# Toward a Chemo-Enzymatic Synthesis of Vancomycin and Its Analogs

> **NIH NIH R01** · PRINCETON UNIVERSITY · 2022 · $310,309

## Abstract

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.

## Key facts

- **NIH application ID:** 10439760
- **Project number:** 5R01GM129496-04
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Mohammad R Seyedsayamdost
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $310,309
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439760

## Citation

> US National Institutes of Health, RePORTER application 10439760, Toward a Chemo-Enzymatic Synthesis of Vancomycin and Its Analogs (5R01GM129496-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10439760. Licensed CC0.

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