scholarly journals A mixture of three engineered phosphotriesterases enables rapid detoxification of the entire spectrum of known threat nerve agents

2019 ◽  
Author(s):  
Dragana Despotovic ◽  
Einav Aharon ◽  
Artem Dubovetskyi ◽  
Haim Leader ◽  
Yacov Ashani ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Entire Range ◽  
Nerve Agents ◽  
Ester Bond ◽  
Minimal Impact ◽  
Entire Spectrum ◽  
Enzyme Cocktail ◽  
Enzymatic Detoxification ◽  
Single Enzyme

AbstractNerve agents are organophosphates that potently inhibit acetylcholinesterase and their enzymatic detoxification has been a long-standing goal. Nerve agents vary widely in size, charge, hydrophobicity, and the cleavable ester bond. A single enzyme is therefore unlikely to efficiently hydrolyze all agents. Here, we describe a mixture of three previously developed variants of the bacterial phosphotriesterase (Bd-PTE) that are highly stable and nearly sequence identical. This mixture enables effective detoxification of a broad spectrum of known threat agents – GA (tabun), GB (sarin), GD (soman), GF (cyclosarin), VX, and Russian-VX. The potential for dimer dissociation and exchange that could inactivate Bd-PTE has minimal impact, and the three enzyme variants are as active in a mixture as they are individually. To our knowledge, this engineered enzyme ‘cocktail’ comprises the first solution for enzymatic detoxification of the entire range of threat nerve agents.

scholarly journals A mixture of three engineered phosphotriesterases enables rapid detoxification of the entire spectrum of known threat nerve agents

2019 ◽  
Vol 32 (4) ◽  
pp. 169-174 ◽  
Author(s):  
Dragana Despotović ◽  
Einav Aharon ◽  
Artem Dubovetskyi ◽  
Haim Leader ◽  
Yacov Ashani ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Entire Range ◽  
Nerve Agents ◽  
Ester Bond ◽  
Minimal Impact ◽  
Entire Spectrum ◽  
Enzyme Cocktail ◽  
Enzymatic Detoxification ◽  
Single Enzyme

Abstract Nerve agents are organophosphates (OPs) that potently inhibit acetylcholinesterase, and their enzymatic detoxification has been a long-standing goal. Nerve agents vary widely in size, charge, hydrophobicity and the cleavable ester bond. A single enzyme is therefore unlikely to efficiently hydrolyze all agents. Here, we describe a mixture of three previously developed variants of the bacterial phosphotriesterase (Bd-PTE) that are highly stable and nearly sequence identical. This mixture enables effective detoxification of a broad spectrum of known threat agents—GA (tabun), GB (sarin), GD (soman), GF (cyclosarin), VX and Russian-VX. The potential for dimer dissociation and exchange that could inactivate Bd-PTE has minimal impact, and the three enzyme variants are as active in a mixture as they are individually. To our knowledge, this engineered enzyme ‘cocktail’ comprises the first solution for enzymatic detoxification of the entire range of threat nerve agents.

scholarly journals Antibacterial Monoclonal Antibodies Do Not Disrupt the Intestinal Microbiome or Its Function

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Omari Jones-Nelson ◽  
Andrey Tovchigrechko ◽  
Matthew S. Glover ◽  
Fiona Fernandes ◽  
Udaya Rangaswamy ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Broad Spectrum ◽  
Gut Microbiome ◽  
Short Chain Fatty Acids ◽  
Intestinal Microbiome ◽  
Bacterial Metabolites ◽  
Minimal Impact ◽  
Fecal Microbiome ◽  
Alpha And Beta Diversity ◽  
Broad Spectrum Antibiotics

ABSTRACT Antibiotics revolutionized the treatment of infectious diseases; however, it is now clear that broad-spectrum antibiotics alter the composition and function of the host’s microbiome. The microbiome plays a key role in human health, and its perturbation is increasingly recognized as contributing to many human diseases. Widespread broad-spectrum antibiotic use has also resulted in the emergence of multidrug-resistant pathogens, spurring the development of pathogen-specific strategies such as monoclonal antibodies (MAbs) to combat bacterial infection. Not only are pathogen-specific approaches not expected to induce resistance in nontargeted bacteria, but they are hypothesized to have minimal impact on the gut microbiome. Here, we compare the effects of antibiotics, pathogen-specific MAbs, and their controls (saline or control IgG [c-IgG]) on the gut microbiome of 7-week-old, female, C57BL/6 mice. The magnitude of change in taxonomic abundance, bacterial diversity, and bacterial metabolites, including short-chain fatty acids (SCFA) and bile acids in the fecal pellets from mice treated with pathogen-specific MAbs, was no different from that with animals treated with saline or an IgG control. Conversely, dramatic changes were observed in the relative abundance, as well as alpha and beta diversity, of the fecal microbiome and bacterial metabolites in the feces of all antibiotic-treated mice. Taken together, these results indicate that pathogen-specific MAbs do not alter the fecal microbiome like broad-spectrum antibiotics and may represent a safer, more-targeted approach to antibacterial therapy.

scholarly journals Activation and Deactivation of a Broad-Spectrum Antiviral Drug by a Single Enzyme: Adenosine Deaminase Catalyzes Two Consecutive Deamination Reactions

2003 ◽  
Vol 47 (1) ◽  
pp. 426-431 ◽  
Author(s):  
Jim Zhen Wu ◽  
Heli Walker ◽  
Johnson Y. N. Lau ◽  
Zhi Hong
Keyword(s):  
Adenosine Deaminase ◽  
Broad Spectrum ◽  
Structural Information ◽  
Antiviral Drug ◽  
Therapeutic Index ◽  
Comprehensive Understanding ◽  
Liver Targeting ◽  
Inactive Metabolite ◽  
Single Enzyme

ABSTRACT Ribavirin is an approved broad-spectrum antiviral drug. A liver-targeting prodrug of ribavirin, viramidine, is in clinical trial in an attempt to provide a better therapeutic index. The conversion of viramidine to ribavirin, and of ribavirin to an inactive metabolite through adenosine deaminase, is reported. Kinetic analysis indicates that adenosine deaminase is likely involved in activation of viramidine in vivo, and the process is highly pH sensitive. The differential activities of two consecutive deamination reactions are kinetically studied and interpreted based on adenosine deaminase structural information. A comprehensive understanding of the viramidine and ribavirin deamination mechanism should help in designing better nucleoside therapeutics in the future.

A Strengths-Based Approach to Autism: Neurodiversity and Partnering With the Autism Community

2017 ◽  
Vol 2 (1) ◽  
pp. 56-68 ◽  
Author(s):  
Amy L. Donaldson ◽  
Karen Krejcha ◽  
Andy McMillin
Keyword(s):  
Broad Spectrum ◽  
First Language ◽  
Family Members ◽  
Community Identity ◽  
Speech Language Pathologists

The autism community represents a broad spectrum of individuals, including those experiencing autism, their parents and/or caregivers, friends and family members, professionals serving these individuals, and other allies and advocates. Beliefs, experiences, and values across the community can be quite varied. As such, it is important for the professionals serving the autism community to be well-informed about current discussions occurring within the community related to neurodiversity, a strengths-based approach to partnering with autism community, identity-first language, and concepts such as presumed competence. Given the frequency with which speech-language pathologists (SLPs) serve the autism community, the aim of this article is to introduce and briefly discuss these topics.

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