinical development, with several companies contributing to different steps in different years. While our work on dalbavancin development stopped at the previous company, intriguingly our current pipeline includes two more Lipid II-binding natural products or derivatives thereof. In particular, we will focus on the properties of NAI-107 and related lantibiotics, which originated from recent screening and characterization efforts.

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