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Microbial Engineering For Therapeutics Free Ebo...

Microbiome-based therapeutics, designed to improve human health by altering the associated microbial communities, may employ modulatory, additive, or subtractive approaches. Modulatory therapies involve altering the composition or activity of the endogenous microbiota via the administration of nonliving agents or prebiotics (for a review of prebiotics, see Frei et al., 2015). Additive therapies supplement the microbiota with natural or engineered microorganisms (de Moreno de LeBlanc and LeBlanc, 2014; Derrien and van Hylckama Vlieg, 2015; Varankovich et al., 2015; Marchesi et al., 2016; see Figures 10-1A and 10-1B), given either individually or as collections of strains. Subtractive therapies aim to modulate host interactions by eliminating specific members of the microbiome (see Figure 10-1C). In the future, additive and subtractive approaches may be used together to achieve greater effects on the microbiome.

Microbial Engineering for Therapeutics free ebo...

Hyperammonemia is another metabolic condition for which engineering the microbiota may prove effective. In the gut, bacterial ureases convert urea made by the liver to ammonia and carbon dioxide. Hyperammonemia occurs when too much ammonia accumulates systemically, and leads to neurotoxicity and encephalopathy in people with liver disease. In mouse models, reconstituting the microbiota altered community-wide urea metabolism (Shen et al., 2015). When the endogenous microbiota was depleted and a defined microbial community exhibiting low urease activity was transplanted, urease levels remained stable for months (Shen et al., 2015). The redefined microbiota enhanced survival and reduced cognitive defects associated with hyperammonemia in a hepatic injury model. Thus, modifying an existing microbial community can protect against metabolic diseases. Furthermore, microbes have been genetically engineered to degrade ammonia and shown to reduce systemic ammonia levels when fed to mice (Nicaise et al., 2008). Such therapies are currently being developed by companies for clinical trials (Synlogic, 2017).

In addition to using natural phage isolates, phages can be modified to carry extra or alternative functions to expand their utility. Immunoglobulin-like protein domains on the capsids of certain phages' exterior enhance association with mucus (Barr et al., 2013), a mechanism that could potentially be used to localize phage to particular parts of the body or to extend residence time in the gut. Host range can be reprogrammed to alter the bacterial targets (Ando et al., 2015) and genes can be inserted to improve the killing of biofilms (Lu and Collins, 2007). Additionally, phages have been used to deliver DNA to bacteria that reverses antibiotic resistance (Lu and Collins, 2009; Edgar et al., 2012) or to achieve nonspecific (Westwater et al., 2003; Hagens et al., 2004; Krom et al., 2015) or sequence-specific (Bikard et al., 2014; Citorik et al., 2014) antimicrobial activity toward targeted cells. New tools such as CRISPR-Cas (Kiro et al., 2014) genome editing and construction methods, including Gibson (Gibson et al., 2009) and yeast (Ando et al., 2015) assembly, will facilitate future engineering efforts. Phages as therapeutics for microbiota-related diseases represent a promising area of investigation, and using them as tools to alter microbial communities could enable systematic probing of these populations for discovery and validation in the study of health and the microbiome.

The development of microbiota-based therapeutics has been accelerated by progress in synthetic biology and our understanding of host-associated microbial consortia. However, numerous challenges arise in bringing this work to the clinic. Many advances in microbiome therapeutics have been validated using rodent models, but the ability to generalize these findings to humans has yet to be comprehensively tested. In addition, the development of fully autonomous cellular therapies requires biosensors that are clinically relevant biosensors and genetic circuits that are robust. Finally, the translation of basic research to clinical applications depends on setting up regulatory frameworks to address unique issues with living therapeutics.

Therapeutics targeting the human microbiome are undergoing rapid development and attracting broad interest due to their potential benefits. Current additive and subtractive strategies to manipulate the human microbiome include engineering bacteria to produce therapeutic molecules, constituting natural or artificial consortia to modulate the host, and applying selective antimicrobials. Challenges in creating microbiome therapeutics include engineering microbial therapies that are well adapted to specific environments in the body or able to achieve stable colonization, discovering or constructing clinically relevant biosensors, engineering robust and effective synthetic gene circuits that can function in vivo, and establishing regulatory frameworks to account for safety and biocontainment concerns in addition to therapeutic efficacy. Given the deep interactions between host and microbe that are being uncovered, we envision that various approaches to engineering the microbiome have the potential to transform the treatment of challenging human diseases.

This book highlights the recent advances in the field of microbial engineering and its application in human healthcare. It underscores the systemic and synthetic biology approaches for engineering microbes and discusses novel treatments for inflammatory bowel diseases based on engineered probiotics.

The book also reviews the different options and methods for engineering microbes, ranging from recombinant DNA technology to designing microbes for targeting specific sites and delivering therapeutics. Further, it discusses genetically engineered microorganisms for smart diagnostics and describes current approaches in microbial gene editing using CRISPR-Cas9-based tools. Lastly, it summarizes the potential applications of human microbiome engineering in improving human health and explores potential strategies for scaling-up the production of engineered microbial strains for commercial purposes, as well as the challenges. Given its scope, this book is a valuable resource for students, researchers, academics and entrepreneurs interested in understanding microbial engineering for the production of commercial products.

It is essential to select standards to facilitate progress in this growing field. Microbial strains, animal models, and testing methods should be selected and characterized to serve as a baseline for making meaningful comparisons of specific agents and particular treatment strategies. Otherwise, conflicting results will impede progress. Choosing suitable standards, however, may prove a difficult challenge. Some experts suggest systematically screening microbial strains to evaluate their prospects as therapeutic agents, while others argue that freezing specific options too early would be a mistake and could impede progress. In any case, strains chosen early to serve as standards are not meant to be optimal for use in medical practice, but to be used in foundation research that will lead to improvements in the overall technology. S. typhimurium strain UK-1, which is considered a standard for recombinant vaccine research, may be a good candidate for use as a standard strain in this emerging field of research on therapeutic microbes.

This book provides expert reviews and perspectives on how to engineer microbial metabolism for chemical synthesis. Major metabolic pathways or networks in microbial systems, including glycolysis, citric acid and photosynthesis, are briefly summarized. Following this, the metabolic engineering efforts of extending these pathways and networks for the biosynthesis of various chemicals are reviewed with the emphasis on the biochemical reactions and engineering strategies. The potential of these pathways for further metabolic engineering are also discussed. From graduate to professional level, cellular metabolism and metabolic engineering applications are introduced to the readers gradually and systematically, making it perfect for students, researchers and practitioners of chemistry, biochemistry and metabolic engineering. 041b061a72


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