Dr. Andrew Lowell
Department of Chemistry
Friday, September 15, 2023
Room 120 – Meyerhoff Chemistry Building
Host: Dr. Joe Bennett
“Forgotten antibiotics: Semisynthetic approaches and biosynthetic studies”
Antimicrobial resistance (AMR) poses a major threat to human health, a problem accentuated by the lack of new antibiotic discovery over the past several decades. One rich source of potential antibiotics is the many antimicrobial natural products that were previously identified but remain undeveloped. This category of neglected antibiotics is surprisingly large with follow-up ranging from structurally unknown isolates to well-characterized molecules with high activity and new methods of inhibition. Two of these forgotten antibiotics are blasticidin S and thermorubin, both of which inhibit protein synthesis.
The thermorubin biosynthetic cluster is hypothesized to include the formation of an unusual non-terminal pyrone. Produced by the thermophilic bacteria Laceyella sacchari, expression and use of enzymes from this cluster show favorable stability properties retaining significant activity up to 50 °C. Continued biosynthetic and synthetic studies on this tetracyclic naphthoisocoumarin natural product thus enables insight into thermorubin’s unique mechanism of action in the ribosome and use of its enzymes as robust biocatalysts.
Semisynthetic modification of blasticidin S to refine its broad-spectrum activity specifically for bacteria is underway to convert this cytotoxin into an antibiotic. Production of a series of derivatives of this highly polar, zwitterionic compound was accomplished in as few as one synthetic step using a single semisynthetic step. New analogs were screened against gram-positive and gram-negative bacteria, showing a marked increase in antibacterial activity and selectivity for pathogenic bacteria versus human cells relative to blasticidin S.
Coupled with computer-aided drug design, these biosynthetic and semisynthetic approaches enable us to learn about how antibiotics and broad-spectrum inhibitors bind to the ribosome as well create promising leads for new classes of antimicrobials.