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Antimicrobial/Anti-Infective Materials: Principles and Applications: materials for medical devices and general healthcare applications.
Table of contents
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- Antimicrobial/Anti-Infective Materials
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.
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.
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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. 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. Biosynthetic Engineering of Antibacterial Natural Products. 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.
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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. 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.
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.
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The Indigenous Human Microbiota. 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. 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. 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.
Cardiac catheterization lab/EP lab - Infectious Disease Advisor
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.
Current Strategies for Antibacterial Vaccine Development. 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. 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.
Recent Advances in Vaccine Adjuvants. 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. 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.
Antibodies for Antibacterials. 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.
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. 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. Microsphere technology is an established technique that is successful in offering long-lasting effects of agents. Depending on the physicochemical properties of encapsulated drugs and polymeric excipients, microspheres can be programmed for content release by diffusion or erosion, or a combination of both.
Materials that have come into wide use and those that generated the most profit for microspheres seem to be the aliphatic poly esters such as poly lactide PLA , poly glycolide PGA and especially the copolymer of lactide and glycolide poly lactide-co-glycolide PLGA. Polymeric microspheres are attractive because of their biocompatibility, biodegradability and capability of encapsulating various drugs via both oral and injection route.
However, it is difficult to manufacture microspheres in large quantities and maintain drug stability as well. By the combination of two or more materials, the extended-release delivery system can offer the advantage of facilitated adjustment of desired drug-release patterns, mechanical properties and drug release mechanisms. For this reason, more attention has to be paid when using this type of formulation. Composite microspheres combined with bioactive wollastonite with biodegradable poly hydroxybutyrate-polyhydroxyvalerate PHBV showed much lower release rate of gentamicin than the pure PBHV microspheres, which was credited to the formation of apatite layer on their surface.
Besides, incorporation of microspheres into scaffolds can abolish the initial burst by a combination of pore diffusion and polymer erosion. The objective of using mucoadhesive or bioadhesive controlled drug delivery system is to prolong their residence at a specific site of delivery, thus facilitating the drug absorption process. For mucoadhesive agent, first-pass metabolism in the liver and presystemic elimination in the GI tract is avoided as the mucosa is well supplied with both vascular and lymphatic drainage. The commonly used bioadhesive polymers include polyacrylic acid, cellulosic, polysaccharide and natural polymers such as acacia gum and alginic acid.
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Besides, high-molecular-weight polymers such as polyvinylpyrrolidone and poly ethylene glycol PEG also have the feature of bioadhesion.