Investigating the Mechanism of Action of Thanatin in Escherichia coli

Authors:

Liam Spencer, Cait Moffatt, Dan Kahne

Date Created:

2025-01-01

Course Title:

Professor:

Not specified

About Paper:

The escalation of antibiotic resistance has created an urgent need of thanatin’s ▯-hairpin binding to LptA. Here, we explore the fornovelantibiotics, particularlyagainstGram-negativepathogens hypothesisthatthanatin’sN-terminaltailisimplicatedinthanatin’s like Escherichia coli. Gram-negative species are especially mechanism of action (MOA). challenging to kill because the molecule lipopolysaccharide (LPS) in their outer membrane forms a permeability barrier which Minimum inhibitory concentrations of thanatin and thanatin truncations show that certain residues of the N-terminal prevents the entry of many antibiotics. The lipopolysaccharide tail are required for antimicrobial activity. Using in vivo transport (Lpt) complex, formed by the seven essential proteins photocrosslinking, we explore the effects of thanatin’s tail on Lpt LptA-LptG, facilitates the movement of LPS to the outer membrane, making it an attractive drug target. protein-protein interactions and find that thanatin changes LptA’s C-terminal interacting partner. The 21-residue natural peptide thanatin, which features a C- We are using mass spectrometry to identify LptA’s thanatin- terminal ▯-hairpin and a N-terminal unstructured tail, exhibits antimicrobial activity against E. coli. Thanatin’s ▯-hairpin induced interacting partner and in vivo approaches to investigate localizes to LptA’s interaction interface with LptC, leading to thethe hypothesis that this species is implicated in thanatin’s MOA. Our long-term aim is to elucidate thanatin’s MOA and better hypothesis in the field that thanatin kills by preventing proper Lpunderstand the Lpt complex, which could enable the rational complex assembly at the LptC-LptA interface. However, we have design of thanatin-inspired antibiotics or antibiotic potentiators for foundthatcovalentfusionoftheLptC-LptAinterfacedoesnotlend anyresistanceagainstthanatin,implyingthatkillingisindependent treatment of Gram-negative infections.

Abstract:

The escalation of antibiotic resistance has created an urgent need of thanatin’s ▯-hairpin binding to LptA. Here, we explore the fornovelantibiotics, particularlyagainstGram-negativepathogens hypothesisthatthanatin’sN-terminaltailisimplicatedinthanatin’s like Escherichia coli. Gram-negative species are especially mechanism of action (MOA). challenging to kill because the molecule lipopolysaccharide (LPS) in their outer membrane forms a permeability barrier which Minimum inhibitory concentrations of thanatin and thanatin truncations show that certain residues of the N-terminal prevents the entry of many antibiotics. The lipopolysaccharide tail are required for antimicrobial activity. Using in vivo transport (Lpt) complex, formed by the seven essential proteins photocrosslinking, we explore the effects of thanatin’s tail on Lpt LptA-LptG, facilitates the movement of LPS to the outer membrane, making it an attractive drug target. protein-protein interactions and find that thanatin changes LptA’s C-terminal interacting partner. The 21-residue natural peptide thanatin, which features a C- We are using mass spectrometry to identify LptA’s thanatin- terminal ▯-hairpin and a N-terminal unstructured tail, exhibits antimicrobial activity against E. coli. Thanatin’s ▯-hairpin induced interacting partner and in vivo approaches to investigate localizes to LptA’s interaction interface with LptC, leading to thethe hypothesis that this species is implicated in thanatin’s MOA. Our long-term aim is to elucidate thanatin’s MOA and better hypothesis in the field that thanatin kills by preventing proper Lpunderstand the Lpt complex, which could enable the rational complex assembly at the LptC-LptA interface. However, we have design of thanatin-inspired antibiotics or antibiotic potentiators for foundthatcovalentfusionoftheLptC-LptAinterfacedoesnotlend anyresistanceagainstthanatin,implyingthatkillingisindependent treatment of Gram-negative infections.

Source:

Harvard / Harvard College | Quincy House | Neuroscience | 2028 / 2025

Topics:

thanatin, lpta, antibiotic, coli, hairpin, moa, tail, lpt, complex, mechanism, action, escherichia

Co-authors:

@liamspencer370 , @caitmoffatt189 , @dankahne371