| |
| author |
Jonah Fine
| | title |
Biosynthesis and Semi-synthesis of Kibdelomycin
| | abstract |
Kibdelomycin is a broad-spectrum antibiotic isolated from Kibdelosporangium
banguiense and was discovered by a very sophisticated Staphylococcus aureus Fitness Test
(SaFT) assay at Merck that inhibited topoisomerase II activity. About the same time,
amycolamicin, an identical compound produced by Amycolatopsis sp. MK575-fF5, was reported
with the similar activity but was discovered using a standard antibiotic assay. Kibdelomycin
inhibits bacterial growth by potently inhibiting topoisomerase II, specifically, DNA gyrase B and
ParE. Kibdelomycin showed broad-spectrum gram-positive antibacterial activity but only modest
potency against gram-negative ESKAPE pathogens, despite potent inhibition of E. coli gyrase B
activity (IC50 60 nM), indicating a lack of target access affected by entry/efflux instead of a lack
of target engagement. Kibdelomycin showed no cross-resistance to known antibiotics including
quinolones which inhibit gyrase, indicating its high potential as a new antibiotic. X-ray crystal
structure analysis bound to S. aureus GyrB and ParE showed unique U-shaped binding with multi-point contacts helping to attain low frequency of resistance. This structure provides an opportunity
for structure-guided chemical modification to improve its gram-negative antibacterial profile. We
focused on three independent groups of studies to improve upon understanding kibdelomycin with
the goal of discovering a broad-spectrum antibacterial compound. These studies include
the biosynthesis of kibdelomycin, isolation and structure elucidation of and biological evaluation
of new congeners of kibdelomycin, and synthetic modification of kibdelomycin and determination
of minimum structural requirement for antibacterial activity. Biosynthesis studies confirmed the
direct incorporation of pyruvates, valine, and proline which should benefit in designing potentially
tailored metabolites. A new approach of repeated batch fermentation led to enhanced production
of trace metabolites leading to discovery and characterization of two new kibdelomycin congeners
A-1 and A-2 with modest activity. Semi-synthetic studies of kibdelomycin and related simple
pyrrole amides show that the full molecular framework is essential for strong activity, as suggested
by static X-ray data. However, these studies do suggest that modifications to the topmost sugar of
kibdelomycin may yield improved properties.
| | school |
The College of Liberal Arts, Drew University
| | degree |
B.S. (2026)
|
| advisor |
Sheo B. Singh
|
| committee |
Adam Cassano
Erik Anderson
|
| full text | JFine.pdf |
| |
