Natural products account for two-thirds of the antibacterial pharmacopeia and are therefore privileged scaffolds. These complex molecules have inspired novel synthetic methods and positively impacted the fields of biochemistry, molecular biology, and medicine. The proposed project is inspired by albocycline, a unique 14-membered macrolactone with potent, narrow-spectrum activity against the ?superbug? methicillin- resistant Staphylococcus aureus (MRSA). We have validated that albocycline is effective against MRSA and vancomycin-resistant S. aureus strains; moreover, it is non-toxic to human cells. In 2013, Tomoda reported that albocycline inhibited peptidoglycan (i.e., bacterial cell wall) synthesis in macromolecular assays. Using biochemical assays and molecular modeling, we demonstrated that albocycline was a weak (mM) inhibitor of MurA from S. aureus. Consistent with its narrow-spectrum profile, albocycline did not inhibit MurA from E. coli. Based on our results and those of Tomoda, we conclude it must have additional bacterial targets. Significantly, we recently completed a modular, step-efficient total synthesis of the natural product driven by novel chemistry of N-sulfinyl metallodienamines. Accordingly, in Aim 1 we propose to prepare albocycline analogs (including probes) by semi- and diverted total synthesis to explore the chemical space about this privileged scaffold.
In Aim 2, we will co-crystallize albocycline in complex with MurA based on exciting preliminary results and employ structure-based analog design. We will also identify the target(s) of albocycline to determine its mode-of-action using computational chemistry, chemical proteomics and genomics approaches, in addition to a novel metabolic labeling methodology. Finally, in Aim 3 we will evaluate the biological activity of all albocycline analogs. At the end of the four-year project period, we will have (1) a deeper understanding of how albocycline exerts its antibacterial action; (2) a library of tool compounds and antibiotic lead candidates that selectively modulate their target(s); and most significantly, (3) a bona fide launching point for the development of novel, narrow-spectrum antibiotics to treat recalcitrant MRSA, VISA, and VRSA (i.e., the project's long-term goal).

Public Health Relevance

Approximately two-thirds of all antibiotics are derived from natural products. By studying their mechanism of action and by systematic structural modification, medicine has saved countless lives. However, the rapid development of bacterial resistance to antibiotic drugs coupled with marked changes in the Pharmaceutical Sector has resulted in a global health crisis. This project seeks to understand how albocycline, a natural product with potent antibiotic activity against resistant Staphylococcus aureus strains such as MRSA, exerts its action and to develop novel analogs with improved properties. The long-term goal is to deliver new antibiotics to avert a post-antibiotic era.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM126221-02S1
Application #
9981542
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
2018-09-01
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Temple University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122