Synthetic Biology and Therapies for Infectious Diseases

Ando, Hiromitsu; Citorik, Robert J.; Cleto, Sara; Lemire, Sébastien; Mimee, Mark; Lu, Timothy K.

doi:10.1002/9783527676132.ch7

Cited by 2 publications

(4 citation statements)

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“…The availability of high-throughput bacterial genome editing tools coupled with advancement in DNA synthesis technologies provides new opportunities for metabolic engineering of large gene clusters in microbial hosts. By rational combination of gene parts, biosynthesis can be potentially reprogrammed for generation of novel small molecules for therapeutic purposes [48]. This is further facilitated by in silico whole genome mining and software algorithms that predict the gene clusters which can be used in biosynthetic pathway engineering for production of novel antibiotics [48, 74].…”

Section: Discussionmentioning

confidence: 99%

“…By rational combination of gene parts, biosynthesis can be potentially reprogrammed for generation of novel small molecules for therapeutic purposes [48]. This is further facilitated by in silico whole genome mining and software algorithms that predict the gene clusters which can be used in biosynthetic pathway engineering for production of novel antibiotics [48, 74]. This offers huge potential for combinatorial biosynthesis of natural product analogs for the discovery of novel antibiotics, as in the example of antibiotic daptomycin described in the earlier section [41].…”

Section: Discussionmentioning

confidence: 99%

“…Attenuated live vaccines are created by decreasing the virulence of the pathogen to weaken their infection potential without compromising the robust host immune response that is required for protection during future infections that could be caused by the same pathogen (For example: MTBVAC against Mycobacterium tuberculosis [46], Ty21a against Salmonella typhi [47]). There is a growing focus on using recombinant DNA technology for producing attenuated strains of pathogenic bacteria [48]. Genome engineering tools are now being routinely explored for the possibility of reducing bacterial virulence.…”

Section: Main Textmentioning

confidence: 99%

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Bacterial genome engineering and synthetic biology: combating pathogens

et al. 2016

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BackgroundThe emergence and prevalence of multidrug resistant (MDR) pathogenic bacteria poses a serious threat to human and animal health globally. Nosocomial infections and common ailments such as pneumonia, wound, urinary tract, and bloodstream infections are becoming more challenging to treat due to the rapid spread of MDR pathogenic bacteria. According to recent reports by the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC), there is an unprecedented increase in the occurrence of MDR infections worldwide. The rise in these infections has generated an economic strain worldwide, prompting the WHO to endorse a global action plan to improve awareness and understanding of antimicrobial resistance. This health crisis necessitates an immediate action to target the underlying mechanisms of drug resistance in bacteria.ResearchThe advent of new bacterial genome engineering and synthetic biology (SB) tools is providing promising diagnostic and treatment plans to monitor and treat widespread recalcitrant bacterial infections. Key advances in genetic engineering approaches can successfully aid in targeting and editing pathogenic bacterial genomes for understanding and mitigating drug resistance mechanisms. In this review, we discuss the application of specific genome engineering and SB methods such as recombineering, clustered regularly interspaced short palindromic repeats (CRISPR), and bacterial cell-cell signaling mechanisms for pathogen targeting. The utility of these tools in developing antibacterial strategies such as novel antibiotic production, phage therapy, diagnostics and vaccine production to name a few, are also highlighted.ConclusionsThe prevalent use of antibiotics and the spread of MDR bacteria raise the prospect of a post-antibiotic era, which underscores the need for developing novel therapeutics to target MDR pathogens. The development of enabling SB technologies offers promising solutions to deliver safe and effective antibacterial therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

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Bacterial genome engineering and synthetic biology: combating pathogens

et al. 2016

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“…Researchers have attempted a multitude of approaches to access new natural products, such as discovering novel producer strains in less-exploited niches, like the human microbiome ( 6 ); activating silent gene clusters; and engineering genes, modules, domains, and pathways in heterologous, genetically tractable hosts ( 7 ). The first report on the successful assembly of new natural products by combining heterologous and unrelated biosynthetic genes dates back to 1985 ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

An Engineered Synthetic Pathway for Discovering Nonnatural Nonribosomal Peptides in Escherichia coli

Cleto

2017

mBio

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Peptides that are synthesized independently of the ribosome in plants, fungi, and bacteria can have clinically relevant anticancer, antihemochromatosis, and antiviral activities, among many other. Despite their natural origin, discovering new natural products is challenging, and there is a need to expand the chemical diversity that is accessible. In this work, we created a novel, compressed synthetic pathway for the heterologous expression and diversification of nonribosomal peptides (NRPs) based on homologs of siderophore pathways from Escherichia coli and Vibrio cholerae. To enhance the likelihood of successful molecule production, we established a selective pressure via the iron-chelating properties of siderophores. By supplementing cells containing our synthetic pathway with different precursors that are incorporated into the pathway independently of NRP enzymes, we generated over 20 predesigned, novel, and structurally diverse NRPs. This engineering approach, where phylogenetically related genes from different organisms are integrated and supplemented with novel precursors, should enable heterologous expression and molecular diversification of NRPs.

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Synthetic Biology and Therapies for Infectious Diseases

Cited by 2 publications

References 401 publications

Bacterial genome engineering and synthetic biology: combating pathogens

Bacterial genome engineering and synthetic biology: combating pathogens

An Engineered Synthetic Pathway for Discovering Nonnatural Nonribosomal Peptides in Escherichia coli

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