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Editor’s Choice Articles Virtual Issue

2012

Contents A bacterial reporter panel for the detection and classification of antibiotic substances Sahar Melamed, Chaim Lalush, Tal Elad, Sharon Yagur-Kroll, Shimshon Belkin, Rami Pedahzur Cyclic di-nucleotides: new era for small molecules as adjuvants Rimma Libanova, Pablo D. Becker, Carlos A. Guzmรกn Vaccination in the elderly Evelyna Derhovanessian, Graham Pawelec Hydrogen production by recombinant Escherichia coli strains Toshinari Maeda, Viviana Sanchez-Torres , Thomas K. Wood Vaccines for the future: learning from human immunology Ennio De Gregorio, Rino Rappuoli Bio-palladium: from metal recovery to catalytic applications Simon De Corte, Tom Hennebel, Bart De Gusseme, Willy Verstraete, Nico Boon Natural products for cancer chemotherapy Arnold L. Demain, Preeti Vaishnav A novel antimicrobial protein for plant protection consisting of a Xanthomonas oryzae harpin and active domains of cecropin A and melittin Yi-Zhou Che, Yu-Rong Li, Hua-Song Zou, Li-Fang Zou, Bing Zhang, Gong-You Chen Biotechnological uses of enzymes from psychrophiles R. Cavicchioli, T. Charlton, H. Ertan, S. Mohd Omar, K. S. Siddiqui, T. J. Williams Mathematical models of cell factories: moving towards the core of industrial biotechnology Marija Cvijovic, Sergio Bordel, Jens Nielsen

Bifidobacterium population analysis in the infant gut by direct mapping of genomic hybridization patterns: potential for monitoring temporal development and effects of dietary regimens Rolf Boesten, Frank Schuren, Kaouther Ben Amor, Monique Haarman, Jan Knol, Willem M. de Vos Engineering Streptomyces coelicolor for heterologous expression of secondary metabolite gene clusters Juan Pablo Gomez-Escribano, Mervyn J. Bibb

A bacterial reporter panel for the detection and classification of antibiotic substances Sahar Melamed, Chaim Lalush, Tal Elad, Sharon Yagur-Kroll, Shimshon Belkin, Rami Pedahzur Volume 5, Issue 4, July 2012

Summary The ever-growing use of pharmaceutical compounds, including antibacterial substances, poses a substantial pollution load on the environment. Such compounds can compromise water quality, contaminate soils, livestock and crops, enhance resistance of microorganisms to antibiotic substances, and hamper human health. We report the construction of a novel panel of genetically engineered Escherichia coli reporter strains for the detection and classification of antibiotic substances. Each of these strains harbours a plasmid that carries a fusion of a selected gene promoter to bioluminescence (luxCDABE) reporter genes and an alternative tryptophan auxotrophy-based nonantibiotic selection system. The bioreporter panel was tested for sensitivity and responsiveness to diverse antibiotic substances by monitoring bioluminescence as a function of time and of antibiotic concentrations. All of the tested antibiotics were detected by the panel, which displayed different response patterns for each substance. These unique responses were analysed by several algorithms that enabled clustering the compounds according to their functional properties, and allowed the classification of unknown antibiotic substances with a high degree of accuracy and confidence.

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Cyclic di-nucleotides: new era for small molecules as adjuvants Rimma Libanova, Pablo D. Becker, Carlos A. GuzmĂĄn Volume 5, Issue 2, March 2012

Summary The implementation of vaccination as an empiric strategy to protect against infectious diseases was introduced even before the advent of hygiene and antimicrobials in the medical practice. Nevertheless, it was not until a few decades ago that we really started understanding the underlying mechanisms of protection triggered by vaccination. Vaccines were initially based on attenuated or inactivated organisms. Subunit vaccines were then introduced as more refined formulations, exhibiting improved safety profiles. However, purified antigens tend to be poorly immunogenic and often require the use of adjuvants to achieve adequate stimulation of the immune system. Vaccination strategies, such as mucosal administration, also require potent adjuvants to improve performance. In the 1990s, immunologists found that pathogens could be sensed as ‘danger signals’ by receptors recognizing conserved motifs. Although our knowledge is still limited, tremendous advances were made in the understanding of host defence mechanisms regulated by these evolutionary conserved receptors, and the molecular structures which are recognized by them. This opened a new era in adjuvant development. Some of the latest players arrived to this field are the cyclic di-nucleotides, which are ubiquitous prokaryotic intracellular signalling molecules. This review is focused on their potential for the development of vaccines and immunotherapies.

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Vaccination in the elderly Evelyna Derhovanessian, Graham Pawelec Volume 5, Issue 2, March 2012

Summary There is a general consensus that the elderly do not respond as well to vaccination as the young, but robust studies are few and far between. Most refer to influenza vaccination, but even here, adequate immunological and clinical data are surprisingly thin on the ground. The meta-analysis by Goodwin et al. from 2006 is still the most comprehensive that we have. They reviewed 31 antibody response studies comparing influenza vaccination efficacy in groups of elderly and younger adults. They reported that the adjusted odds ratio (OR) of responses in elderly versus young adults ranged from 0.24 to 0.59 for the three influenza antigens used in the vaccines. They concluded that rather than the estimated 70–90% clinical vaccine efficacy in younger adults, this figure was only 17–53% in the elderly, depending on which viruses were prevalent that year. They stated that ‘this highlights the need for more immunogenic vaccine formulations for the elderly’. How to achieve this? There are three areas where we may consider alterations to increase vaccine efficacy: (i) make the vaccine more potent; (ii) use adjuvants to enhance immunity; and (iii) apply immune modulators or other interventions to alter host immunity generally. We will consider these three options, focusing on influenza vaccination, in this mini-review.

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Hydrogen production by recombinant Escherichia coli strains Toshinari Maeda, Viviana Sanchez-Torres , Thomas K. Wood Volume 5, Issue 2, March 2012

Summary The production of hydrogen via microbial biotechnology is an active field of research. Given its ease of manipulation, the best-studied bacterium Escherichia coli has become a workhorse for enhanced hydrogen production through metabolic engineering, heterologous gene expression, adaptive evolution, and protein engineering. Herein, the utility of E. coli strains to produce hydrogen, via native hydrogenases or heterologous ones, is reviewed. In addition, potential strategies for increasing hydrogen production are outlined and whole-cell systems and cell-free systems are compared.

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Vaccines for the future: learning from human immunology Ennio De Gregorio, Rino Rappuoli Volume 5, Issue 2, March 2012

Summary Conventional vaccines have been extremely successful in preventing infections by pathogens expressing relatively conserved antigens through antibody-mediated effector mechanisms. Thanks to vaccination some diseases have been eradicated and mortality due to infectious diseases has been significantly reduced. However, there are still many infections that are not preventable with vaccination, which represent a major cause of mortality worldwide. Some of these infections are caused by pathogens with a high degree of antigen variability that cannot be controlled only by antibodies, but require a mix of humoral and cellular immune responses. Novel technologies for antigen discovery, expression and formulation allow now for the development of vaccines that can better cope with pathogen diversity and trigger multifunctional immune responses. In addition, the application of new genomic assays and systems biology approaches in human immunology can help to better identify vaccine correlates of protection. The availability of novel vaccine technologies, together with the knowledge of the distinct human immune responses that are required to prevent different types of infection, should help to rationally design effective vaccines where conventional approaches have failed.

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Bio-palladium: from metal recovery to catalytic applications Simon De Corte, Tom Hennebel, Bart De Gusseme, Willy Verstraete, Nico Boon Volume 5, Issue 1, January 2012

Summary While precious metals are available to a very limited extent, there is an increasing demand to use them as catalyst. This is also true for palladium (Pd) catalysts and their sustainable recycling and production are required. Since Pd catalysts exist nowadays mostly under the form of nanoparticles, these particles need to be produced in an environment-friendly way. Biological synthesis of Pd nanoparticles (‘bio-Pd’) is an innovative method for both metal recovery and nanocatalyst synthesis. This review will discuss the different bio-Pd precipitating microorganisms, the applications of the catalyst (both for environmental purposes and in organic chemistry) and the state of the art of the reactors based on the bio-Pd concept. In addition, some main challenges are discussed, which need to be overcome in order to create a sustainable nanocatalyst. Finally, some outlooks for bio-Pd in environmental technology are presented.

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Natural products for cancer chemotherapy Arnold L. Demain, Preeti Vaishnav Volume 4, Issue 6, November 2011

Summary For over 40 years, natural products have served us well in combating cancer. The main sources of these successful compounds are microbes and plants from the terrestrial and marine environments. The microbes serve as a major source of natural products with anti-tumour activity. A number of these products were first discovered as antibiotics. Another major contribution comes from plant alkaloids, taxoids and podophyllotoxins. A vast array of biological metabolites can be obtained from the marine world, which can be used for effective cancer treatment. The search for novel drugs is still a priority goal for cancer therapy, due to the rapid development of resistance to chemotherapeutic drugs. In addition, the high toxicity usually associated with some cancer chemotherapy drugs and their undesirable side-effects increase the demand for novel anti-tumour drugs active against untreatable tumours, with fewer side-effects and/or with greater therapeutic efficiency. This review points out those technologies needed to produce the anti-tumour compounds of the future.

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A novel antimicrobial protein for plant protection consisting of a Xanthomonas oryzae harpin and active domains of cecropin A and melittin Yi-Zhou Che, Yu-Rong Li, Hua-Song Zou, Li-Fang Zou, Bing Zhang, Gong-You Chen Volume 4, Issue 6, November 2011

Summary Discoveries about antimicrobial peptides and plant defence activators have made possible the de novo and rational design of novel peptides for use in crop protection. Here we report a novel chimeric protein, Hcm1, which was made by linking the active domains of cecropin A and melittin to the hypersensitive response (HR)-elicitor Hpa1 of Xanthomonas oryzae pv. oryzicola, the causal agent of rice bacterial leaf streak. The resulting chimeric protein maintained not only the HR-inducing property of the harpin, but also the antimicrobial activity of the cecropin A-melittin hybrid.

Hcm1 was purified from engineered Escherichia coli and evaluated in terms of the minimal inhibitory concentration (MIC) and the 50% effective dose (ED50) against important plant pathogenic bacteria and fungi. Importantly, the protein acted as a potential pesticide by inducing disease resistance for viral, bacterial and fungal pathogens. This designed drug can be considered as a lead compound for use in plant protection, either for the development of new broad-spectrum pesticides or for expression in transgenic plants.

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Biotechnological uses of enzymes from psychrophiles R. Cavicchioli, T. Charlton, H. Ertan, S. Mohd Omar, K. S. Siddiqui, T. J. Williams Volume 4, Issue 4, July 2011

Summary The bulk of the Earth's biosphere is cold (e.g. 90% of the ocean's waters are ≤ 5°C), sustaining a broad diversity of microbial life. The permanently cold environments vary from the deep ocean to alpine reaches and to polar regions. Commensurate with the extent and diversity of the ecosystems that harbour psychrophilic life, the functional capacity of the microorganisms that inhabitat the cold biosphere are equally diverse. As a result, indigenous psychrophilic microorganisms provide an enormous natural resource of enzymes that function effectively in the cold, and these cold-adapted enzymes have been targeted for their biotechnological potential. In this review we describe the main properties of enzymes from psychrophiles and describe some of their known biotechnological applications and ways to potentially improve their value for biotechnology. The review also covers the use of metagenomics for enzyme screening, the development of psychrophilic gene expression systems and the use of enzymes for cleaning.

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Mathematical models of cell factories: moving towards the core of industrial biotechnology Marija Cvijovic, Sergio Bordel, Jens Nielsen Volume 4, Issue 5, September 2011

Summary Industrial biotechnology involves the utilization of cell factories for the production of fuels and chemicals. Traditionally, the development of highly productive microbial strains has relied on random mutagenesis and screening. The development of predictive mathematical models provides a new paradigm for the rational design of cell factories. Instead of selecting among a set of strains resulting from random mutagenesis, mathematical models allow the researchers to predict in silico the outcomes of different genetic manipulations and engineer new strains by performing gene deletions or additions leading to a higher productivity of the desired chemicals. In this review we aim to summarize the main modelling approaches of biological processes and illustrate the particular applications that they have found in the field of industrial microbiology.

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Bifidobacterium population analysis in the infant gut by direct mapping of genomic hybridization patterns: potential for monitoring temporal development and effects of dietary regimens Rolf Boesten, Frank Schuren, Kaouther Ben Amor, Monique Haarman, Jan Knol, Willem M. de Vos Volume 4, Issue 3, May 2011

Summary A bifidobacterial mixed-species microarray platform was used in a proof-of-principle study to address the composition and development of bifidobacteria in DNA extracted from faecal samples. These were collected in a time-course of 2 years since birth and derived from human infants that were breastfed, standard formula-fed or received a prebiotic formula during their weaning period. A set of over 50 samples was analysed, testifying for the throughput of the designed platform for multiple genome hybridizations. The generated data revealed that faecal samples of breastfed infants contained a high abundance of genomic DNA homologous to Bifidobacterium breve. In contrast, faecal samples from standard formula-fed infants lacked detectable amounts of this B. breve DNA but contained genes with high similarity to B. longum. Remarkably, infants that received breastmilk and later a prebiotic formula consisting of a standard formula milk containing a mixture of specific galacto- and fructo-oligosaccharides, continued to harbour a B. brevedominant faecal population. One infant that received standard formula in combination with the additional B. lactis Bb12 culture, contained significant amounts of faecal DNA belonging to Bb12 but only during the period of ingestion.

The microarray platform showed sufficient sensitivity to analyse the B. breve group at the strain level. Overall, the B. breve populations observed in the faecal samples of the studied infants showed a stable composition over time and were unique per infant. In conclusion, our results show the applicability of comparative genome hybridization to study bifidobacterial populations in infant faecal samples without the use of any amplification step.

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Engineering Streptomyces coelicolor for heterologous expression of secondary metabolite gene clusters Juan Pablo Gomez-Escribano, Mervyn J. Bibb Volume 4, Issue 2, March 2011

Summary We have constructed derivatives of Streptomyces coelicolor M145 as hosts for the heterologous expression of secondary metabolite gene clusters. To remove potentially competitive sinks of carbon and nitrogen, and to provide a host devoid of antibiotic activity, we deleted four endogenous secondary metabolite gene clusters from S. coelicolor M145 – those for actinorhodin, prodiginine, CPK and CDA biosynthesis. We then introduced point mutations into rpoB and rpsL to pleiotropically increase the level of secondary metabolite production.

Introduction of the native actinorhodin gene cluster and of gene clusters for the heterologous production of chloramphenicol and congocidine revealed dramatic increases in antibiotic production compared with the parental strain. In addition to lacking antibacterial activity, the engineered strains possess relatively simple extracellular metabolite profiles. When combined with liquid chromatography and mass spectrometry, we believe that these genetically engineered strains will markedly facilitate the discovery of new compounds by heterologous expression of cloned gene clusters, particularly the numerous cryptic secondary metabolic gene clusters that are prevalent within actinomycete genome sequences.

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Microbial Biotechnology