Event
CHBE Seminar: Dr. Daniel C. Nelson, UMD
Friday, November 20, 2026
11:00 a.m.
Room 2108 Chemical and Nuclear Engineering Building
Patricia Lorenzana
301-405-1935
plorenza@umd.edu
One Scaffold, Two Pathogens: Domain Engineering of PlyC-Based Endolysins
Abstract: Bacteriophage endolysins are peptidoglycan hydrolases that lyse Gram-positive bacteria from without, offering a mechanism of killing that is mechanistically distinct from antibiotics and largely unaffected by existing resistance determinants. Endolysins are modular, with catalytic domains that cleave the peptidoglycan and cell wall-binding domains that determine host range, a modularity that enables chimeragenesis: the recombination of domains from different endolysins into a single enzyme with a novel activity/specificity profile. The multimeric endolysin PlyC exhibits among the highest specific activities of any characterized endolysin, but its native binding domain does not recognize streptococcal pathogens of clinical interest. We engineered a chimeric endolysin, ClyX-1, by inserting the choline-binding domain of Cpl-1 in between the PlyC catalytic domains, redirecting activity toward Streptococcus pneumoniae. ClyX-1 shows over 100-fold higher bacteriolytic activity than Cpl-1 against pneumococcal serotypes and resistant clinical isolates, improves survival in murine infection models, and disrupts pneumococcal biofilms. Applying the same platform to a distinct pathogen, we generated ClyX-2 by fusing the PlyC catalytic domains to the binding domain of PlySs2, which recognizes an epitope conserved across streptococcal species, broadening specificity to Group B Streptococcus (GBS), a leading cause of neonatal sepsis, meningitis, and stillbirth. ClyX-2 kills planktonic GBS and degrades mature biofilms at low micromolar concentrations, remains active at vaginal pH and in cervicovaginal mucus, spares the commensal Lactobacillus crispatus, and lowers GBS-induced inflammatory signaling in vaginal epithelial cell culture models. Together, ClyX-1 and ClyX-2 show that a single catalytic scaffold can be redirected through binding domain substitution to produce endolysins with either narrow or broad streptococcal specificity, establishing chimeragenesis as a general strategy for engineering endolysin therapeutics.
Biography: Daniel C. Nelson is a Professor and Head of the Laboratory of Antimicrobial Discovery at the University of Maryland, based at the Institute for Bioscience and Biotechnology Research (IBBR) in Rockville, where he chairs the IBBR Fellows Assembly. Dr. Nelson’s research focuses on bacterial pathogenesis, bacterial biofilms, and the development of bacteriophage-derived proteins as diagnostic and antimicrobial agents. The central theme of his work is the study of proteins involved in the bacteriophage lytic system, particularly endolysins, enzymes that bind to and degrade bacterial cell walls. These proteins represent a promising alternative to conventional antibiotics. While a postdoctoral fellow with Dr. Vincent Fischetti at The Rockefeller University, Dr. Nelson conducted the first study demonstrating the in vivo efficacy of an endolysin against a bacterial infection. Since joining the University of Maryland in 2007, Dr. Nelson’s laboratory has conducted structure-function studies of several active endolysins and now designs engineered variants with enhanced activity, broader host range, and improved thermostability. Active projects target Streptococcus pneumoniae, Streptococcus agalactiae, Clostridioides difficile, and Staphylococcus aureus. Dr. Nelson is co-founder of ExoLytics, Inc., a biotechnology company translating endolysin technologies to address unmet medical needs. In 2025, he was elected a Fellow of the National Academy of Inventors in recognition of his extensive patent portfolio in endolysin technologies. He regularly serves on NIH study sections, has acted as a Department of Defense subject matter expert on antibiotic resistance, and consults or collaborates with public and private organizations pursuing bacterial antimicrobial technologies.
