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Genomics Accelerated Discovery of Antimicrobial Natural Products from Bacteria

Wilson, Jake
http://orcid.org/0000-0003-3033-1452
http://rave.ohiolink.edu/etdc/view?acc_num=osu1713364517546197

Abstract Details

2024, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
The emergence and spread of antimicrobial resistance (AMR) has created an urgent need for new antibiotics. Despite the looming threat of AMR, the antimicrobial drug development pipeline is sparse, and without action, return to a pre-antibiotic era is conceivable. Microbial natural products are the source of most clinically used antibiotics, and continue to be an excellent source of lead compounds. Further, the advent of genomics and detection of natural product biosynthetic gene clusters (BGCs) has revolutionized the study of microbial metabolism, making possible the targeted discovery of chemically unusual and biologically active compounds. Phosphonate natural products are defined by a direct C-P bond, and are renowned for their inhibitory properties. The phosphonate moiety is analogous to carboxylate and phosphate ester functional groups on primary metabolites, enabling chemical mimicry and competitive or suicide inhibition of essential metabolic enzymes. Biosynthesis of nearly all known phosphonates is initiated by phosphoenolpyruvate mutase (PepM), which catalyzes the isomerization of phosphoenolpyruvate to phosphonopyruvate, forming the characteristic C-P bond. Further, genes involved in phosphonate biosynthesis tend to co-localize with pepM on the genome of the producing organism in BGCs. Genome mining has proven to be an invaluable tool in phosphonate discovery efforts, enabling the targeted discovery of unprecedented enzymatic transformations and metabolites. This thesis describes genomics accelerated discovery of novel and bioactive phosphonate natural products from microbes. Phosphonoalamides are phosphonoalanine-containing peptides originally discovered in Streptomyces spp. While actinobacteria are the producers of most known phosphonates, bioinformatic analyses have shown that other taxa are replete with phosphonate biosynthetic potential. Detection of a phosphonoalamide BGC encoded by Bacillus spp. enabled the isolation of phosphonalamide E and F from Bacillus velezensis, a plant growth promoting rhizobacterium. Phosphonoalamide E is an N-Ala-PnAla-C dipeptide, whereas phosphonoalamide F is an N-Ala-Ala-PnAla-C tripeptide. Both exhibited broad spectrum antimicrobial activity against a panel of human and plant pathogens. Further, bioinformatic analyses demonstrated that Firmicutes encode an array of yet to be discovered phosphonoalanine containing metabolites. Terrestrial microbes are the producers of most known phosphonates, with fewer studies focusing on the phosphonate metabolism of marine organisms. We detected a phosphonate BGC encoded by the marine actinobacterium Salinospora pacifica. Heterologous expression of this BGC enabled the isolation and chemical characterization of salinosporaphos A-C, a series of aminomethylphosphonate-containing phosphonopeptides. Salinosporaphos A was shown to contain an amino acid unprecedented in Nature, which we identified as dehydromethylaspartate. Salinosporaphos A and B were shown to have antimicrobial activity against select Gram-negative bacteria. Collectively, discovery of these phosphonates expands our knowledge of phosphonate metabolism in taxonomically diverse bacteria, and raises interesting questions about their biosyntheses, which must be characterized to facilitate the genomics accelerated discovery of additional phosphonate inhibitors.
Kou-San Ju (Advisor)
Liva Rakotondraibe (Committee Member)
Karl Werbovetz (Committee Member)
James Fuchs (Committee Member)
288 p.
Chemistry
Antibiotics; genome mining; natural products

Recommended Citations

Citations

  • Wilson, J. (2024). Genomics Accelerated Discovery of Antimicrobial Natural Products from Bacteria [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1713364517546197

    APA Style (7th edition)

  • Wilson, Jake. Genomics Accelerated Discovery of Antimicrobial Natural Products from Bacteria. 2024. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1713364517546197.

    MLA Style (8th edition)

  • Wilson, Jake. "Genomics Accelerated Discovery of Antimicrobial Natural Products from Bacteria." Doctoral dissertation, Ohio State University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=osu1713364517546197

    Chicago Manual of Style (17th edition)

osu1713364517546197
© 2024, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.