TY - JOUR
T1 - Cloacaenodin, an Antimicrobial Lasso Peptide with Activity against Enterobacter
AU - Carson, Drew V.
AU - Patiño, Monica
AU - Elashal, Hader E.
AU - Cartagena, Alexis Jaramillo
AU - Zhang, Yi
AU - Whitley, Megan E.
AU - So, Larry
AU - Kayser-Browne, Angelo K.
AU - Earl, Ashlee M.
AU - Bhattacharyya, Roby P.
AU - Link, A. James
N1 - Funding Information:
We thank István Pelczer (Princeton University NMR Facility) for the help in acquiring the NMR spectra. We thank Professor Daniel Cohen (Princeton University Department of Mechanical and Aerospace Engineering) and members of the Cohen group for the use of and assistance with microscopy. We thank all members of the Link lab for helpful feedback and discussion. This work was supported by US National Institutes of Health (NIH) grant GM107036 to AJL, as well as NIH grant U19AI110818 to the Broad Institute. We also acknowledge the support of the Princeton University SEAS Funds for the funding towards the Focused Research Team for Precision Antibiotics.
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2023/1/13
Y1 - 2023/1/13
N2 - Using genome mining and heterologous expression, we report the discovery and production of a new antimicrobial lasso peptide from species related to the Enterobacter cloacae complex. Using NMR and mass spectrometric analysis, we show that this lasso peptide, named cloacaenodin, employs a threaded lasso fold which imparts proteolytic resistance that its unthreaded counterpart lacks. Cloacaenodin has selective, low micromolar, antimicrobial activity against species related to the E. cloacae complex, including species implicated in nosocomial infections and against clinical isolates of carbapenem-resistant Enterobacterales. We further used site-directed mutagenesis to probe the importance of specific residues to the peptide’s biosynthesis, stability, and bioactivity.
AB - Using genome mining and heterologous expression, we report the discovery and production of a new antimicrobial lasso peptide from species related to the Enterobacter cloacae complex. Using NMR and mass spectrometric analysis, we show that this lasso peptide, named cloacaenodin, employs a threaded lasso fold which imparts proteolytic resistance that its unthreaded counterpart lacks. Cloacaenodin has selective, low micromolar, antimicrobial activity against species related to the E. cloacae complex, including species implicated in nosocomial infections and against clinical isolates of carbapenem-resistant Enterobacterales. We further used site-directed mutagenesis to probe the importance of specific residues to the peptide’s biosynthesis, stability, and bioactivity.
KW - Enterobacter cloacae
KW - RiPPs
KW - antimicrobial lasso peptide
KW - carbapenem-resistant Enterobacterales
KW - cloacaenodin
KW - genome mining
UR - http://www.scopus.com/inward/record.url?scp=85144253028&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85144253028&partnerID=8YFLogxK
U2 - 10.1021/acsinfecdis.2c00446
DO - 10.1021/acsinfecdis.2c00446
M3 - Article
C2 - 36519726
AN - SCOPUS:85144253028
SN - 2373-8227
VL - 9
SP - 111
EP - 121
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 1
ER -