RT Journal Article
SR Electronic
T1 High-throughput discovery of peptide activators of a bacterial sensor kinase
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.01.446581
DO 10.1101/2021.06.01.446581
A1 Kathryn R. Brink
A1 Andrew M. Mu
A1 Ky V. Hoang
A1 Ken Groszman
A1 John S. Gunn
A1 Jeffrey J. Tabor
YR 2021
UL http://biorxiv.org/content/early/2021/06/01/2021.06.01.446581.abstract
AB Bacteria use two-component system (TCS) signaling pathways to sense and respond to peptides involved in host defense, quorum sensing, and inter-bacterial warfare. However, little is known about the peptide-sensing capabilities of these TCSs. Here, we develop a high-throughput E. coli display method to characterize the effects of human antimicrobial peptides (AMPs) on the pathogenesis-regulating TCS PhoPQ of Salmonella Typhimurium. We find that PhoPQ senses AMPs comprising diverse sequences, structures, and biological functions. Using thousands of AMP variants, we identify sub-domains and biophysical features responsible for PhoPQ activation. We show that most of the newfound activators induce PhoPQ in S. Typhimurium, suggesting a role in virulence regulation. Finally, we find that PhoPQ homologs from Klebsiella pneumoniae and extraintestinal pathogenic E. coli, which occupy different in vivo niches, exhibit distinct AMP response profiles. Our high-throughput method enables new insights into the specificities, mechanisms, and evolutionary dynamics of TCS-mediated peptide sensing in bacteria.Competing Interest StatementThe authors declare the following competing interests: Rice University has filed a patent application on the use of PhoPQ for antimicrobial peptide biosensing and J.J.T. is the founder of PanaBio, a company that engineers diagnostic and therapeutic bacteria.