Benjamin England, Graduate Student, Dowd Lab, GW Department of Chemistry

The Department of Chemistry Presents:  Ben England, Graduate Student, Dowd Lab, GW Department of Chemistry.  Ben will discuss Staphylococcus-Specific Prodrugs Towards Targeted Antibiotics

Ubiquitous use of broad-spectrum antibiotics has driven antibiotic resistance since the discovery of penicillin in 1928. First line clinical treatment for staphylococcal infections often includes beta lactams or fluoroquinolones, which have historically been celebrated for their activity against gram-negative and gram-positive microbes. Broad-spectrum antibiotics are also known to kill commensal flora. This can cause gut dysbiosis, which is often accompanied by gastrointestinal discomfort and malabsorption, followed by infections by opportunistic pathogens. Clostridium difficile infections are known to occur in patients after receiving fluoroquinolone or beta lactam antibiotics. Additionally, repeated exposure to broad spectrum antibiotics cultivates resistance phenotypes within the host’s commensal microbiome which can propagate genes associated with survival in the face of our best therapeutic options. Genus- specific antimicrobial drugs are urgently needed to alleviate selection pressure on commensal flora. To this end, we have chosen a prodrug strategy wherein an effective but broadly active therapeutic is modified with a carefully tuned ester protecting group to be microbially activated once in the presence of a Staphylococcal activating enzyme, rendering the drug Staphylococcus-specific. In this work, we synthesized, characterized, and tested a series of acyloxymethylene (ACOM) prodrugs of beta lactam warheads in vitro to begin to map the substrate space of two recently identified Staphylococcal enzymes, GloB and FrmB. We examine the effect of varying the warhead as well as varying the protecting group on their activity against wild type and mutant Staphylococcus aureus strains.

BIO

Ben graduated with a B.A. in chemistry from McDaniel College in Westminster, MD in 2019. His research in medicinal chemistry under Dr. Cynthia Dowd has focused on the synthesis, design, and assessment of novel prodrugs of antibiotics as well as antiparasitic therapies.