Gavin Williams
Head
he/him
Department Head
LORD Corporation Distinguished Scholar
GLBT Advocate 2020-2021
Dabney Hall 850
Bio
Education
B.Sc. Biochemistry The University of Wales 1998
Ph.D. Chemical Biology University of Leeds 2002
Area(s) of Expertise
The Williams Lab is interested in combining the power of biology and organic chemistry to provide access to new complex organic molecules. More specifically, we leverage enzyme engineering, biocatalysis, metabolic engineering, organic chemistry, and synthetic biology to access and diversify the structures of natural products. These efforts form an innovative and powerful platform for drug discovery.
Publications
- Current State-of-the-Art Toward Chemoenzymatic Synthesis of Polyketide Natural Products , CHEMBIOCHEM (2023)
- Targeted enzyme modifications enable regioselective biosynthesis of fluorinated polyketides , CHEM CATALYSIS (2022)
- Computationally-guided exchange of substrate selectivity motifs in a modular polyketide synthase acyltransferase , NATURE COMMUNICATIONS (2021)
- Development of Genetically Encoded Biosensors for Reporting the Methyltransferase-Dependent Biosynthesis of Semisynthetic Macrolide Antibiotics , ACS SYNTHETIC BIOLOGY (2021)
- Protein engineering for natural product biosynthesis and synthetic biology applications , PROTEIN ENGINEERING DESIGN & SELECTION (2021)
- Transcription factor-based biosensors: a molecular-guided approach for natural product engineering , CURRENT OPINION IN BIOTECHNOLOGY (2021)
- An artificial pathway for polyketide biosynthesis , Nature Catalysis (2020)
- Cheminformatics Analysis and Modeling with MacrolactoneDB , Scientific Reports (2020)
- Computationally-guided exchange of substrate selectivity motifs in a modular polyketide synthase acyltransferase , (2020)
- SIME: synthetic insight-based macrolide enumerator to generate the V1B library of 1 billion macrolides , Journal of Cheminformatics (2020)
Grants
Training in the application of chemical principles is essential for modern research across a number of disciplines ranging from Chemistry and Biochemistry to Biology, Engineering and Medicine. Acknowledging this need, NC State University has launched a new research and training program called the Chemistry of Life Program (CLP) and initiated an innovative graduate training program, the Chemistry of Life Training Program (CLTP), as a core element. A key aspect of this program is core training, both lecture and experimental, in core chemical biology principles and techniques. This not only facilitates completion of the students?????????????????? dissertation research, but also lays the basis for career opportunities in academic, government, and industrial research settings. To achieve this, the CLTP has partnered with the Comparative Medicine Institute and Biotechnology Training Program to synergize this program across our campus though at least 4 Colleges and 7 Departments. A trans-departmental Executive Committee will lead the operation of the CLTP and oversee sub-committees focusing on program elements. The specific objectives of the training program are: 1) Ensure technical proficiency and training in responsible and rigorous science; 2) Provide an educational and training experience that is in line with graduate students?????????????????? expectations for an interdisciplinary future; and, 3) Nurture robust PhD graduation outcomes. Six slots (three in year 1) are requested that will be augmented by four slots (two in year 1) from University resources. The program requirements include a minor in the Chemistry of Life; a course in professional development/ scientific rigor and reproducibility; courses in research ethics; and an annual research symposium/retreat. These requirements are in addition to those associated with the student??????????????????s particular Department or Program for the doctoral degree. During their two-year appointment to the training grant, trainees will also benefit from an exploratory laboratory rotation program, co-mentorship across disciplines, access to development workshops on topics like research commercialization, and the opportunity to be guided through mentorship of undergraduate researchers on a team science project. This program will also provide a central focus for faculty of the various disciplines involved in this training effort to seek out new opportunities for formal and informal research collaboration as part of the broader CLP program.
The scaffolds of >80,000 isoprenoids or the prenyl side-chain of thousands of diverse natural products are derived from the isoprene building block. The isoprene structural motif plays a critical role in modulating the biological activity of natural products and determines their utility as tools to study and treat various human diseases. However, our ability to diversify the structures of isoprenoids is extremely limited because enzymatic routes to them are not broad in scope and are difficult to manipulate. This proposal seeks to develop novel strategies that will greatly expand the synthetic utility and functional understanding of enzymes involved in the biosynthesis of isoprenoids and prenylated natural products. The expected outcomes of this study include new chemical building blocks for accessing natural products, unprecedented understanding of the specificity of enzymes, one-pot strategies for natural product diversification, engineered microbes for scalable access to natural products, new tools for directed evolution of terpene biosynthesis in microbial hosts, and diversified natural products with potential therapeutic applications.
Isoprenoids are a diverse class of compounds with a broad range of applications in medicine and industry. Their extraction from natural sources is both challenging and potentially harmful to the environment, while the enormous structural complexity of many isoprenoids makes traditional chemical synthesis nontrivial. Modern metabolic engineering and synthetic biology approaches have overcome some of these difficulties, but issues related to metabolic flux and the limited availability of the universal isoprenoid precursors complicate their widespread implementation. The overall objective of this proposal is to develop an efficient strategy for the synthesis of both natural and unnatural (poly)prenyl-PPs for downstream applications. The role of the PI here is to contribute to Specific Aim #2 by probing and developing isoprenoid methyltransferases to incorporate additional diversity into the polyprenyl-PPs. Completion of the proposed work will offer unprecedented access to uniquely bioactive isoprenoid libraries not readily accessible via traditional methods, and it will deepen our fundamental understanding of four enzyme classes while also developing them into useful biocatalysts.
The overall objective of this proposal is to construct genetically encoded biosensors for the detection of macrolides and their analogues. These biosensors will enable the application of a broad range of synthetic biology approaches to optimize the production of natural products and their analogues. The results are expected to have broad positive impact and lead to vertical advances in natural product synthesis, synthetic biology, and metabolic engineering by (1) developing strategies for the construction of genetically encoded biosensors, (2) extending our understanding of repressor protein function, (3) providing new approaches for engineering polyketide biosynthesis, (4) advancing new strategies for natural product biosynthesis, and (5) enabling access to biologically active natural products not readily accessible by conventional organic synthesis or genetic manipulation.
Fluorescence activated cell sorting (FACS) is a technique that involves sorting away select cells (or objects) from complex mixtures based on their intrinsic or acquired fluorescence. FACS is a transformative technology that allows the study of the unculturable microbes (which are numerically dominant in nature) and accomplish tasks that are highly laborious or impossible complete in other ways; the technology has led to significant discoveries in many microbial research fields (e.g. ecology, genetics, physiology, symbiosis/interactions, bioengineering, and bio-prospecting), and nearly single-handedly forged new fields of research, e.g. single cell genomics and transcriptomics, which involves the study of DNA and mRNA from individual cells. More than 25 North Carolina State University (NCSU) faculty, belonging to 4 colleges, have needs for FACS in their research or teaching programs; however, NCSU lacks a FACS instrument optimized for the analysis of non-mammalian microbial cells (e.g. bacteria, archaea and fungi), and to our knowledge, no ???????????????microbe optimized?????????????????? instrument is available at research universities within the Research Triangle of North Carolina (e.g. UNC-CH, Duke University). Here, funds are requested to acquire a Becton Dickinson FACSMelody flow cytometer, a versatile (3 excitation laser, 9-color detection) and ???????????????turn key?????????????????? system, which fundamentally enables microbiological research that is highly laborious or impossible to accomplish without it. The FACSMelody is powerful yet simple to use and generates easy to grasp visual (flow cytometric) data ?????????????????? making it a good potential training and educational tool for undergraduate/graduate courses and workshops. A FACSMelody system is ideal for getting FACS technology rapidly and easily into the hands of faculty in need. Overall, a FACS system for non-mammalian microbial research is needed for NCSU to be innovative, internationally competitive at attracting new faculty and highly talented students, and foster creative future proposals.
We have partially validated the function of a novel and previously unknown CRISPR dubbed ????????????????Sery-CRISPR???????????????. The goal here is to complete its characterization and precisely describe the required components, its gene editing effectiveness, and its scope of use in various organisms. This will facilitate the ability to license the technology.
This proposal addresses the urgent need to develop new and efficient routes to access and manufacture antibiotics. More specifically, we seek to assess the feasibility of using genetically encoded biosensors in a high-throughput format to identify engineered microbes with the ability to make essential precursors to antibiotics.
Polyketide synthases (PKSs) construct a large array of natural products called polyketides. Many polyketides have been produced in microbial hosts by expressing PKS machinery and supplying key precursor small molecules such as 'extender units'. Yet, our ability to produce modified polyketide analogues for drug discovery is restricted by the requirement to provide tailored biosynthetic pathways for non-natural extender units. Here, we propose a 'synthetic biology' approach to provide prototype bacterial strains by designing and constructing an artificial biosynthetic pathway for the generation and installation of a broad array of extender units into polyketides. This platform is expected to be flexible with regard to the target host and polyketide.
Natural products are an important source of drugs with wide-ranging biological activities. Many natural products are polyketides and are biosynthesized by large modular enzymes called polyketide synthases (PKSs). The modularity of PKSs presents several strategies for manipulating these enzymes for the generation of new polyketide analogues, but many of these strategies fail due to our poor understanding of the structure-function relationship in these enzymes. Here, we propose a comprehensive program of PKS engineering that will take advantage of combined evolutionary and chemical biology methods to reprogram the polyketide biosynthetic machinery.
Biosensors will be developed for the detection of a broad range of drugs and used to guide the high-throughput engineering of drug-synthesizing microbes.