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4. Healthy scents: microbial volatiles as new frontier in antibiotic research?

Author

Avalos Garcia, M., van Wezel, G.P., Raaijmakers, J.M., Garbeva, P.V., Avalos Garcia, M., van Wezel, G.P., Raaijmakers, J.M., and Garbeva, P.V.

Abstract

Microorganisms represent a large and still resourceful pool for the discovery of novel compounds to combat antibiotic resistance in human and animal pathogens. The ability of microorganisms to produce structurally diverse volatile compounds has been known for decades, yet their biological functions and antimicrobial activities have only recently attracted attention. Various studies revealed that microbial volatiles can act as infochemicals in long-distance cross-kingdom communication as well as antimicrobials in competition and predation. Here, we review recent insights into the natural functions and modes of action of microbial volatiles and discuss their potential as a new class of antimicrobials and modulators of antibiotic resistance.

Published
2018

5. Morphology-driven downscaling of Streptomyces lividans to micro-cultivation

Author

Dissel, M.D. van, Wezel, G.P. van, and Dissel D. van, Wezel G.P. van

Subjects
Morphology, 0301 basic medicine, Morphology (linguistics), Microorganism, 030106 microbiology, Mixing (process engineering), Microbiology, Actinobacteria, 03 medical and health sciences, Streptomyces lividans, Botany, Image Processing, Computer-Assisted, Bioreactor, Product formation, Molecular Biology, Micro-cultivation, 030304 developmental biology, Microscopy, Original Paper, 0303 health sciences, Shake flask, biology, Chemistry, 030306 microbiology, Scale (chemistry), High-throughput screening, Antibiotic, General Medicine, biology.organism_classification, equipment and supplies, Streptomyces, Anti-Bacterial Agents, Enzymes, Chemical engineering, Enzyme
Abstract

Actinobacteria are prolific producers of secondary metabolites and industrially relevant enzymes. Growth of these mycelial micro-organisms in small culture volumes is challenging due to their complex morphology. Since morphology and production are typically linked, scaling down culture volumes requires better control over morphogenesis. In larger scale platforms, ranging from shake flasks to bioreactors, the hydrodynamics play an important role in shaping the morphology and determining product formation. Here, we report on the effects of agitation on the mycelial morphology of Streptomyces lividans grown in microtitre plates. Our work shows that at the appropriate agitation rates cultures can be scaled down to volumes as small as 100 µl while maintaining the same morphology as seen in larger scale platforms. Using image analysis and principal component analysis we compared the morphologies of the cultures; when agitated at 1400–1600 rpm the mycelial morphology in micro-cultures was similar to that obtained in shake flasks, while product formation was also maintained. Our study shows that the morphology of actinobacteria in micro-cultures can be controlled in a similar manner as in larger scale cultures by carefully controlling the mixing rate. This could facilitate high-throughput screening and upscaling. Electronic supplementary material The online version of this article (10.1007/s10482-017-0967-7) contains supplementary material, which is available to authorized users.

Published
2017
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6. The evolution of no-cost resistance at sub-MIC concentrations of streptomycin in Streptomyces coelicolor

Author

Westhoff, Sanne, van Leeuwe, Tim Marijn, Qachach, Omar, Zhang, Zheren, van Wezel, G.P., Rozen, Daniel E., Westhoff, Sanne, van Leeuwe, Tim Marijn, Qachach, Omar, Zhang, Zheren, van Wezel, G.P., and Rozen, Daniel E.

Abstract

At the high concentrations used in medicine, antibiotics exert strong selection on bacterial populations for the evolution of resistance. However, these lethal concentrations may not be representative of the concentrations bacteria face in soil, a recognition that has led to questions of the role of antibiotics in soil environments as well as the dynamics of resistance evolution during sublethal challenge. Here we examine the evolution of resistance to sub-minimal inhibitory concentrations (sub-MIC) of streptomycin in the filamentous soil bacterium Streptomyces coelicolor. First, we show that spontaneous resistance to streptomycin causes an average fitness deficit of ~21% in the absence of drugs; however, these costs are eliminated at concentrations as low as 1/10 the MIC of susceptible strains. Using experimental evolution, we next show that resistance to >MIC levels of streptomycin readily evolves when bacteria are exposed to sub-MIC doses for 500 generations. Furthermore, the resistant clones that evolved at sub-MIC streptomycin concentrations carry no fitness cost. Whole-genome analyses reveal that evolved resistant clones fixed some of the same mutations as those isolated at high drug concentrations; however, all evolved clones carry additional mutations and some fixed mutations that either compensate for costly resistance or have no associated fitness costs. Our results broaden the conditions under which resistance can evolve in nature and suggest that rather than low-concentration antibiotics acting as signals, resistance evolves in response to antibiotics used as weapons.

Published
2017

8. Minimum Information about a Biosynthetic Gene cluster

Author

Medema, M.H., Kottmann, R., Yilmaz, P., Cummings, M., Biggins, J.B., Blin, K., de Bruijn, I., Chooi, Y.H., Claesen, J., Coates, R.C., Cruz-Morales, P., Duddela, S., Düsterhus, S., Edwards, D.J., Fewer, D.P., Garg, N., Geiger, C., Gomez-Escribano, J.P., Greule, A., Hadjithomas, M., Haines, A.S., Helfrich, E.J., Hillwig, M.L., Ishida, K., Jones, A.C., Jones, C.S., Jungmann, K., Kegler, C., Kim, H.U., Kötter, P., Krug, D., Masschelein, J., Melnik, A.V., Mantovani, S.M., Monroe, E.A., Moore, M., Moss, N., Nützmann, H.W., Pan, G., Pati, A., Petras, D., Reen, F.J., Rosconi, F., Rui, Z., Tian, Z., Tobias, N.J., Tsunematsu, Y., Wiemann, P., Wyckoff, E., Yan, X., Yim, G., Yu, F., Xie, Y., Aigle, B., Apel, A.K., Balibar, C.J., Balskus, E.P., Barona-Gómez, F., Bechthold, A., Bode, H.B., Borriss, R., Brady, S.F., Brakhage, Axel A., Caffrey, P., Cheng, Yo, Clardy, J., Cox, R.J., De Mot, R., Donadio, S., Donia, M.S., van der Donk, W.A., Dorrestein, P.C., Doyle, Sean, Driessen, A.J., Ehling-Schulz, M., Entian, K.D., Fischbach, M.A., Gerwick, L., Gerwick, W.H., Gross, H., Gust, B., Hertweck, C., Höfte, M., Jensen, S.E., Ju, J., Katz, L., Kaysser, L., Klassen, J.L., Keller, N.P., Kormanec, J., Kuipers, O.P., Kuzuyama, T., Kyrpides, N.C., Kwon, H.J., Lautru, S., Lavigne, R., Lee, C.Y., Linquan, B., Liu, X., Liu, W., Luzhetskyy, A., Mahmud, T., Mast, Y., Méndez, C., Metsä-Ketelä, M., Micklefield, J., Mitchell, D.A., Moore, B.S., Moreira, L.M., Muller, R., Neilan, B.A., Nett, M., Nielsen, J., O'Gara, F., Oikawa, H., Osbourn, A., Osburne, M.S., Ostash, B., Payne, S.M., Pernodet, J.L., Petricek, M., Piel, J., Ploux, O., Raaijmakers, J.M., Salas, J.A., Schmitt, E.K., Scott, B., Seipke, R.F., Shen, B., Sherman, D.H., Sivonen, K., Smanski, M.J., Sosio, M., Stegmann, E., Süssmuth, R.D., Tahlan, K., Thomas, C.M., Tang, Y., Truman, A.W., Viaud, M., Walton, J.D., Walsh, C.T., Weber, T., van Wezel, G.P., Wilkinson, B., Willey, J.M., Wohlleben, W., Wright, G.D., Ziemert, N., Zhang, C., Zotchev, S.B., Breitling, R., Takano, E., Glöckner, F.O., Medema, M.H., Kottmann, R., Yilmaz, P., Cummings, M., Biggins, J.B., Blin, K., de Bruijn, I., Chooi, Y.H., Claesen, J., Coates, R.C., Cruz-Morales, P., Duddela, S., Düsterhus, S., Edwards, D.J., Fewer, D.P., Garg, N., Geiger, C., Gomez-Escribano, J.P., Greule, A., Hadjithomas, M., Haines, A.S., Helfrich, E.J., Hillwig, M.L., Ishida, K., Jones, A.C., Jones, C.S., Jungmann, K., Kegler, C., Kim, H.U., Kötter, P., Krug, D., Masschelein, J., Melnik, A.V., Mantovani, S.M., Monroe, E.A., Moore, M., Moss, N., Nützmann, H.W., Pan, G., Pati, A., Petras, D., Reen, F.J., Rosconi, F., Rui, Z., Tian, Z., Tobias, N.J., Tsunematsu, Y., Wiemann, P., Wyckoff, E., Yan, X., Yim, G., Yu, F., Xie, Y., Aigle, B., Apel, A.K., Balibar, C.J., Balskus, E.P., Barona-Gómez, F., Bechthold, A., Bode, H.B., Borriss, R., Brady, S.F., Brakhage, Axel A., Caffrey, P., Cheng, Yo, Clardy, J., Cox, R.J., De Mot, R., Donadio, S., Donia, M.S., van der Donk, W.A., Dorrestein, P.C., Doyle, Sean, Driessen, A.J., Ehling-Schulz, M., Entian, K.D., Fischbach, M.A., Gerwick, L., Gerwick, W.H., Gross, H., Gust, B., Hertweck, C., Höfte, M., Jensen, S.E., Ju, J., Katz, L., Kaysser, L., Klassen, J.L., Keller, N.P., Kormanec, J., Kuipers, O.P., Kuzuyama, T., Kyrpides, N.C., Kwon, H.J., Lautru, S., Lavigne, R., Lee, C.Y., Linquan, B., Liu, X., Liu, W., Luzhetskyy, A., Mahmud, T., Mast, Y., Méndez, C., Metsä-Ketelä, M., Micklefield, J., Mitchell, D.A., Moore, B.S., Moreira, L.M., Muller, R., Neilan, B.A., Nett, M., Nielsen, J., O'Gara, F., Oikawa, H., Osbourn, A., Osburne, M.S., Ostash, B., Payne, S.M., Pernodet, J.L., Petricek, M., Piel, J., Ploux, O., Raaijmakers, J.M., Salas, J.A., Schmitt, E.K., Scott, B., Seipke, R.F., Shen, B., Sherman, D.H., Sivonen, K., Smanski, M.J., Sosio, M., Stegmann, E., Süssmuth, R.D., Tahlan, K., Thomas, C.M., Tang, Y., Truman, A.W., Viaud, M., Walton, J.D., Walsh, C.T., Weber, T., van Wezel, G.P., Wilkinson, B., Willey, J.M., Wohlleben, W., Wright, G.D., Ziemert, N., Zhang, C., Zotchev, S.B., Breitling, R., Takano, E., and Glöckner, F.O.

Abstract

A wide variety of enzymatic pathways that produce specialized metabolites in bacteria, fungi and plants are known to be encoded in biosynthetic gene clusters. Information about these clusters, pathways and metabolites is currently dispersed throughout the literature, making it difficult to exploit. To facilitate consistent and systematic deposition and retrieval of data on biosynthetic gene clusters, we propose the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard.

Published
2015

11. Diversity and functions of volatile organic compounds produced by Streptomyces from a disease-suppressive soil

Author

Cordovez da Cunha, V., Carrion Bravo, V.J., Etalo, D.W., Mumm, R., Zhu, H., van Wezel, G.P., Raaijmakers, J.M., Cordovez da Cunha, V., Carrion Bravo, V.J., Etalo, D.W., Mumm, R., Zhu, H., van Wezel, G.P., and Raaijmakers, J.M.

Abstract

In disease-suppressive soils, plants are protected from infections by specific root pathogens due to the antagonistic activities of soil and rhizosphere microorganisms. For most disease-suppressive soils, however, the microorganisms and mechanisms involved in pathogen control are largely unknown. Our recent studies identified Actinobacteria as the most dynamic phylum in a soil suppressive to the fungal root pathogen Rhizoctonia solani. Here we isolated and characterized 300 isolates of rhizospheric Actinobacteria from the Rhizoctonia-suppressive soil. Streptomyces species were the most abundant, representing approximately 70% of the isolates. Streptomyces are renowned for the production of an exceptionally large number of secondary metabolites, including volatile organic compounds (VOCs). VOC profiling of 12 representative Streptomyces isolates by SPME-GC-MS allowed a more refined phylogenetic delineation of the Streptomyces isolates than the sequencing of 16S rRNA and the house-keeping genes atpD and recA only. VOCs of several Streptomyces isolates inhibited hyphal growth of R. solani and significantly enhanced plant shoot and root biomass. Coupling of Streptomyces VOC profiles with their effects on fungal growth, pointed to VOCs potentially involved in antifungal activity. Subsequent assays with five synthetic analogs of the identified VOCs showed that methyl 2-methylpentanoate, 1,3,5-trichloro-2-methoxy benzene and the VOCs mixture have antifungal activity. In conclusion, our results point to a potential role of VOC-producing Streptomyces in disease suppressive soils and show that VOC profiling of rhizospheric Streptomyces can be used as a complementary identification tool to construct strain-specific metabolic signatures

Published
2015

12. DNA cleavage and antitumour activity of platinum(II) and copper(II) compounds derived from 4-methyl-2-N-(2-pyridylmethyl)aminophenol: spectroscopic, electrochemical and biological investigation

Author

Roy, S., Maheswari, P.U., Lutz, M., Spek, A.L., den Dulk, H., Barends, S., van Wezel, G.P., Hartl, F., Reedijk, J., Rontgen participation programme, Dep Scheikunde, and Sub Crystal and Structural Chemistry

Abstract

The reaction of the redox-active ligand, Hpyramol (4-methyl-2-N-(2-pyridylmethyl)aminophenol) with K2PtCl4 yields monofunctional square-planar [Pt(pyrimol)Cl], PtL-Cl, which was structurally characterised by single-crystal X-ray diffraction and NMR spectroscopy. This compound unexpectedly cleaves supercoiled double-stranded DNA stoichiometrically and oxidatively, in a non-specific manner without any external reductant added, under physiological conditions. Spectro-electrochemical investigations of PtL-Cl were carried out in comparison with the analogue CuL-Cl as a reference compound. The results support a phenolate oxidation, generating a phenoxyl radical responsible for the ligand-based DNA cleavage property of the title compounds. Time-dependent in vitro cytotoxicity assays were performed with both PtL-Cl and CuL-Cl in various cancer cell lines. The compound CuL-Cl overcomes cisplatin-resistance in ovarian carcinoma and mouse leukaemia cell lines, with additional activity in some other cells. The platinum analogue, PtL-Cl also inhibits cell-proliferation selectively. Additionally, cellular-uptake studies performed for both compounds in ovarian carcinoma cell lines showed that significant amounts of Pt and Cu were accumulated in the A2780 and A2780R cancer cells. The conformational and structural changes induced by PtL-Cl and CuL-Cl on calf thymus DNA and X174 supercoiled phage DNA at ambient conditions were followed by electrophoretic mobility assay and circular dichroism spectroscopy. The compounds induce extensive DNA degradation and unwinding, along with formation of a monoadduct at the DNA minor groove. Thus, hybrid effects of metal-centre variation, multiple DNA-binding modes and ligand-based redox activity towards cancer cell-growth inhibition have been demonstrated. Finally, reactions of PtL-Cl with DNA model bases (9-Ethylguanine and 5-GMP) followed by NMR and MS showed slow binding at Guanine-N7 and for the double stranded self complimentary oligonucleotide d(GTCGAC)2 in the minor groove.

Published
2009

13. Phenanthroline derivatives with improved selectivity as dna-targeting anticancer or antimicrobial drugs

Author

Roy, S., Hagen, K.D., Maheswari, P.U., Lutz, M., Spek, A.L., Reedijk, J., van Wezel, G.P., R¿ntgenparticipatieprogramma, and Dep Scheikunde

Abstract

Phenanthroline derivatives are of interest due to their potential activity against cancer, and viral, bacterial, and fungal infections. In a search for highly specific antitumor and antibacterial compounds, we report the activities of 1,10-phenanthroline-5,6-dione (phendione or L1), dipyrido[3,2-a:2’,3’-c]phenazine (dppz or L2), and their corresponding platinum complexes ([PtL1Cl2] and [PtL2Cl2]), and provide the solid-state 3D structure for [PtL1Cl2]. It is generally known that a toxic metal ion coordinated to an active organic moiety leads to a synergistic effect; however, we report herein that the platinum complexes [PtL1Cl2] and [PtL2Cl2] have weaker activities relative to those of the free ligands, especially against bacteria. Testing these agents against a variety of human cancer cell lines revealed that L1 and [PtL1Cl2] were at least as active as cisplatin against several of the cell lines (including a cisplatin-resistant cell line). The absence of antibacterial activity of [PtL1Cl2] removes the detrimental effect of phenanthrolines toward intestinal flora, suggesting a highly promising new strategy for the development of anticancer drugs with reduced side effects.

Published
2008

14. Unique Ligand-Based Oxidative DNA Cleavage by Zinc(II) Complexes of Hpyramol and Hpyrimol

Author

Maheswari, P.U., Barends, S., Özalp-Yaman, S., de Hoog, P., Casellas, H., Teat, S.J., Massera, C., Lutz, M., Spek, A.L., van Wezel, G.P., Gamez, P., Reedijk, J., R¿ntgenparticipatieprogramma, and Dep Scheikunde

Abstract

The zinc(II) complexes reported here have been synthesised from the ligand 4-methyl-2-N-(2-pyridylmethyl)aminophenol (Hpyramol) with chloride or acetate counterions. All the five complexes have been structurally characterised, and the crystal structures reveal that the ligand Hpyramol gradually undergoes an oxidative dehydrogenation to form the ligand 4-methyl-2-N-(2-pyridylmethylene)aminophenol (Hpyrimol), upon coordination to ZnII. All the five complexes cleave the φX174 phage DNA oxidatively and the complexes with fully dehydrogenated pyrimol ligands were found to be more efficient than the complexes with non-dehydrogenated Hpyramol ligands. The DNA cleavage is suggested to be ligand-based, whereas the pure ligands alone do not cleave DNA. The DNA cleavage is strongly suggested to be oxidative, possibly due to the involvement of a non-diffusible phenoxyl radical mechanism. The enzymatic religation experiments and DNA cleavage in the presence of different radical scavengers further support the oxidative DNA cleavage by the zinc(II) complexes.

Published
2007

15. Structured morphological modeling as a framework for rational strain design of Streptomyces species

Author

Celler, K. (author), Picioreanu, C. (author), Van Loosdrecht, M.C.M. (author), Van Wezel, G.P. (author), Celler, K. (author), Picioreanu, C. (author), Van Loosdrecht, M.C.M. (author), and Van Wezel, G.P. (author)

Abstract

Successful application of a computational model for rational design of industrial Streptomyces exploitation requires a better understanding of the relationship between morphology—dictated by microbial growth, branching, fragmentation and adhesion—and product formation. Here we review the state-of-the-art in modeling of growth and product formation by filamentous microorganisms and expand on existing models by combining a morphological and structural approach to realistically model and visualize a three-dimensional pellet. The objective is to provide a framework to study the effect of morphology and structure on natural product and enzyme formation and yield. Growth and development of the pellet occur via the processes of apical extension, branching and cross-wall formation. Oxygen is taken to be the limiting component, with the oxygen concentration at the tips regulating growth kinetics and the oxygen profile within the pellet affecting the probability of branching. Biological information regarding the processes of differentiation and branching in liquid cultures of the model organism Streptomyces coelicolor has been implemented. The model can be extended based on information gained in fermentation trials for different production strains, with the aim to provide a test drive for the fermentation process and to pre-assess the effect of different variables on productivity. This should aid in improving Streptomyces as a production platform in industrial biotechnology., Biotechnology, Applied Sciences

Published
2012
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16. DNA cleavage and antitumour activity of platinum(II) and copper(II) compounds derived from 4-methyl-2-N-(2-pyridylmethyl)aminophenol: spectroscopic, electrochemical and biological investigation

Author

Rontgen participation programme, Dep Scheikunde, Sub Crystal and Structural Chemistry, Roy, S., Maheswari, P.U., Lutz, M., Spek, A.L., den Dulk, H., Barends, S., van Wezel, G.P., Hartl, F., Reedijk, J., Rontgen participation programme, Dep Scheikunde, Sub Crystal and Structural Chemistry, Roy, S., Maheswari, P.U., Lutz, M., Spek, A.L., den Dulk, H., Barends, S., van Wezel, G.P., Hartl, F., and Reedijk, J.

Published
2009

18. Unique Ligand-Based Oxidative DNA Cleavage by Zinc(II) Complexes of Hpyramol and Hpyrimol

Author

R¿ntgenparticipatieprogramma, Dep Scheikunde, Maheswari, P.U., Barends, S., Özalp-Yaman, S., de Hoog, P., Casellas, H., Teat, S.J., Massera, C., Lutz, M., Spek, A.L., van Wezel, G.P., Gamez, P., Reedijk, J., R¿ntgenparticipatieprogramma, Dep Scheikunde, Maheswari, P.U., Barends, S., Özalp-Yaman, S., de Hoog, P., Casellas, H., Teat, S.J., Massera, C., Lutz, M., Spek, A.L., van Wezel, G.P., Gamez, P., and Reedijk, J.

Published
2007

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