Infectious disease is the second leading cause of death worldwide, the growing number of antibiotic-resistant microbes threatens to further worsen this public crisis, but the pipeline for new antibiotics is running dry. Diabetes affects nearly 26 million people in the US, as many as 1 in 3 American adults will have diabetes in 2050 if present trends continue, and yet current approved therapies suffer from inadequate efficacy and/or liabilities. The discovery of platensimycin (PTM) and platencin (PTN) as selective and potent bacterial and mammalian fatty acid synthase inhibitors and the demonstrated efficacy of PTM and PTN in animal models as a new class of antibacterial and antidiabetic drug leads are therefore of exceptional importance. However, development of PTM and PTN into commercial drugs faces formidable obstacles, including improvement of the drugs' pharmacokinetics and the inevitable emergence of resistance. We propose in this application to: (i) characterize the PTM and PTN biosynthetic pathways, (ii) engineer the PTM and PTN biosynthetic machinery to generate novel analogues, and (iii) investigate PTM and PTN self-resistance in the native producers and acquired resistance in clinically relevant pathogens. Our hypotheses are: (i) studies of PTM and PTN biosynthesis promise to uncover new chemistry and enzymology, (ii) exploration of diterpenoid synthase specificity and tailoring enzyme promiscuity provides an outstanding opportunity to generate novel analogues, (iii) comparison and contrast of PTM and PTN self-resistance in the producers to acquired resistance in pathogens provides an excellent opportunity to understand, and therefore predict and combat future PTM or PTN resistance in clinical settings. The long-term goal of our research is to develop PTM and PTN into a new class of clinically useful antibacterial and antidiabetic drugs.
The specific aims for this grant period are: (i) functional characterization of the PTM and PTN biosynthetic machinery in vivo and biochemical characterization of the novel enzymes for PTM and PTN biosynthesis in vitro, (ii) engineering of the PTM and PTN biosynthetic machinery for novel PTM and PTN analogues, (iii) investigation of the molecular mechanisms of PTM and PTN self-resistance in the producers and acquired resistance in pathogens. The outcomes of the proposed studies will include: (i) PTM and PTN biosynthesis as a model system for bacterial diterpenoid natural products, (ii) novel chemistry and enzymology for diterpenoid biosynthesis, (iii) PTM and PTN analogues with improved pharmacokinetic properties as antibacterial and antidiabetic drug leads, and (iv) molecular mechanisms of PTM and PTN resistance.

Public Health Relevance

Platensimycin (PTM) and platencin (PTN) are potent fatty acid synthase inhibitors and have emerged as promising novel antibacterial and antidiabetic drug leads. This project aims at characterizing the PTM and PTN biosynthetic machineries, engineering novel PTM and PTN analogues, and investigating PTM and PTN resistance mechanisms. The resultant PTM and PTN analogues will be evaluated for the development of clinically useful antibacterial and antidiabetic drugs, while comparison and contrast of PTM and PTN self-resistance in the native producers and acquired resistance in pathogens will help understand, thereby predicting and combating future drug resistance in the clinical settings.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM114353-03
Application #
9384754
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
2015-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458
Rudolf, Jeffrey D; Chang, Chin-Yuan; Ma, Ming et al. (2017) Cytochromes P450 for natural product biosynthesis in Streptomyces: sequence, structure, and function. Nat Prod Rep 34:1141-1172
Dong, Liao-Bin; Rudolf, Jeffrey D; Lin, Li et al. (2017) In vivo instability of platensimycin and platencin: Synthesis and biological evaluation of urea- and carbamate-platensimycin. Bioorg Med Chem 25:1990-1996
Falzone, Maria; Crespo, Emmanuel; Jones, Klarissa et al. (2017) Nutritional control of antibiotic production by Streptomyces platensis MA7327: importance of l-aspartic acid. J Antibiot (Tokyo) 70:828-831
Qiu, Lin; Tian, Kai; Pan, Jian et al. (2017) A Facile Semi-Synthetic Approach towards Halogen-Substituted Aminobenzoic Acid Analogues of Platensimycin. Tetrahedron 73:771-775
Rudolf, Jeffrey D; Dong, Liao-Bin; Shen, Ben (2017) Platensimycin and platencin: Inspirations for chemistry, biology, enzymology, and medicine. Biochem Pharmacol 133:139-151
Rudolf, Jeffrey D; Dong, Liao-Bin; Manoogian, Karina et al. (2016) Biosynthetic Origin of the Ether Ring in Platensimycin. J Am Chem Soc 138:16711-16721
Dong, Liao-Bin; Rudolf, Jeffrey D; Shen, Ben (2016) Antibacterial sulfur-containing platensimycin and platencin congeners from Streptomyces platensis SB12029. Bioorg Med Chem 24:6348-6353
Dong, Liao-Bin; Rudolf, Jeffrey D; Shen, Ben (2016) A Mutasynthetic Library of Platensimycin and Platencin Analogues. Org Lett 18:4606-9
Rudolf, Jeffrey D; Dong, Liao-Bin; Cao, Hongnan et al. (2016) Structure of the ent-Copalyl Diphosphate Synthase PtmT2 from Streptomyces platensis CB00739, a Bacterial Type II Diterpene Synthase. J Am Chem Soc 138:10905-15
Smanski, Michael J; Zhou, Hui; Claesen, Jan et al. (2016) Synthetic biology to access and expand nature's chemical diversity. Nat Rev Microbiol 14:135-49

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