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Using Chemical Tools to Identify and Inhibit Serine Hydrolases in Commensal Bacteria.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Using Chemical Tools to Identify and Inhibit Serine Hydrolases in Commensal Bacteria./
作者:	Keller, Laura Jane.
面頁冊數:	1 online resource (183 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-11, Section: B.
Contained By:	Dissertations Abstracts International84-11B.
標題:	Mass spectrometry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30399004click for full text (PQDT)
ISBN:	9798379474218

Using Chemical Tools to Identify and Inhibit Serine Hydrolases in Commensal Bacteria.
Keller, Laura Jane.

Using Chemical Tools to Identify and Inhibit Serine Hydrolases in Commensal Bacteria. - 1 online resource (183 pages)

Source: Dissertations Abstracts International, Volume: 84-11, Section: B.

Thesis (Ph.D.)--Stanford University, 2023.

Includes bibliographical references

With rising rates of antimicrobial resistance and an increasing understanding of how commensal bacteria in the human microbiota affect a wide variety of diseases, it is of utmost importance to discover novel bacterial drug targets. In particular, microbiota-related diseases are often characterized by a dysbiotic microbial community and a bloom of pathobiont bacteria. Thus, identifying selective targets that can decrease the fitness of a subset of bacterial species within a community without having broad-spectrum effects will be critical. Previous work has utilized a chemoproteomics technique called activity-based protein profiling (ABPP), which uses chemical probes that can covalently modify catalytic active enzymes, to identify relevant druggable enzymes in several bacterial pathogens. This approach is especially powerful for identifying serine hydrolases, a broad superfamily of enzymes with functions in metabolism and cell signaling in mammals. While they have not previously been studied in commensal bacteria, these functions suggest serine hydrolases may be important for bacteria to maintain themselves in complex communities, and their diversity hints at their potential as selective drug targets. In Chapter 2, a combination of bioinformatics and ABPP were utilized to identify serine hydrolases in the skin commensal bacterium Staphylococcus epidermidis, most of which had close homologs in other staphylococcal species including the pathobiont Staphylococcus aureus. In particular, the lipase SeFphB is a functional homolog of the virulence factor SaFphB in S. aureus and has varying activity levels across clinical isolates of S. epidermidis. While loss of SaFphB has been previously shown to be important in infection, SeFphB does not play a role in commensal skin colonization by S. epidermidis. These results suggest that SaFphB is still a viable drug target and potential off-target effects on SaFphB homologs in the skin microbiota likely will not be detrimental. In Chapter 3, a pipeline to predict serine hydrolases bioinformatically across gut commensal bacteria was paired with ABPP to identify homologs of the human protease DPP4 (hDPP4) in the model symbiont Bacteroides thetaiotaomicron. One enzyme, BT4193, was demonstrated to be a functional homolog of hDPP4 and could be inhibited by hDPP4-targeting drugs that are used for the treatment of type 2 diabetes. Furthermore, BT4193 plays an important role in envelope integrity and in B. thetaiotaomicron fitness in complex bacterial communities, indicating that off-target inhibition of bacterial enzymes by existing FDA-approved drugs can affect the gut microbiota. In totality, this work explores the diversity of serine hydrolases across commensal bacteria, characterizes the function of a skin commensal lipase and a gut commensal protease, and highlights the potential of serine hydrolases in commensal bacteria as selective drug targets.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798379474218Subjects--Topical Terms:

551172
Mass spectrometry.
Index Terms--Genre/Form:

542853
Electronic books.

Using Chemical Tools to Identify and Inhibit Serine Hydrolases in Commensal Bacteria.
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500 $a Advisor: Bhatt, Ami;Jarosz, Daniel;Sonnenburg, Justin;Bogyo, Matthew.
502 $a Thesis (Ph.D.)--Stanford University, 2023.
504 $a Includes bibliographical references
520 $a With rising rates of antimicrobial resistance and an increasing understanding of how commensal bacteria in the human microbiota affect a wide variety of diseases, it is of utmost importance to discover novel bacterial drug targets. In particular, microbiota-related diseases are often characterized by a dysbiotic microbial community and a bloom of pathobiont bacteria. Thus, identifying selective targets that can decrease the fitness of a subset of bacterial species within a community without having broad-spectrum effects will be critical. Previous work has utilized a chemoproteomics technique called activity-based protein profiling (ABPP), which uses chemical probes that can covalently modify catalytic active enzymes, to identify relevant druggable enzymes in several bacterial pathogens. This approach is especially powerful for identifying serine hydrolases, a broad superfamily of enzymes with functions in metabolism and cell signaling in mammals. While they have not previously been studied in commensal bacteria, these functions suggest serine hydrolases may be important for bacteria to maintain themselves in complex communities, and their diversity hints at their potential as selective drug targets. In Chapter 2, a combination of bioinformatics and ABPP were utilized to identify serine hydrolases in the skin commensal bacterium Staphylococcus epidermidis, most of which had close homologs in other staphylococcal species including the pathobiont Staphylococcus aureus. In particular, the lipase SeFphB is a functional homolog of the virulence factor SaFphB in S. aureus and has varying activity levels across clinical isolates of S. epidermidis. While loss of SaFphB has been previously shown to be important in infection, SeFphB does not play a role in commensal skin colonization by S. epidermidis. These results suggest that SaFphB is still a viable drug target and potential off-target effects on SaFphB homologs in the skin microbiota likely will not be detrimental. In Chapter 3, a pipeline to predict serine hydrolases bioinformatically across gut commensal bacteria was paired with ABPP to identify homologs of the human protease DPP4 (hDPP4) in the model symbiont Bacteroides thetaiotaomicron. One enzyme, BT4193, was demonstrated to be a functional homolog of hDPP4 and could be inhibited by hDPP4-targeting drugs that are used for the treatment of type 2 diabetes. Furthermore, BT4193 plays an important role in envelope integrity and in B. thetaiotaomicron fitness in complex bacterial communities, indicating that off-target inhibition of bacterial enzymes by existing FDA-approved drugs can affect the gut microbiota. In totality, this work explores the diversity of serine hydrolases across commensal bacteria, characterizes the function of a skin commensal lipase and a gut commensal protease, and highlights the potential of serine hydrolases in commensal bacteria as selective drug targets.
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