Cell-Free Systems: Ideal Platforms for Accelerating the Discovery and Production of Peptide-Based Antibiotics
Abstract
:1. Introduction
2. PBAs Are Produced through Various Biosynthetic Pathways
Group | Machinery for Biosynthesis | Types of Peptides | Representative Compounds |
---|---|---|---|
I | (a) Translational apparatus | Peptides only containing the 20 canonical amino acids | α-Helical peptides [9], PrAMPs [63,65], WrAMPs [66], RrAMPs [67], disulfide-rich peptides [69,70] |
(b) Translational apparatus and post-translational enzymes | Ribosomally synthesized and post-translationally modified peptides (RiPPs) |
| |
II | (c) Non-ribosomal peptide synthetases (NRPSs) | Non-ribosomal peptides (NRPs) | Lipopeptide surfactants [87], cyclodecapeptides [88], glycopeptide antibiotics [89], mycobactins [90], malleobactins [91] |
3. CFSs as Ideal Platforms for PBA Research
4. Main Research on PBAs Using CFSs
4.1. CFSs Enable the Elucidation of the Mechanism of Action of PBAs
4.2. CFSs Facilitate the Characterization of Biosynthetic Pathways of PBA
4.3. CFSs Enable the Selection of PBAs from a Diverse Library
4.4. CFSs Enable the Synthesis of PBAs with Complex Structures
Section | PBAs | Structural Features | Target Microorganisms |
---|---|---|---|
Section 4.1 | Drosocin |
| Gram-negative bacteria (E. coli) |
Os-C | - | Bacteria | |
P113 |
| Fungi, Bacteria, Yeast | |
Buforin-2 | - | Bacteria | |
Section 4.2 | Goadsporin |
| |
Nisin Z |
| E. coli, B. subtilis | |
Section 4.3 | Salivaricin B |
| Bacteria (S. aureus RN4220) |
Valinomycin |
| Fungi, Gram-positive bacteria | |
Gramicidin S |
| Fungi, Bacteria | |
De novo designed PBAs | - | E. coli (MG1655), B. subtilis (PY79), E. faecium S. aureus (DSM 11729), K. pneumoniae (DSM 30104), A. baumannii, P. aeruginosa (DSM 1117), Enterobacter spp., Y. pestis (EV76), B. anthracis Sterne, S. pneumoniae (D39) | |
Meucin-25 | - | Fungi, Bacteria | |
Cathelicidin-BF | - | Fungi, Bacteria | |
δ-lysin | - | Gram-positive bacteria | |
Section 4.4 | SFTI-1 |
| Fungi |
Kalata B1 |
| Gram-positive bacteria | |
AA139 |
| Gram-negative bacteria | |
HT-1 |
| Bacteria | |
Capistruin |
| Gram-negative bacteria | |
Thiocillin |
| Fungi, Gram-positive bacteria |
5. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Type | Peptide | Proposed Antibacterial Mechanisms | Target Gram-Negative Pathogens and MIC | Target Gram-Positive Pathogens and MIC | MIC for MDR |
---|---|---|---|---|---|
Peptides | Magainin II [19,20] |
|
|
|
|
Melittin [21,22,23] |
|
|
|
| |
LL-37 [24,25,26] |
|
|
|
| |
Buforin II [20,27] |
|
|
|
| |
Cecropin P1 [20] |
|
|
|
| |
Indolicidin [20] |
|
|
|
| |
PR-39 [23,28] |
|
|
|
| |
Vancomycin [29,30] |
| - |
|
| |
Daptomycin [23,31] |
| - |
|
| |
Polymyxin [32,33] |
|
|
|
| |
Small molecules | Ciprofloxacin [27,34] |
|
|
|
|
Gentamicin [27,35] |
|
|
|
| |
Tetracycline [36,37] |
|
|
|
|
Types of PTMs | PTM Reactions | PBAs | ||
---|---|---|---|---|
Cyclization | Bridging reactions | Thioether formation |
|
|
Disulfide bond formation (Cysteine oxidation) |
|
| ||
Head-to-tail cyclization |
|
| ||
Cyclodehydration | Heterocycle formation |
|
| |
Alkylation | N-methylation |
|
| |
Glycosylation | N-Glycosylation |
| ||
|
| |||
S-Glycosylation |
| |||
O-glycosylation |
|
|
Mechanisms (Section 4.1) | Biosynthetic Pathways (Section 4.2) | Selections (Section 4.3) | Synthesis (Section 4.4) | |
---|---|---|---|---|
Methods | Mutagenesis of PBAs [148] | Identification of biosynthetic pathways [149,150,151] | Screening of multiple variants [139,152] | Inducing proper folding [153,154] |
Qualitative and quantitative analysis on biomolecules [16,63,155,156] | Enzyme promiscuity for substrates [157,158,159,160,161,162,163] | Optimization of reaction conditions [164,165,166] | Chemo-enzymatic modification [167] | |
Kinetic analysis of enzymes [152] | Integration of deep generative models [168,169] | |||
Generation of diverse environments through microfluidic system [170] | ||||
Target peptide selection using mRNA displays [171,172] |
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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Park, H.; Jin, H.; Kim, D.; Lee, J. Cell-Free Systems: Ideal Platforms for Accelerating the Discovery and Production of Peptide-Based Antibiotics. Int. J. Mol. Sci. 2024, 25, 9109. https://doi.org/10.3390/ijms25169109
Park H, Jin H, Kim D, Lee J. Cell-Free Systems: Ideal Platforms for Accelerating the Discovery and Production of Peptide-Based Antibiotics. International Journal of Molecular Sciences. 2024; 25(16):9109. https://doi.org/10.3390/ijms25169109
Chicago/Turabian StylePark, Hyeongwoo, Haneul Jin, Dayeong Kim, and Joongoo Lee. 2024. "Cell-Free Systems: Ideal Platforms for Accelerating the Discovery and Production of Peptide-Based Antibiotics" International Journal of Molecular Sciences 25, no. 16: 9109. https://doi.org/10.3390/ijms25169109