"... a comprehensive suite that provides both breadth and depth ... provides a rich resource for the researcher, student, and educator ... an important reference book that provides a current overview of the biochemical underpinnings of the major features of the N cycle, while also providing some topical examples of the details of the N cycle in several environments, including plant symbiosis, the terrestrial environment, and the human microbiome. It is has previously been difficult to find research and education resources that provide readable, yet detailed, overviews of N cycle biology and chemistry, and this book nicely couples these high-level overviews that are likely to be highly cited, with a number of very specific topics. I suspect this book will be a major reference for many years to come, despite the rapid pace of research." from Jonathan Zehr (University of California, Santa Cruz, USA) writing in ASM Microbe read more ...

Nitrogen Cycling in Bacteria: Molecular Analysis Edited by: James W. B. Moir ISBN: 978-1-904455-86-8 Publisher: Caister Academic Press Publication Date: July 2011 Cover: hardback "a major reference for many years to come" (ASM Microbe)

"a beneficial purchase for any institution or systems biology consortium ... a valuable resource that will appeal to experimentalists and modellers alike." from Alison Graham (Newcastle University, UK) writing in Microbiology Today (2012) 39: 237 read more ...

Systems Microbiology: Current Topics and Applications Edited by: Brian D. Robertson and Brendan W. Wren ISBN: 978-1-908230-02-7 Publisher: Caister Academic Press Publication Date: June 2012 Cover: hardback "a valuable resource" (Micro. Today)

from Rico Barsacchi, Varadharajan Sundaramurthy, Kees Korbee, Jacques Neefjes, Tom Ottenhoff, Tiziana Scanu and Marino Zerial writing in Systems Microbiology: Current Topics and Applications:

Host-microbe interactions are complex phenomena spanning multiple levels of complexity, from environmental and ecological factors up to the cellular and genetic levels of host responses. At each of these levels a relationship is established between one or more microorganisms and the host, resulting in formation of various forms of associations ranging from symbiosis to parasitism. Pathogens have the potential to cause disease in their hosts through host-pathogen interactions in which host defences are challenged by the invasive capacities of the pathogen. The aim of this chapter is to give an outline of attempts made to unravel the components of host-pathogen interactions at the cellular and molecular levels and to discuss strategies to skew the balance in favour of the host, focusing our attention on crucial intracellular pathogens causing globally relevant diseases such as tuberculosis, gastroenteritis, influenza and malaria.

Further reading: Systems Microbiology   Related publications

from Chris P. Barnes, Maxime Huvet, Nathan Harmston and Michael P.H. Stumpf writing in Systems Microbiology: Current Topics and Applications:

Modelling methodologies in the life- and biomedical sciences are hampered by the complexity of the processes and systems at work. Modelling studies into prokaryotic systems require the elucidation of the mechanistic model. In this chapter we introduction modelling methodologies and discuss the problem of model (and parameter) inference. We comment on state-of-the-art research questions and provide a general discussion on how models can and should be used in order to better understand the structure, function and dynamics of biological systems. The aim is not to provide an introduction to modelling per se, but to provide readers with an overview on the available methodologies. The modelling approach chosen depends on the biological question at hand as well as a range of social factors.

Further reading: Systems Microbiology   Related publications

from Sylvain Tollis, Navin Gopaldass, Thierry Soldati and Robert G. Endres writing in Systems Microbiology: Current Topics and Applications:

Phagocytosis is the fundamental cellular process by which eukaryotic cells bind and engulf particles by deforming their plasma membrane. Particle engulfment involves particle recognition by cell-surface receptors, signalling, and remodelling of the actin cytoskeleton to guide the membrane around the particle in a zipper-like fashion. The signalling complexity is daunting, involving hundreds of different molecular species during the initial stages of engulfment. For instance, the well-characterised immune Fcγ and the integrin CR3 receptors signal to tyrosine kinases and Rho GTPases, ultimately regulating a wide variety of proteins, which direct actin polymerization and myosin-motor proteins for force generation and contraction. Despite the signalling complexity, phagocytosis also depends strongly on simple biophysical parameters, such as shape and cell stiffness, or membrane biophysical properties that are independent of the type of cell or particle. We argue that these emergent, universal features are particularly important to address in order to explain this evolutionary well-conserved and robust mechanism. In this chapter we review these universal features to describe the principles of phagocytosis. Specifically, we use a recently published model of phagocytic engulfment as a guide. Finally, we discuss state-of-the-art live-cell fluorescence microscopy, recently used to elucidate the dynamics of phospholipids, actin polymerization and myosins in the particle-shape recognition by the amoeba Dictyostelium.

Further reading: Systems Microbiology   Related publications

from Dany J.V. Beste and Johnjoe McFadden writing in Systems Microbiology: Current Topics and Applications:

Despite decades of research many aspects of the biology of Mycobacterium tuberculosis remain unclear and this is reflected in the antiquated tools available to treat and prevent tuberculosis. Consequently, this disease remains a serious public health problem responsible for 2 to 3 million deaths each year. Important discoveries linking M. tuberculosis metabolism and pathogenesis have renewed interest in the metabolic underpinning of the interaction between the pathogen and its host. Whereas, previous experimental studies tended to focus on the role of single genes, antigens or enzymes the central paradigm of systems biology is that the role of any gene cannot be determined in isolation from its context. Therefore systems approaches examine the role of genes and proteins embedded within a network of interactions. We here examine the application of this approach to studying metabolism of M. tuberculosis. Recent advances in high throughput experimental technologies, such as functional genomics and metabolomics, provide datasets that can be analysed with computational tools such as flux balance analysis. These new approaches allow metabolism to be studied on a genome scale and have already been applied to gain insights into the metabolic pathways utilized by M. tuberculosis in vitro and identify potential drug targets. The information from these studies will fundamentally change our approach to tuberculosis research and lead to new targets for therapeutic drugs and vaccines.

Further reading: Systems Microbiology   Related publications

from Dirk Bumann writing in Systems Microbiology: Current Topics and Applications:

Microbial infections still cause around one quarter of all deaths globally, despite the advances that have been made in the treatment of infectious disease. The increasing occurrence of drug resistant pathogens, both old and new, coupled with an increasingly mobile human population has creatd many novel opportunities for potential pathogens to meet new human hosts. All of this requires new prevention and control strategies but progress has been slow, despite recent technological advances and increased investment. The rapid increase in data proved difficult to translate into practical applications for human health care, and new approaches and analyses are needed to make the most of new opportunities. One of these is the use of the new tools of systems biology and this chapter will review the application of these to microbial pathogens.

Further reading: Systems Microbiology   Related publications

"... excellent volume ... This book is an essential reference for anyone interested in antibiotic resistance or discovery but also contains interesting chapters on the human microbiota and on current strategies for vaccine development. I highly recommend that you add this to your shelves." from Matt Hutchings (University of East Anglia, UK) writing in Microbiology Today (2012) read more ...

Emerging Trends in Antibacterial Discovery: Answering the Call to Arms Edited by: Alita A. Miller and Paul F. Miller ISBN: 978-1-904455-89-9 Publisher: Caister Academic Press Publication Date: August 2011 Cover: hardback "I highly recommend that you add this to your shelves" (Microbiol. Today)

from Olga Lomovskaya and Helen I. Zgurskaya writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

Multidrug efflux pumps adversely affect both the clinical effectiveness of existing antibiotics as well as the discovery process to find new ones. In this chapter, we summarize recent advances in structural and functional analyses of multi-component efflux pumps from Gram-negative bacteria with the focus on transporters belonging to the Resistance-Nodulation-cell Division superfamily. The unquestionably significant impact of these pumps on the effectiveness of antibiotics in clinical settings and their emerging role in bacterial pathogenesis makes them attractive targets for inhibition. We discuss modes of inhibition and current efforts to develop effective inhibitors of multidrug efflux pumps.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Eivind Almaas, Per Bruheim, Rahmi Lale and Svein Valla writing in Systems Microbiology: Current Topics and Applications:

The functional repertoire of an organism's metabolic network is closely linked to its phenotype and potential for utility in metabolic engineering applications. In this chapter, we discuss a systems biology view of Escherichia coli metabolism by integrating current genome-scale computational modelling approaches with available molecular genetics tools, as well as the experimental framework for metabolite and metabolic flux determination.

Further reading: Systems Microbiology   Related publications

from Diana Clausznitzer, Judith P. Armitage and Robert G. Endres writing in Systems Microbiology: Current Topics and Applications:

Bacterial chemotaxis is a paradigm for biological sensing and information transmission. The chemotaxis signal-transduction pathway allows cells to sense chemicals in their surroundings in order to regulate flagellated rotary motors, thus allowing them to swim towards nutrients and away from toxins. Importantly, cells are able to sense with remarkably high sensitivity over a wide range of chemical background concentrations. To make this possible, chemoreceptors do not signal independently but form clusters for amplification and integration of signals, as well as for adaptation to persistent stimulation. While chemotaxis in Escherichia coli has been exceptionally well characterised, new experimental facts still require revisions of existing models and thus further increase our understanding of sensing and signalling in bacteria. Additionally, experiments on other bacterial species such as Bacillus subtilis and Rhodobacter sphaeroides indicate that bacteria other than E. coli can have substantially different and more complex chemotaxis pathways, which provides renewed challenges for experimentalists and modellers alike. Here we discuss our current understanding as well as the frontiers of bacterial chemotaxis research.

Further reading: Systems Microbiology   Related publications

from Theresa Kouril, Alexey Kolodkin, Melanie Zaparty, Ralf Steuer, Peter Ruoff, Hans V. Westerhoff, Jacky Snoep, Bettina Siebers and the SulfoSYS consortium writing in Systems Microbiology: Current Topics and Applications:

Life at high temperature challenges the stability of macromolecules and cellular components, but also the stability of metabolites, which has received little attention. For the cell, the thermal instability of metabolites means it has to deal with the loss of free energy and carbon, or in more extremes, it might result in the accumulation of dead-end compounds. In order to elucidate the requirements and principles of metabolism at high temperature, we used a comparative blueprint modelling approach of the lower part of the glycolysis cycle. The conversion of glyceraldehyde 3-phosphate to pyruvate from the thermoacidophilic Crenarchaeon Sulfolobus solfataricus P2 (optimal growth-temperature 80ºC) was modelled based on the available blueprint model of the eukaryotic model organism Saccharomyces cerevisiae (optimal growth-temperature of 30ºC). In S. solfataricus only one reaction is different, namely glyceraldehyde-3-phosphate is directly converted into 3-phosphoglycerate by the non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase, omitting the extremely heat-instable 1,3-bisphosphoglycerate. By taking the temperature dependent non-enzymatic (spontaneous) degradation of 1,3-bisphosphoglycerate in account, modelling reveals that a hot lifestyle requires a cool design.

Further reading: Systems Microbiology   Related publications

from Olga M. Pena, John D. F. Hale and Robert E.W. Hancock writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

The increasing problem of resistance to antimicrobial agents, combined with the limited development of novel agents to treat infectious diseases is a serious threat to human morbidity and mortality around the world. Among the available strategies available to create new therapeutic agents is the enhancement of the multifunctional properties of the natural anti-infectives, cationic host defense (antimicrobial) peptides (HDPs). This chapter will provide a summary of our current understanding of the different types of HDPs including natural and synthetic peptides and their antimicrobial and immunomodulatory modes of action. Additionally, we will describe new approaches to peptide design and discuss both the therapeutic potential and prospective challenges in the utilization of peptides for antibacterial

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Elaine R. Lee, Kenneth F. Blount and Ronald R. Breaker writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

The need for new antibacterial drug targets increases as antibiotic resistant pathogens continue to arise. Researchers have recently begun to investigate whether structured noncoding RNAs such as riboswitches can be exploited as targets for new classes of antimicrobial compounds. Riboswitches are gene control elements made entirely of RNA, and in bacteria they are usually located in the 5' untranslated regions (UTRs) of messenger RNAs. These elements are capable of forming complex structures that selectively bind to specific fundamental metabolites and often control the expression of proteins critical for bacterial metabolism and survival. In principle, novel ligands could be designed that target specific riboswitches and alter the expression of the critical genes they regulate. Several riboswitch classes have begun to be examined as potential targets for new classes of antibacterial compounds. Herein we present some of the data generated by efforts to validate riboswitches as drug targets and discuss some of the key unanswered questions that will determine the ultimate success of antibacterial compounds that interact with these RNAs.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Leigh G. Monahan, Michael A. D'Elia and Elizabeth J. Harry writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

The alarming rise of antibiotic resistant bacteria in hospitals and the community has exposed a critical need for new drugs that are not merely variants of older antibiotics, but target previously unexploited proteins and pathways. The wealth of available knowledge on the process of bacterial cell division implicates the division pathway as an excellent potential target, and has aided target-driven approaches to identify novel inhibitors. In this chapter we discuss the therapeutic potential of inhibiting bacterial divison based on a strong foundation of basic research into the division mechanism and its regulation in model bacteria, and more recently, clinically relevant pathogens. In addition, we review the progress made towards identifying division inhibitors, describe new approaches for antibacterial drug development targeting division and discuss the potential challenges for the future of this exciting new area of antibacterial discovery.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Stephen Spiro writing in Nitrogen Cycling in Bacteria: Molecular Analysis:

Nitric oxide (NO) is synthesised in bacteria as a product of the reduction of nitrite or the oxidation of arginine. NO is growth inhibitory, due to its ability to inhibit respiratory oxidases and [Fe-S] cluster containing dehydratases. NO also reacts with oxygen and biologically relevant oxygen radicals (such as superoxide) to generate a number of other toxic reactive nitrogen species. NO detoxification is typically accomplished by oxidation to nitrate, or reduction to nitrous oxide or ammonia, and these activities have been associated with a variety of enzymes. In many cases, expression of the genes encoding NO detoxification activities is controlled by NO-sensitive regulatory proteins. This Chapter describes the different pathways for NO synthesis and consumption in bacteria, and the mechanisms and roles of the associated regulatory proteins. The Chapter also reviews the growing body of evidence that implicates NO in regulating other physiological processes, including [Fe-S] cluster biogenesis, metabolism, motility and biofilm development.

Further reading: Nitrogen Cycling in Bacteria: Molecular Analysis

from Elizabeth M. Baggs and Laurent Philippot writing in Nitrogen Cycling in Bacteria: Molecular Analysis:

Terrestrial ecosystems are a major source of nitrous oxide (N₂O), with soils accounting for ~70% of the atmospheric loading of this greenhouse gas. Here we provide a synthesis of current understanding of the environmental regulation of N₂O production and reduction through different microbial pathways, presenting examples of where measured emissions have been related to characterizations of the underpinning microbial communities. We explore the direct and indirect influence of plants on rhizosphere N₂O production, reduction and net emission, and the interactions between N₂O production and methane oxidation, as examples of coupling between the C and N cycles that need to be considered when developing appropriate and more targeted strategies for greenhouse gas mitigation.

Further reading: Nitrogen Cycling in Bacteria: Molecular Analysis

from Cristina Sánchez, Eulogio J. Bedmar and María J. Delgado writing in Nitrogen Cycling in Bacteria: Molecular Analysis:

Rhizobia are soil, Gram-negative bacteria with the unique ability to establish a N₂-fixing symbiosis on legume roots and on the stems of some aquatic legumes. During this interaction bacteroids, as rhizobia are called in the symbiotic state, are contained in intracellular compartments within a specialized organ, the nodule, where they fix N₂. When faced with a shortage of oxygen some rhizobia species are able to switch from O₂-respiration to using nitrates to support respiration in a process known as denitrification. The complete denitrification pathway comprises the sequential reduction of nitrate or nitrite to dinitrogen, via the gaseous intermediates nitric oxide and nitrous oxide. The enzymes involved in denitrification are nitrate-, nitrite-, nitric oxide- and nitrous oxide reductase, encoded by nar/nap, nir, nor and nos genes, respectively. In recent years it has emerged that many rhizobia species have genes for enzymes of some or all of the four reductase reactions for denitrification. In fact, denitrification can be readily observed in many rhizobia species, in their free-living form, in legume root nodules, or in isolated bacteroids. This chapter will focus on update progress on denitrification by rhizobia under free-living and symbiotic conditions.

Further reading: Nitrogen Cycling in Bacteria: Molecular Analysis

from Robert G.K. Donald and Annaliesa S. Anderson writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

Prophylactic anti-bacterial vaccines have been responsible for a drastic reduction in global bacterial diseases. Older vaccines made from attenuated whole cells or lysates have been largely replaced by less reactogenic acellular vaccines made with purified components, including capsular polysaccharides and their conjugates to protein carriers, inactivated toxins (toxoids) and proteins. Examples of vaccines in each category are reviewed to illustrate underlying strategies and associated technological advances such as polysaccharide conjugation and recombinant protein expression. In addition, progress and the current status in the development of new vaccines to prevent diseases caused by N. meningitidis serogroup B, S. aureus and C. difficle is summarized. Future progress will likely bring to the clinic passive immunotherapies based on monoclonal antibodies and new adjuvants, especially for use in vaccines against intracellular pathogens.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Arturo Casadevall writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

At the beginning of the 21^st century the therapeutic paradigm for the treatment of infectious diseases can be summarized by three words: kill the bug. In other words, the overwhelming majority of therapeutic interventions against microbial diseases are designed to help the host by damaging the microbe directly and/or interfering with its ability to replicate in tissue (Casadevall, 2006). This strategy has been termed the second age of antimicrobial therapy and was preceded by the era of serum therapy, which differed in the fundamental manner that serum was primarily an immunotherapeutic agent than enhanced host defenses (Casadevall, 2006). First and second age therapeutics differed in other ways including the chemistry of the therapeutic agent, their specificity and the form of manufacturing (Table 1). Second age therapeutics have been were tremendously successful and brought numerous drugs to the market that have saved countless lives. However, there are major trends at work that have significantly reduced the overall efficacy of second age therapeutics including widespread antimicrobial resistance, the emergence of new pathogenic microbes for which there are few drugs available and an epidemic of immunocompromised hosts where antimicrobial therapy is often less effective. Microbe-targeting strategies are limited in that they neglect the host; consequently, there are very few treatment strategies that aim to achieve a therapeutic outcome by enhancing host defenses. Microbe-targeting strategies include both microbe-specific and -non-specific drugs, each of which can put tremendous selection pressure on microbes that often result in the emergence of resistance. Non-specific microbe-targeting strategies have the additional problem that they can select for resistance in non-targeted microbes and their effects on host flora can have a variety of unintended deleterious consequences on host homeostasis. This chapter will consider these strategies in light of their historical development and analyze the advantages and disadvantages of specific and non-specific antimicrobial strategies.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Jay Fitzgerald, Younjoo Lee and Chaitan Khosla writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

Since the discovery of penicillin, the development of anti-infective drugs has been a central theme in the pharmaceutical industry through much of the 20^th century. However, the pace of developing new anti-infective agents has precipitously declined in the past two decades. The main reason for this change is an economic one - whereas the technical and regulatory risks associated with the development of a new broad-spectrum antibiotic are deemed unacceptably high, the financial returns derived from a targeted (narrow-spectrum) antibiotic are unattractive to the pharmaceutical industry. Meanwhile, the need for new anti-infective agents continues to be as urgent as ever. New business models are called for, ones that are grounded in the possibilities and realities of 21st century technologies for antibiotic discovery and development. This chapter discusses, using four selected examples, the opportunities for harnessing modern biosynthetic insights and engineering methods to discover new antibiotics.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from John W. Peters, Eric S. Boyd, Trinity Hamilton and Luis M. Rubio writing in Nitrogen Cycling in Bacteria: Molecular Analysis:

The large majority of biological nitrogen fixation occurs by the activity of Mo-nitrogenase. Mo-nitrogenase is found in a wide variety of bacteria and some Archaea and is a complex two component enzyme that contains multiple metal-containing prosthetic groups. The biochemistry of nitrogenase has a rich history and the enzyme is a model system for examining more general processes in biology such as electron transfer, metal-cofactor assembly, and even nucleotide dependent signal transduction. In addition, studies examining nitrogenase has pushed the envelope in terms of the practical application of various spectroscopic methods. This chapter treats the historical perspective and development of key advances in our understanding of the biochemistry of Mo-nitrogenase from its infancy and early beginnings in the 1960s to the state of the field today.

Further reading: Nitrogen Cycling in Bacteria: Molecular Analysis

from Marc Strous writing in Nitrogen Cycling in Bacteria: Molecular Analysis:

Although nitrate is a powerful electron acceptor, it was generally believed that it could not be used to activate recalcitrant substrates such as ammonium and methane. Only in the past decades, bacteria were identified that could activate these compounds. These bacteria have become known as anaerobic ammonium oxidizing ('anammox') bacteria and 'denitrifying methanotrophs'. Each makes use of a different and so far unique pathway of nitrate reduction with dinitrogen gas as the end product. Anammox bacteria activate ammonia with nitric oxide, leading to the production of hydrazine (N₂H₄). Denitrifying methanotrophs dismutate two molecules of nitric oxide into molecular oxygen (O₂) and nitrogen (N₂). In this chapter bacteria, pathways, cell biology and environmental relevance are discussed.

Further reading: Nitrogen Cycling in Bacteria: Molecular Analysis

from Alex J. O'Neill writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

Antibiotic resistance is conferred by heritable genetic determinants that enable a bacterium to grow and cause disease in the presence of therapeutically-achievable concentrations of the corresponding antibiotic. However, bacteria may also become refractory to the killing action of antibacterial agents in ways that do not fit this definition, and which are collectively referred to here as 'antibiotic survival'. These phenomena, which include drug indifference, tolerance, persistence, and the recalcitrance of biofilms to antibacterial agents, are believed to play a central role in antibacterial treatment failure. In addition, they can extend the duration of treatment required to resolve bacterial infections, and facilitate the emergence of acquired antibiotic resistance. This chapter will provide an overview of the different types of antibiotic survival, and will discuss chemotherapeutic approaches to minimising or overcoming the problems that they present to effective antibacterial treatment.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from James W. B. Moir writing in Nitrogen Cycling in Bacteria: Molecular Analysis:

Surfaces of the human body exposed to the environment are heavily colonised by bacteria. The bacteria that live in these environments are frequently exposed to anoxia and to nitric oxide which is generated by the host. Dealing with these two environmental factors often involves implementing nitrogen cycle processes to (i) maintain growth and survival by respiration in the absence of oxygen, and (ii) detoxify the free radical nitric oxide. In this chapter I explore the nitrogen cycling processes relevant to the human body environment. Whilst microbial colonisation is part of the normal physiology of the human body, the body can also be exposed to pathogenic bacteria which also utilise nitrogen cycling processes. Specific sections deal with the processes and consequences of nitrogen cycling by key human pathogens Pseudomonas aeruginosa, Mycobacterium tuberculosis and the pathogenic Neisseria species N. meningitidis and N. gonorrhoeae.

Further reading: Nitrogen Cycling in Bacteria: Molecular Analysis

from Shilpa Bali and Stuart J. Ferguson writing in Nitrogen Cycling in Bacteria: Molecular Analysis:

The respiratory reactions of the nitrogen cycle are those of denitrification, the successive reductions of nitrate, nitrite, nitric oxide and nitrous oxide to nitrogen gas, and those of nitrification, oxidation of ammonium first to nitrite and then to nitrate. These reactions are catalysed by enzymes containing one or more of the cofactors, heme (non-covalent as in b-type hemes, or covalent as in c-type hemes), iron sulphur, molybdenum and copper centres. With the exception of molybdenum, these redox active cofactors are also integral to the operation of the respiratory chain systems that deliver electrons to and from the individual enzymes. This chapter gives an overview of current knowledge about how each of these cofactor types is attached to their respective apo-proteins, in the context that many of the proteins are located on the periplasmic side of the membrane and delivery to that compartment is either as an unfolded protein, and thus mediated by the sec system, or as a folded protein and thus facilitated by the tat system.

Further reading: Nitrogen Cycling in Bacteria: Molecular Analysis

from Bret R. Sellman and C. Ken Stover writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

Prior to the use of antibiotics, antibody (or serum) therapy was used with some success to treat bacterial infections. Antibiotics almost completely replaced the use of antibody therapies for bacterial disease with few exceptions. Based upon the information available at the time, this was an obvious progression given the broader spectrum activity of antibiotics. Antibiotics revolutionized medicine and the approach to treating infectious disease. In addition to their broad spectrum, they exhibited few side-effects relative to the potential for serum sickness (following the administration of equine immune serum) and they were inexpensive. But bacterial resistance to antibiotics became evident in the decades to follow, and we are now faced with a shortage of effective antibiotics and a need for alternative approaches to stand-alone antibiotic therapy. One such approach which could supplement antibiotic use, thereby removing some of the selective pressure from antibiotics, is monoclonal antibody therapy or prophylaxis. Recent advances in monoclonal antibody technology and discovery strategies and the ability to make a fully human antibody have led to the marketing of ~30 recombinant antibodies and Fc fusion proteins to treat a variety of human diseases. Although this technology has yet to yield an antibacterial product, many clinical and preclinical programs are underway to explore varied and novel approaches to monoclonal antibody-based anti-infectives.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Alita A. Miller and Paul F. Miller writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

A global public health crisis due to antibiotic resistance may be imminent. Several organizations are working to mitigate the lack of new, effective drugs either in development or in the clinic by proposing strategies for re-investment in antibacterial research. Although it is imperative that regulatory issues be resolved and strategic policies be put in place, it is equally important to define the scientific path required to address this crisis. The goal of this textbook, therefore, is to offer new ways of thinking about antibiotics and technical solutions for the resistance problems we face. By summarizing innovative new concepts and approaches from leading experts around the world, we hope to enable the implementation of the re-investment strategies that are so urgently needed.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Audrey N. Schuetz and Yi-Wei Tang writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

Despite the rising numbers of multidrug resistant pathogens, and their continuously emerging resistance patterns, few novel antibacterial agents have been approved or released recently. In order to combat this problem, efforts are being made to extend the utility of existing antibiotics as long as possible, while attempting to develop new drugs. The clinical practice of evidence-based therapy, based on diagnosing early and narrowing antimicrobial coverage, with timely administration of an antibiotic, may help alleviate the problem. Diagnostic procedures optimized for accuracy and turn-around time further improve patient therapy. We review techniques currently in use in diagnostic microbiology, such as direct microscopic examination, rapid biochemical and antigen testing, microorganism culture, serologic diagnosis, and a variety of molecular diagnostic techniques. In addition, we introduce various emerging diagnostic techniques, which show promise in their application towards a more exact antibacterial practice. Such emerging technologies include ultra high-throughput sequencing, microarray science, quantum dots, PCR electrospray ionization mass spectrometry, atomic force microscopy, and carbon nanotubes. Point-of-care testing devices are also reviewed. As diagnostic methods have changed over the years, the novel applications of these technologies hold promise in their rapidity and accuracy, while showing potential application in drug target testing and drug discovery.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Jörg Simon writing in Nitrogen Cycling in Bacteria: Molecular Analysis:

Nitrogen compounds serve as electron donor and electron acceptor substrates in several modes of microbial respiration such as nitrification, nitrate reduction, denitrification and nitrite ammonification. There are several well-established model bacteria for each of these processes and in many, though not all, cases the various dehydrogenases and reductases involved in the conversion of nitrogen compounds have been thoroughly characterized including the determination of high-resolution structure models. On the other hand, the architecture of complete respiratory electron transport chains is often less-well known, especially with respect to donor:quinone dehydrogenase and quinol:acceptor reductase systems that connect the membranous quinone/quinol pool to the oxidative or reductive part of an electron transport chain. Notably, a rather limited number of redox-active protein modules has evolved that is employed by different bacteria in a versatile manner. Occasionally, bacterial species even display different electron transport chain set-ups despite using the same type of substrate-converting enzyme. This article highlights commonalities and differences in the organisation of bacterial respiratory electron transport chains that are involved in environmentally important N-cycle processes and discusses the relevance of this knowledge in the context of microbial bioenergetics and (meta)genomics.

Further reading: Nitrogen Cycling in Bacteria: Molecular Analysis

from Haruaki Tomioka writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease to cause morbidity and death. However, the development of new drugs for the treatment and prophylaxis of TB has been slow. Therefore, novel types of antituberculous drugs, which act on the unique drug targets in MTB pathogens, particularly the drug targts related to the establishment of mycobacterial dormancy in host's macrophages, are urgently needed. In this context, it should be noted that current anti-TB drugs mostly target the metabolic reactions and proteins which are essential for the growth of MTB in extracellular milieus. It may also be promising to develop another type of drug that exerts an inhibitory action against bacterial virulence factors which cross talk and interfer with signaling pathways of MTB-infected host immunocompetent cells such as lymphocytes, macrophages and NK cells, thereby changing the intracelluar milieus favorable to intramacrophage survival and growth of infected bacilli. In this chapter, I will describe recent approaches to identify and establish novel potential drug targets in MTB, especially those related to mycobacterial dormancy and cross-talk with cellular signaling pathways.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Thomas Bjarnsholt, Tim Tolker-Nielsen and Michael Givskov writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

It is now evident that bacteria assume the biofilm mode of growth during chronic infections. The important hallmarks of biofilm infections are development of local inflammations, extreme tolerance to the action of conventional antimicrobial agents and an almost infinite capacity to evade the host defense systems in particular innate immunity. In the biofilm mode, bacteria use cell to cell communication termed quorum-sensing (QS) to coordinate expression of virulence, tolerance towards a number of antimicrobial agents and shielding against the host defense system. Chemical biology approaches may allow for the development of new treatment strategies focusing on interference with cell to cell communication with the aim of primarily disabling expression of virulence, immune shielding and antibiotic tolerance. Here we present our experience with screening and testing small molecule chemistry for N-acyl homoserine lactone dependent QS inhibition. In addition we present our thoughts with respect to advantages and potential limitations of the intervention strategies described.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Risini D. Weeratna and Michael J. McCluskie writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

Infectious disease remains one of the main causes of mortality and morbidity worldwide. Vaccination has had the greatest impact of any medical intervention technique in controlling infectious diseases. Most notably, eradication of smallpox was achieved through concerted and rigorous mass vaccination programs, and the incidence of diphtheria, pertussis, polio and other childhood diseases have been significantly reduced through routine infant immunization. However, with a move away from whole-killed vaccines for safety reasons, a key challenge in realizing the full potential of vaccination has been the lack of immunogenicity of many novel vaccines especially in certain populations such as the elderly and the immunocompromised. Adjuvants are a key component in enhancing immunogenicity of vaccines. Furthermore, adjuvants can play a vital role in facilitating the induction of the appropriate type of immunity that is required to either prevent, such as in prophylactic vaccines, or to treat, such as in therapeutic vaccines. Therefore, careful consideration of the choice of adjuvants becomes quintessential for developing an effective vaccine. This chapter focuses on the importance of choosing the correct adjuvant or adjuvant combination to induce the appropriate immune responses to control the target pathogen.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Ronald J. Quinn and Jeffrey E. Janso writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

Natural products and derivatized natural products, produced mainly by actinomycetes, have been one of the most successful sources of drugs used to treat and cure infectious diseases. However, many bacteria have quickly become resistant to the majority of antibiotics in use today prompting an urgent need to discover new classes of antibacterial compounds. The goal of this chapter is to summarize some of the recent advances that favorably position natural products drug discovery in the quest to discover new antibacterial agents. This includes new sources of biodiversity such as plants and the oceans as well as the overlooked potential within common soil-derived actinomycetes. Other encouraging advancements include: (1) the development of new culturing techniques, which have enabled the isolation of microbes that were once thought to be uncultivable, (2) the impact of sequencing technology and bioinformatics that have made strain dereplication more reliable and revealed that actinomycete genomes encode far more secondary metabolite gene clusters than originally thought and (3) the use of innovative methods to express and exploit these orphan biosynthetic pathways. Finally, the ability to dereplicate, isolate and elucidate the structure of natural products from less and less sample quantity will also be discussed.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from L. Silvia Munoz-Price, and John P. Quinn writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

We summarize the epidemiology, clinical presentation, and current treatment options for the most clinically relevant multidrug resistant Gram-positive and Gram-negative organisms. Additionally, we describe the challenges faced by pharmaceutical companies within the antimicrobial research and development field, especially the disproportion between the degree of investment (both monetary and time) required and the relatively small profit antimicrobial agents bring. Finally, some potential solutions for the lack of antimicrobial agents are discussed. These include more widespread use of the Orphan Drug Act, patent extensions, and the Biomedical Advanced Research and Development Authority (BARDA).

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Juilee Thakar and Eric T. Harvill writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

Integrated pharmacokinetic-pharmacodynamic models are commonly used to study the in vivo dynamics of antimicrobial agents and bacterial pathogens. These models are extremely useful for understanding the properties of antimicrobial agents such as absorption, transport, rate of binding, etc. However, they fail to consider within-host aspects of the infectious process that are likely to affect the bacterial-host interactions. For example, immune-mediated mechanisms to contain bacteria or limit their access to nutrients can also affect the access of a drug to its bacterial target. Alternatively, pathogens have various strategies to sequester themselves from host immune mechanisms that can also affect the access of therapeutic agents. The search for new antibacterial agents that will be effective in vivo can be substantially informed by an understanding of the within-host dynamics of bacterial pathogens. Mathematical modeling of immune responses can assist in this process by providing new predictions, by offering mechanistic understanding and by revealing the gaps in our current understanding. Such models are based on experiments that reveal the components of the immune system that play important roles during infections. But knowing the components alone usually provides only a static picture of bacterium-host interactions. Mathematical models aim to use the information obtained from experiments to construct the interactions and dependencies between various components. Thus mathematical models offer a mechanistic understanding of the interplay between various immunological processes and simulations of these models give a dynamic view of the entire process. In this chapter we will first provide an overview of pharmacokinetic and pharmacodynamic models followed by a review of some of the immunological processes involved in bacterial infections which are generally ignored in pharmacodynamic models but are likely to affect access or activity of treatments. We will then discuss the development of mathematical models by different approaches. We will end the chapter by exploring implications of these models in the discovery of new antibacterial agents.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Rob J.M. van Spanning writing in Nitrogen Cycling in Bacteria: Molecular Analysis:

Specialized denitrifiers recruit 2 β-propeller enzymes in their anaerobic nitrate respiratory electron transfer network, one of which is an iron containing cd₁-type nitrite reductase, termed NirS, and the other is a copper containing nitrous oxide reductase, NosZ. Together they complement a full denitrification pathway along with nitrate and nitric oxide reductases for the sequential reduction of nitrate to dinitrogen gas. These enzymes are tightly controlled on the level of expression and activity not only according to an energetic hierarchy but also to ensure a balanced conversion of the N-oxides and to prevent the accumulation of the toxic intermediates nitrite and nitric oxide. The adaptive response during the switch from aerobic respiration to denitrification is orchestrated by a dedicated signal transduction network that integrates environmental and intracellular signals and passes these on to the DNA. Amongst these signals are oxygen, denitrification intermediates (nitrate, nitrite, nitric oxide), the redox state of the respiratory components, and metal availability (copper, iron). The coordinate acquisition of these metals during the oxic-anoxic shift is a challenge since their bioavailability requires different reduction states and oxygen tensions.

Further reading: Nitrogen Cycling in Bacteria: Molecular Analysis

from Heather B. Felise, Toni Kline & Samuel I. Miller writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

Antibiotic resistance is threatening our ability to treat bacterial diseases. Scientific development to define new antibacterial targets, including those that inhibit microbial virulence rather than target essential cellular functions, is required to develop the therapeutics of the future. In this chapter we will discuss the feasibility of Gram-negative secretion systems as therapeutic targets, provide a synopsis of current research on the identification and development of secretion inhibitors, and discuss their possible future utility as antimicrobial agents.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Adam M. Nelson and Vincent B. Young writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

Recent technological advances have expanded the tools available for study of the indigenous human microbiota. One of the early limitations in this field was the difficulty in recovering most residents of the community via standard culture-based methods. Many residents of the flora are anaerobic or microoxic, require specific nutrients, or are dependant on microbe-microbe/microbe-host interactions that are difficult to replicate in vitro, thus making their cultivation difficult. Naturally, the easiest species to grow in the laboratory have been the best studied. However, these cultivatable species are only a fraction of the total population of the microbiota. This chapter will introduce both the culture and non-culture based techniques being used to look deeper into the population structure both on a temporal and spatial scale. It will also discuss how disruptions (including those mediated by the administration of antibiotics) of the microbiota can produce changes in human health, and outline ongoing efforts by the National Institutes of Health and international investigators to study the indigenous microbiota.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Robert van Lis, Anne-Lise Ducluzeau, Wolfgang Nitschke and Barbara Schoepp-Cothenet writing in Nitrogen Cycling in Bacteria: Molecular Analysis:

On modern planet Earth, a multitude of nitrogen cycle enzymes equilibrate the atmospheric reservoir of dinitrogen with the more oxidized and more reduced nitrogen compounds essential for life. The respective enzymes are elaborate entities and the reactions performed are complicated and in cases energetically challenging. Nitrogen, however, must have been a crucial element already at life's very beginnings which raises the question how the primordial nitrogen cycle of emerging life in the Archaean - necessarily using simpler and likely fewer enzymes - may have evolved into the very complex network of present planet Earth. To address this question, we have analysed molecular phylogenies of the presently known enzymes involved in the present day nitrogen cycle. The results collected and presented in this chapter indicate that in the Archaean, the enzymatic part of this cycle was restricted to a partial segment of the modern energy conserving denitrification pathway and that abiotic redox conversions of nitrogen specific to the geoenvironment of the Archaean were the evolutionary precursors of many reactions now requiring enzyme catalysis. As found in recent years for other core metabolic processes, the biological nitrogen cycle appears to be evolutionarily rooted in inorganic chemistry.

Further reading: Nitrogen Cycling in Bacteria: Molecular Analysis

from David Richardson writing in Nitrogen Cycling in Bacteria: Molecular Analysis:

The redox reactions of the nitrogen cycle comprise a large number of oxidative and reductive reactions that are catalysed by wide variety of enzymes with different catalytic centres. These enzymes are frequently organised as multi-protein complexes and in some recently emerging cases enzymes catalysing different reactions of the N-cycle appear to form super-complexes. This review will survey some of these N-cycle protein complexes.

Further reading: Nitrogen Cycling in Bacteria: Molecular Analysis

from Jason Gill and Ryland F. Young III writing in Emerging Trends in Antibacterial Discovery: Answering the Call to Arms:

A bacteriophage, or "phage", is a virus that infects bacteria. This chapter is aimed at assessing the record and potential of the use of phage and phage-derived molecules in antibacterial therapeutics and prophylactics. Unlike other areas of current biomedicine, phage therapy has a long history that pre-dates even the basics of modern biology, and even the development of phage biology itself. Thus it is important to reflect on the historical record to establish a context before considering the more recent literature and, finally, the prospects and obstacles facing phage therapy at the current time. In addition, although the study of phage was vibrant through the mid 1970s, the last decades of the 20^th and the first decade of the 21^st centuries witnessed a drastic contraction in the number of phage biology laboratories. This has led now to an odd situation where interest and activity in phage research are outstripping the available expertise. Accordingly, a section of this chapter is devoted to a summary of the fundamental characteristics of bacteriophage that would be important to the prospective phage therapist. Next, we present a review and metareview of the recent phage therapy literature and then summarize the current practices in the field. Finally, we consider the future, in terms of what should be done, according to our perspective. Please note that throughout this text, we define terminology for elements and concepts important to phage biology and its practical applications. We have done this in an overt attempt to simplify the text, but in some cases we admit to promoting what we think is better and less confusing terminology than that currently in general use. To this end, a glossary is provided at the end of the chapter.

Further reading: Emerging Trends in Antibacterial Discovery: Answering the Call to Arms

from Conrado Moreno-Vivián, Víctor M. Luque-Almagro, Purificación Cabello, M. Dolores Roldán and Francisco Castillo writing in Nitrogen Cycling in Bacteria: Molecular Analysis:

The incorporation of inorganic nitrogen into cell material is known as nitrogen assimilation. Usually, ammonium is the preferred inorganic nitrogen source for microorganisms. Ammonium assimilation requires the transport of this ion into the cells and its further incorporation into carbon skeletons, mainly through the glutamine synthetase-glutamate synthase pathway. Alternatively, glutamate dehydrogenase may also contribute to ammonium assimilation under certain conditions. Glutamine synthetase is the key enzyme for the regulation of ammonium assimilation; its activity is usually controlled by reversible covalent modification or feedback mechanisms and, at the gene expression level, transcription is often controlled by general nitrogen regulatory systems that vary depending on the organisms. In addition, ammonium transport is also subjected to regulation by carbon and nitrogen availability. Oxidized nitrogen compounds like nitrate and nitrite may be also used as nitrogen sources by many bacteria and archaea. Nitrate assimilation requires nitrate transport into the cells and two enzymes, nitrate and nitrite reductases, which catalyze the two-electron reduction of nitrate to nitrite and the six-electron reduction of nitrite to ammonium, respectively. These assimilatory enzymes are structural and functionally different to respiratory nitrate and nitrite reductases. Control of nitrate assimilation in different organisms may involve distinct regulatory proteins and mechanisms, but usually the process is regulated by nitrate and/or nitrite induction (pathway-specific control) and by ammonium repression (general nitrogen control).

Further reading: Nitrogen Cycling in Bacteria: Molecular Analysis