Seminar: "New Antibiotics Targeting DNA Replication: Structure-Function Studies of Griselimycin" - Nicholas Sawyer

Seminar:

"New Antibiotics Targeting DNA Replication: Structure-Function Studies of Griselimycin"

Nicholas Sawyer, Ph.D.
Assistant Professor
Bioorganic Chemistry/Chemical Biology; Fordham University

The discovery and clinical application of antibiotic natural products represent milestones in human history, reducing mortality rates in both humans and domestic animals. However, misuse and overuse of antibiotics has led to an increase in evolved resistance to antibiotics, threatening the future clinical effectiveness of antibiotic treatments. New antibiotics, especially those with new modes of action, are urgently needed to contend with this growing crisis. Bacterial DNA replication represents a promising but underutilized target for antibiotics, as disrupting replication is expected to slow the transfer of antibiotic resistance genes in addition to limiting bacterial growth.
   
We are currently studying the peptide natural product griselimycin, an antibiotic isolated from Streptomyces sp. that disrupts DNA replication. Griselimycin binds to the sliding clamp protein, an essential factor for processive DNA replication, and inhibits the clamp’s interactions with DNA polymerases. While griselimycin is highly potent against mycobacteria and related bacterial genera, its complex and highly modified structure are limiting factors in synthesis and scalable production. To better understand the connection between griselimycin’s structure and function, we have chemically synthesized a library of griselimycin analogs and studied how individual peptide modifications influence both binding to the sliding clamp protein and antibiotic potency using the model mycobacterial species M. smegmatis. Unexpectedly, we find that many of griselimycin’s functional groups appear to be dispensable for clamp binding with relatively small impacts on antibiotic potency. These insights offer a promising path to griselimycin analogs that are easier to synthesize as new antibiotic candidates.