Cyclophane Polypeptides for Drug-Resistant Gram-Negative Bacteria
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Solution Overview
Problem
There is an urgent need for new antibiotics effective against Carbapenem-resistant Enterobacteriaceae (CRE) and Extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) due to their resistance to existing antibiotics, leading to severe infections and high mortality rates.
Innovation Solution
Development of polypeptides with specific three-residue motifs connected by cyclophane moieties, which are biosynthesized using a ribosomally synthesized and post-translationally modified peptide (RiPP) pathway, involving rSAM/SPASM maturases to modify and export the peptides, demonstrating antibacterial activity against drug-resistant bacteria.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibiotics are used to treat Gram-negative bacterial infections, then existing treatments can be effective, but resistance mechanisms develop and existing antibiotics become ineffective
Solution Approach 1:
The patent changes the chemical and structural parameters of the antibacterial agent by creating novel polypeptides with specific three-residue motifs (X1-X2-X3 where X1 is aromatic) that form cyclophane moieties. These structural parameter changes enable the peptides to target and inhibit resistance mechanisms in Gram-negative bacteria while maintaining efficacy against drug-resistant strains
Solution Approach 2:
The patent employs composite structural elements by combining multiple functional motifs within a single polypeptide sequence. The peptides integrate specific three-residue cyclophane-containing motifs with additional functional residues (including aromatic residues at the C-terminus) to create a composite molecular structure that simultaneously targets multiple bacterial processes and overcomes resistance mechanisms
2Reliability
If new antibiotics are developed to treat drug-resistant bacteria, then mortality rates can be reduced, but the complexity of peptide synthesis and characterization increases
Solution Approach 1:
The patent segments the peptide structure into distinct functional modules: a core three-residue motif (X1-X2-X3) that forms the cyclophane moiety, optional spacer residues (1-3 amino acids), and C-terminus residues (at least two, including aromatic). This segmentation allows systematic variation of each module to optimize activity while managing synthesis complexity through modular design
Solution Approach 2:
The patent applies local quality by assigning specific functional roles to different regions of the polypeptide: the X1-X2-X3 motif (particularly the aromatic X1) is responsible for cyclophane formation and primary bacterial cell targeting, while the C-terminus aromatic residues contribute to membrane interaction and permeabilization. This localized functional assignment guides selective optimization of each region
3Reliability
If polypeptides with specific three-residue motifs are synthesized, then antibacterial activity can be achieved, but the cost and time of production increase
Solution Approach 1:
The patent performs preliminary computational design and prediction of optimal peptide sequences and structures before synthesis. By pre-identifying the critical three-residue motifs and their cyclophane configurations, the synthesis process can be directly targeted to produce only the active compounds, avoiding time-consuming trial-and-error approaches
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The polypeptides exhibit antibacterial activity with minimal inhibitory concentrations of 2-10 μg/mL, effectively inhibiting Gram-negative bacteria, including drug-resistant strains, and show potential in treating infections and reducing resistance mechanisms.
Implementation Method 1
RiPP pathways involving radical S-adenosylmethionine (rSAM) enzymes in their biosynthesis are of particular interest due to their ability to catalyze distinct chemically-demanding reactions leading to unique and bioactive RiPP natural products
Implementation Method 2
The polypeptides exhibit antibacterial activity with minimal inhibitory concentrations of 2-10 μg/mL, effectively inhibiting Gram-negative bacteria, including drug-resistant strains
Data Source
AI summary
The present disclosure concerns a polypeptide comprising a first three residue motif (from a N-terminus) and a second three residue motif, the first and second three residue motif optionally separated by 1 to 3 amino acid residue, and at least two C-terminus residues. The three residue motif is each represented by X1-X2-X3. Each X1 is a residue independently selected from tryptophan, phenylalanine, tyrosine, histidine, an unnatural aromatic amino acid residue or a derivative thereof. Each X2 and X3 are independently any amino acid residue. X1 and X3 in each motif are connected to form a cyclophane moiety. At least one of the two C-terminus residues is an aromatic residue. The present disclosure also concerns a method of producing the polypeptide.