from David E. Whitworth writing in Bacterial Regulatory Networks:

Two-component systems (TCSs) are signalling pathways found abundantly in prokaryotes, and they are the dominant mechanism for stimulus-responsive adaptation in such organisms. An ever-increasing number of physiological phenomena are known to be regulated by TCSs, including cell cycle progression, pathogenesis, motility, and biofilm formation. The basic TCS comprises a receptor protein (sensor kinase) which autophosphorylates in response to a stimulus. The phosphoryl group is then directly transferred to a response regulator protein (the second component) that has a phosphorylation-dependent effector function. While the most basic TCSs are relatively well understood, there are many 'atypical' systems, which exhibit additional mechanistic features (for instance, regulation of sub-cellular location, intrinsic and extrinsic phosphatase activities, and cross-communication between TCSs), adding complexity to their signalling properties. The relatively recent availability of complete prokaryotic genome sequences has also provided new opportunities to appreciate global features of TCS function. For example, analyses have provided insights into TCS evolution, which in turn have yielded computational methods for evaluating TCS protein partnerships. This chapter provides an overview of the common features of TCSs from a historical perspective, and then describes current understanding regarding the mechanisms of TCS function. Finally, outstanding questions regarding TCS function are discussed.

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from Efthimia Lioliou, Cédric Romilly, Thomas Geissmann, François Vandenesch and Pascale Romby writing in Bacterial Regulatory Networks:

Many pathogenic bacteria cause serious diseases in humans, animals, and plants. Due to the appearance of resistance to multiple antibiotics, it has become important to fully understand the regulatory networks that lead to the production of virulence factors that help the bacteria combat the host defense machinery, acquire nutrients, and survive and/or proliferate within the host. In recent years, complex interplays between transcriptional regulatory proteins, two-component systems, and regulatory RNAs have been described, establishing the gene expression patterns in pathogenic bacteria. In this review, several examples will illustrate the diversity of regulatory RNAs and how they are integrated into the regulatory circuits required for virulence gene expression, with special emphasis on the mechanisms of regulation at the molecular level.

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from Pierre Cornelis and Simon C. Andrews writing in Bacterial Regulatory Networks:

For the vast majority of bacteria, iron is an essential element that is not readily available due to the poor solubility of the oxidized Fe³⁺ form that prevails aerobically. Because of this, bacteria inhabiting aerobic niches often suffer deficiencies in iron supply. Pathogenic bacteria experience a particularly acute form of iron-restriction. This arises from the host's 'iron-withdrawal response' to infection, whereby iron availability is constrained by increasing lactoferrin (an iron-chelating, bacteriostatic, extracellular glycoprotein) levels and reducing the degree of iron saturation for the circulating iron-transport protein, transferrin. The importance of iron to bacteria stems from its multiple metabolic roles. Examples of its crucial metabolic involvement include redox-stress resistance (e.g. heme-bearing catalases) and DNA manufacture (di-Fe containing ribonucleotide reductases). Although indispensible, iron is an unfriendly, hazardous metal as the Fe²⁺-triggered Fenton reaction produces destructive reactive oxygen species (ROS) such as superoxide (O2^-), hydrogen peroxide (H₂O₂) as well as the highly reactive hydroxyl radical (^˚OH).

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from Zulma R. Suárez-Moreno, Juan F. González, Giulia Devescovi and Vittorio Venturi writing in Bacterial Regulatory Networks:

Bacteria regulate gene expression in a population dependent manner using a sophisticated mechanism based on the production and sensing of chemical signals, known as quorum sensing. Such synchronized response in bacterial populations constitutes a form of multicellularity and enables adaption and survival in challenging environments. Although current evidence shows that the predominant signaling molecules produced by Gram-negative bacteria are N-acyl derivatives of homoserine lactones (AHLs), bacteria use a wide variety of signals. In this chapter we provide an overview of quorum sensing in Gram-negative bacteria, and discuss current and future trends in this field of research.

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from Charles J. Dorman writing in Bacterial Regulatory Networks:

H-NS is an abundant DNA binding protein that has been found to influence the expression of hundreds of genes in those Gram-negative bacteria, chiefly Escherichia coli and Salmonella enterica, where its regulatory effects have been investigated. It also has the potential to organize the structure of the nucleoid. H-NS has a preference for binding to A+T-rich DNA and this preference underlies its targeting of genes that have been acquired by horizontal transfer. H-NS usually acts as a transcriptional silencer by binding to a nucleation site followed by lateral spreading with or without the creation of DNA-protein-DNA bridges; it may also act as an architectural component in the nucleoid. Bacteria use a multitude of mechanisms to displace H-NS or to attenuate its negative influence on gene expression. A paralogue of H-NS, called StpA, is an efficient RNA chaperone and controls a regulon of genes in S. enterica by influencing expression of the RpoS sigma factor. Orthologues of H-NS have been discovered on large self-transmissible plasmids, introducing a new dimension in considerations of the roles of H-NS-like proteins in horizontal gene transfer. Importantly, analogues of H-NS are now being discovered and characterized in Gram-negative bacteria such as Pseudomonas that are only distantly related to E. coli, in the medically important actinomycete Mycobacterium tuberculosis and even in Gram-positive organisms such as Bacillus subtilis.

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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 Karlijn C. Bastiaansen, Wilbert Bitter and María A. Llamas writing in Bacterial Regulatory Networks:

Gene expression in bacteria is mainly controlled at the level of transcription initiation. To achieve this process a number of different mechanisms have evolved, one of which is the utilization of alternative sigma factors. Sigma factors are small proteins that associate with the RNA polymerase core enzyme (RNAPc) and direct it to specific promoter sequences, where they initiate gene transcription. Bacteria are able to regulate transcription initiation by synthesizing and activating different sigma factors that recognize different promoter consensus sequences. The largest group of alternative sigma factors consists of the so-called extracytoplasmic function (ECF) sigma factors that regulate gene expression in response to cell envelope stresses or environmental stimuli. The activity of ECF sigma factors is controlled by anti-sigma factors and a complex cascade of regulated (proteolytic) modifications. In gram-negative bacteria, ECF sigma factors are also controlled by cell-surface signalling (CSS), a regulatory system that includes an outer membrane receptor in the signal transduction pathway. In this chapter we will discuss the general composition and function of ECF sigma factors and their role in cell envelope stress responses and CSS.

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from J. Maxwell Dow, Yvonne McCarthy, Karen O'Donovan, Delphine Caly and Robert P. Ryan writing in Bacterial Regulatory Networks:

Cyclic di-GMP is now recognised as an almost universal second messenger in eubacteria that acts to regulate a wide range of functions including developmental transitions, adhesion, biofilm formation, motility and the synthesis of virulence factors. Cyclic di-GMP is synthesised from two GTP molecules by diguanylate cyclases that have a GGDEF domain and degraded by phosphodiesterases with either an EAL or HD-GYP domain. These proteins often have associated signal input domains, suggesting that their enzymatic activity may be modulated by different environmental or cellular cues. Cyclic di-GMP exerts a regulatory action through binding to diverse receptors that include a small protein domain called PilZ, transcription factors, enzymatically-inactive GGDEF, EAL or HD-GYP domains and riboswitches. The multiplicity of GGDEF, EAL and HD-GYP proteins together with a range of receptors within the same bacterial cell indicates the considerable complexity of cyclic di-GMP signalling. This has led to the concept of discrete pools of the nucleotide that are generated locally and act to influence intimately associated targets. A number of signalling proteins may be organised in a regulatory network to control a common function(s). Understanding cyclic di-GMP signalling may afford strategies for inhibition of biofilm formation and virulence factor synthesis in bacterial pathogens.

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from James D. Bryers writing in Microbial Biofilms: Current Research and Applications:

Clinically related research on biofilms has expanded exponentially in the past ten years due to the pandemic of nosocomial (hospital-related) infections. Biofilms are thought to cause a significant amount of all human microbial infections, according to the Centers for Disease Control and Prevention. Nosocomial infections are the fifth leading cause of death in the U.S. with more than two million cases annually (or approximately 10% of American hospital patients). The difficulty of eradicating biofilm bacteria with classic systemic antibiotic treatments is a prime concern of medicine. Biofilm bacteria can be up to a thousand times less susceptible to antimicrobial stress than their freely suspended counterparts. This chapter discusses the pathogenesis of a number of biofilm-mediated infections, including: oral infections, biomedical device based infections, osteomyelitis, otitis media, and others. Emerging research in biofilm control and prevention is also reviewed.

Further reading: Microbial Biofilms: Current Research and Applications

from Patricia C. Burrows, Simone C. Wiesler, Zhensheng Pan, Martin Buck and Sivaramesh Wigneshweraraj writing in Bacterial Regulatory Networks:

Amongst the many accessory factors that bind RNA polymerase (RNAp) and serve to control its activities, sigma (σ) factors ubiquitously feature in programming of gene expression in response to abiotic and biotic cues. Here we review the role of the major variant σ factor, σ⁵⁴, in the expression of gene sets used for establishing the virulence of a wide range of pathogenic bacteria. The tight coupling of σ⁵⁴-dependent transcription to signalling pathways underpins the regulation of such systems, and allows a wide dynamic range of gene expression.

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from Kathryn A. Scott, Elizabeth E. Jefferys, Benjamin A. Hall, Mark A. J. Roberts and Judith P. Armitage writing in Bacterial Regulatory Networks:

Chemotaxis is the process by which bacteria migrate towards environments that are favourable for growth. Changes in the concentration of attractants or repellents are detected by receptors, which are usually transmembrane proteins. These receptors transduce the signal to the interior of the cell where a two-component system ultimately leads to changes in motile behaviour. Chemotaxis emerged as a beneficial trait for survival early in the evolution of bacteria and archaea. A core set of proteins is common to the chemosensory networks in many different species. During the evolution of bacteria this core network has diversified and expanded. Here we describe the conserved apparatus in the steps necessary for chemotaxis; sensing of chemoeffectors, signalling to the motility apparatus, rapid signal termination, and adaptation. We then highlight examples from species with complex chemosensory networks to illustrate the variations in chemotactic apparatus that have arisen from the common core.

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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 Robert J. Goldstone, Roman Popat, Matthew P. Fletcher, Shanika A. Crusz and Stephen P. Diggle writing in Microbial Biofilms: Current Research and Applications:

It is now well recognised that populations of bacteria from many Gram-positive and Gram-negative species cooperate and communicate to perform diverse social behaviours including swarming, toxin production and biofilm formation. Communication between bacterial cells involves the production and detection of diffusible signal molecules and has become commonly known as quorum sensing (QS). In addition, an evolutionary perspective on QS illuminates important phenomena which help in understanding the prevalence and diversity of QS phenotypes and strategies under various conditions. The research fields of QS and biofilm formation often overlap with a number of studies demonstrating that QS is an important regulatory mechanism of biofilm formation in a variety of bacterial species. However in contrast, there are conflicting reports, demonstrating that QS appears to play a minimal role in the development of biofilms. Our aim in this review is to highlight the key findings with respect to QS and the subsequent impact on biofilm formation. We also discuss QS and cooperation in the context of social evolution and how this may impact on the development and maintenance of microbial biofilms.

Further reading: Microbial Biofilms: Current Research and Applications

from Venkatachalam Lakshmanan, Amutha Sampath Kumar and Harsh P. Bais writing in Microbial Biofilms: Current Research and Applications:

Microorganisms have historically been studied as planktonic or free-swimming cells, but most exist as sessile communities attached to surfaces, in multicellular assemblies known as biofilms. In the process of coping with both the pathogenic and beneficial interactions, the rhizosphere of plant roots encourages formation of sessile communities that begins with the attachment of free-floating microorganisms to a surface. Certain bacteria such as plant growth promoting rhizobacteria not only induce plant growth but also protect plants from soil-borne pathogens in a process known as biocontrol. Contrastingly, other rhizobacteria in a biofilm matrix may cause pathogenesis in plants. Although research suggests that biofilm formation on plants is associated with biological control and pathogenic response, little is known about how plants regulate this association. The scope of this chapter is restricted to biofilm-forming bacteria and their interactions with terrestrial plants, specifically emphasizing recent work. After an overview of documented interactions between bacteria and plant tissues, we examine some of the more prominent mechanisms of biofilm formation on and around plant surfaces.

Further reading: Microbial Biofilms: Current Research and Applications

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 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 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 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 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 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