Genetically Programmable Pathogen Sense and Destroy

Gupta, Saurabh; Weiss, Ron

doi:10.4016/18510.01

Cited by 7 publications

(11 citation statements)

References 129 publications

(180 reference statements)

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“…The system described herein is sufficiently modular that the trigger and memory circuits could be reengineered to respond to chemical signatures of inflammation, cancer, parasites, or environmental toxins in the gut. In combination with additional genetic circuits, such as the recent search-and-destroy circuits (36)(37)(38), cells could be designed with the memory element described here to diagnose a specific pathogen, and emit a therapeutic. Together, these approaches may allow construction of a new class of engineered probiotic bacteria that serve as benign and transient diagnostics and therapeutics.…”

Section: Discussionmentioning

confidence: 99%

Programmable bacteria detect and record an environmental signal in the mammalian gut

Kotula

Kerns

Shaket

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

324

302

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Significance The human microbiota represents the trillions of bacteria that live on the skin, in the oral, nasal, and aural cavities, and throughout the gastrointestinal tract. The species that live in the gastrointestinal tract, the gut microbiota, closely interact with host cells and have a profound impact on health. To develop tools to effectively monitor the gut microbiota and ultimately help in disease diagnosis, we have engineered Escherichia coli to sense and record environmental stimuli, and demonstrated that E. coli with such memory systems can survive and function in the mammalian gut. This work demonstrates that E. coli can be engineered into living diagnostics capable of nondestructively probing the mammalian gut.

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Section: Discussionmentioning

confidence: 99%

Programmable bacteria detect and record an environmental signal in the mammalian gut

Kotula

Kerns

Shaket

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

324

302

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“…Examples include combined domains of pyocins S1 and AP41 (Sano et al, 1993a) and a pyocin S5/S2 chimer (Elfarash et al, 2014). In addition, active pyocin/colicin hybrids with domains from pyocin S3 and colicin E3 (Gupta et al, 2013; see Potential applications for S-type pyocins) and with domains from pyocins S1 or S2 and colicins E2 or E3 have been engineered (Kageyama et al, 1996). Pyocin S5 and PaeM that do not require translocation to the cytoplasm for killing, exhibit a different domain architecture with the translocation domain preceding the receptor-binding domain (Barreteau et al, 2009;Elfarash et al, 2014).…”

Section: Domain Architecture Of S-type Pyocinsmentioning

confidence: 99%

“…When reaching a threshold intracellular concentration of E7 lysis protein, E. coli cells will burst, causing the release of the pyocin into the environment and killing P. aeruginosa (Saeidi et al, 2011). In a similar system, E. coli sentinels were armed with a chimeric pyocin, constituted of the receptor and translocation domain of pyocin S3 and the killing and immunity domain of colicin E3, under the control of the P las promoter (Gupta et al, 2013). The target detection module provides LasR, specifically interacting with the P. aeruginosa autoinducer.…”

Section: Potential Applications For S-type Pyocinsmentioning

confidence: 99%

Ribosomally encoded antibacterial proteins and peptides fromPseudomonas

2014

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Members of the Pseudomonas genus produce diverse secondary metabolites affecting other bacteria, fungi or predating nematodes and protozoa but are also equipped with the capacity to secrete different types of ribosomally encoded toxic peptides and proteins, ranging from small microcins to large tailocins. Studies with the human pathogen Pseudomonas aeruginosa have revealed that effector proteins of type VI secretion systems are part of the antibacterial armamentarium deployed by pseudomonads. A novel class of antibacterial proteins with structural similarity to plant lectins was discovered by studying antagonism among plant-associated Pseudomonas strains. A genomic perspective on pseudomonad bacteriocinogeny shows that the modular architecture of S pyocins of P. aeruginosa is retained in a large diversified group of bacteriocins, most of which target DNA or RNA. Similar modularity is present in as yet poorly characterized Rhs (recombination hot spot) proteins and CDI (contact-dependent inhibition) proteins. Well-delimited domains for receptor recognition or cytotoxicity enable the design of chimeric toxins with novel functionalities, which has been applied successfully for S and R pyocins. Little is known regarding how these antibacterials are released and ultimately reach their targets. Other remaining issues concern the identification of environmental triggers activating these systems and assessment of their ecological impact in niches populated by pseudomonads.

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“…The modular nature of our design can accommodate further optimization and extension by equipping the bacteria with effector genes of interest. These include effectors to target tumor cells (Anderson et al, 2006;Zhang et al, 2010), to kill bacterial pathogens (Saeidi et al, 2011;Gupta et al, 2013;Hwang et al, 2014), or to degrade environmental pollutants (Furukawa, 2000). For such applications, the programmed safeguard provides an intrinsic mechanism to prevent unintended proliferation of such engineered bacteria, a major safety concern that limits their broad applications.…”

Section: Discussionmentioning

confidence: 99%

Coupling spatial segregation with synthetic circuits to control bacterial survival

Huang

Lee

Tsoi

et al. 2016

Molecular Systems Biology

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Engineered bacteria have great potential for medical and environmental applications. Fulfilling this potential requires controllability over engineered behaviors and scalability of the engineered systems. Here, we present a platform technology, microbial swarmbot, which employs spatial arrangement to control the growth dynamics of engineered bacteria. As a proof of principle, we demonstrated a safeguard strategy to prevent unintended bacterial proliferation. In particular, we adopted several synthetic gene circuits to program collective survival in Escherichia coli: the engineered bacteria could only survive when present at sufficiently high population densities. When encapsulated by permeable membranes, these bacteria can sense the local environment and respond accordingly. The cells inside the microbial swarmbot capsules will survive due to their high densities. Those escaping from a capsule, however, will be killed due to a decrease in their densities. We demonstrate that this design concept is modular and readily generalizable. Our work lays the foundation for engineering integrated and programmable control of hybrid biological–material systems for diverse applications.

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Genetically Programmable Pathogen Sense and Destroy

Cited by 7 publications

References 129 publications

Programmable bacteria detect and record an environmental signal in the mammalian gut

Programmable bacteria detect and record an environmental signal in the mammalian gut

Ribosomally encoded antibacterial proteins and peptides fromPseudomonas

Coupling spatial segregation with synthetic circuits to control bacterial survival

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