(19a) Discovery and Characterization of a Novel Lasso Peptide Using a Guilt By Association Approach

With the rise in resistant bacterial infections jeopardizing the efficacy of the antibiotics developed in the 21^st century, new compounds are needed to combat this potential loss of life that was once treatable. Natural products present us with a plethora of novel compounds that can be harnessed for medicinal purposes. Lasso peptides are a member of the ribosomally synthesized and post-translationally modified peptide class of natural products, and much of the interest on these natural products has focused on their unique lariat-knot shape and narrow-spectrum antimicrobial activity against clinically relevant pathogens.^1,2 Genome mining approaches can be focused on organisms that are “pathogen adjacent” in hopes of discovering lasso peptides with antimicrobial activity against a pathogen of interest.^3-5 This talk will focus on an example of a successful genome mining campaign of this type that resulted in a novel lasso peptide with potent antimicrobial activity. This talk will focus on the solution structure of this novel lasso peptide as determined by 2D NMR experiments as well as a structure-function analysis carried out via mutagenesis of the lasso peptide. These mutagenesis experiments reveal interesting behavior regarding the stability of the lasso peptide. The breadth of the antimicrobial spectrum of activity of this peptide will be discussed as well as its potential in treating nosocomial infections.

1. Montalbán-López M, Scott TA, Ramesh S, Rahman IR, van Heel A, Viel JH, Bandarian V, Dittmann E, Genilloud O, Goto Y, Grande Burgos MJ, Hill C, Kim S, Koehnke J, Latham JA, Link AJ, Martínez B, Nair SK, Nicolet Y, Rebuffat S, Sahl HG, Sareen D, Schmidt EW, Schmitt L, Severinov K, Süssmuth RD, Truman AW, Wang H, Weng JK, van Wezel GP, Zhang Q, Zhong J, Piel J, Mitchell DA, Kuipers OP, van der Donk, WA: New developments in RiPP discovery, enzymology and engineering. Natural Product Reports 2021, 38: 130-239.

2. Tan S, Moore G, Nodwell J: Put a Bow on It: Knotted Antibiotics Take Center Stage. Antibiotics (Basel, Switzerland) 2019, 8(3): 117

1. Cheung-Lee WL, Link AJ: Genome mining for lasso peptides: past, present, and future. Journal of Industrial Microbiology & Biotechnology 2019, 46: 1371-1379.
2. Cheung-Lee WL, Parry ME, Zong C, Jaramillo Cartagena A, Darst SA, Connell ND, Russo R, Link AJ: Discovery of ubonodin, an antimicrobial lasso peptide active against members of the Burkholderia cepacia complex. ChemBioChem 2020, 21: 1335-1340.

5. Metelev M, Arseniev A, Bushin L, Kuznedelov K, Artamonova TO, Kondratenko R, Khodorkovskii M, Seyedsayamdost MR, Severinov K: Acinetodin and Klebsidin, RNA Polymerase Targeting Lasso Peptides Produced by Human Isolates of Acinetobacter gyllenbergii and Klebsiella pneumoniae. ACS Chem. Biol. 2017, 12: 814-824