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Toward a Chemo-Enzymatic Synthesis of Vancomycin and Its Analogs

Award Number: R01GM129496
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Toward a Chemo-Enzymatic Synthesis of Vancomycin and Its Analogs - ABSTRACT Glycopeptide antibiotics (GPAs) are among the most important therapeutic agents world-wide. The founding member of this natural product family, vancomycin, is used a drug of last resort against infections by methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile. Along with a handful of other antibiotics, vancomycin provides an important weapon against “superbugs”, pathogenic bacteria that have acquired resistance to multiple clinical antibiotics. But as resistance to even this last line of defense spreads, it is ever more important to develop means of chemically tailoring vancomycin and other GPAs to create new derivatives that counter known resistance mechanisms. Synthetic derivatization has proven to be a successful method for creating new antibiotics, but this approach is severely restricted within the GPAs, primarily due to their chemical complexity and size. Key to the structural complexity and biological activity of vancomycin are three aromatic crosslinks, consisting of two aryl ether connections and a biaryl carbon-carbon bond. Research over the past 20 years has shown that a cytochrome P450 enzyme (OxyB) installs the first aryl ether bond. The origin of the remaining two crosslinks, however, remained elusive. We recently showed that OxyA, a second P450 enzyme, introduces the second aryl ether crosslink during vancomycin biogenesis. We further recapitulated the enzymatic activity of OxyC and showed that it installs the final biaryl connection, the first demonstration of this reaction in any GPA. Moreover, we have exploited the reactivities of the native biosynthetic metalloenzymes to implement a chemo-enzymatic route for creating a vancomycin aglycone derivative. The stage is set to fully leverage this chemo-enzymatic approach to chemically derivatize vancomycin in the hopes of generating useful second-generation derivatives. In the current application, we propose to complete the chemo-enzymatic synthesis of not just vancomycin, but also of derivatives known to retain bioactivity, even against resistant pathogens. We further propose to build a library of vancomycin analogs that we refer to as “designer vancomycins”, containing modifications that are inaccessible with current methodologies. We will simultaneously explore the detailed chemical mechanism of OxyB and create an innovative solid-phase approach to enhance the efficiency and scalability of our chemo- enzymatic route. Our studies will shed light onto the biosynthesis of vancomycin and enable the most comprehensive effort yet to create GPA variants with unique structures and possibly new bioactivities via an elegant chemo-enzymatic route.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	4	3/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $310,309 )
2022	2022	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	4	6/17/2022	NON-COMPETING CONTINUATION	$310,309
														Subtotal = $310,309

Issue Date FY: 2021 ( Subtotal = $310,309 )
2021	2021	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	3	6/28/2021	NON-COMPETING CONTINUATION	$310,309
														Subtotal = $310,309

Issue Date FY: 2020 ( Subtotal = $310,309 )
2020	2020	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	2	5/22/2020	NON-COMPETING CONTINUATION	$310,309
														Subtotal = $310,309

Issue Date FY: 2019 ( Subtotal = $310,309 )
2019	2019	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	1	7/1/2019	NEW	$310,309
														Subtotal = $310,309

Grand Total All Awards = $1,241,236

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Toward a Chemo-Enzymatic Synthesis of Vancomycin and Its Analogs

Award Number: R01GM129496

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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