Altering Specificity and Enhancing Stability of the Antimicrobial Peptides Nisin and Rombocin through Dehydrated Amino Acid Residue Engineering

Peptides, Journal Year: 2024, Volume and Issue: 174, P. 171152 - 171152

Published: Jan. 13, 2024

Nisin serves as the prototype within lantibiotic group of antimicrobial peptides, exhibiting a broad-spectrum inhibition against Gram-positive bacteria, including important food-borne pathogens and clinically relevant antibiotic-resistant strains. The gene-encoded nature nisin allows for gene-based bioengineering, enabling generation novel derivatives. It has been demonstrated that mutants can be produced with improved functional properties. Here, we particularly focus on uncommon amino acid residues dehydroalanine (Dha) dehydrobutyrin (Dhb), whose functions are not yet fully elucidated. Prior to this study, developed new expression system utilizes modification machinery NisBTC advance expression, resulting in enhanced peptide dehydration efficiency. Through approach, discovered dehydrated Dhb at position 18 rombocin, short variant nisin, displayed four times higher activity compared non-dehydrated strain Lactococcus lactis. Furthermore, observed peptides Dha residue positon exhibited superior Dhb. Upon purifying wild-type its nisinG18/Dha homogeneity, minimum inhibitory concentration (MIC) indicated similar inhibiting growth Bacillus cereus but showed twice MIC values other tested gram-positive Further stability tests properties under different temperatures resistance proteolytic enzymes nisin.

Language: Английский

---

Food and gut originated bacteriocins involved in gut microbe-host interactions

Critical Reviews in Microbiology, Journal Year: 2022, Volume and Issue: 49(4), P. 515 - 527

Published: June 17, 2022

The gut microbes interact with each other as well host, influencing human health and some diseases. Many commensals food originated bacteria produce bacteriocins which can inhibit pathogens modulate microbiota. Bacteriocins have comparable narrow antimicrobial spectrum are attractive potentials for precision therapy of disorders. In this review, the from microbiomes their involvement in interaction between producers ecosystem, along characteristics, types, biosynthesis, functions described discussed. produced by many intestinal among lactic acid (many probiotics) has been paid more attention. Bacteriocin production generally regarded a probiotic trait. They give competitive advantage to bacteria, enabling colonization gut, mediating host ecosystem. fight against unwanted without significant impact on composition commensal assist survive colonize microbial populations. There is great need evaluate utilize potential improved therapeutic implications health.

Language: Английский

---

Improved production of class I lanthipeptides in Escherichia coli

Chemical Science, Journal Year: 2023, Volume and Issue: 14(10), P. 2537 - 2546

Published: Jan. 1, 2023

Expression of Glu-tRNA and its synthetase from lanthipeptide encoding bacteria using pEVOL improves production in E. coli . Often-observed glutathionylation can be reversed LanCL enzymes.

Language: Английский

---

Discovery and engineering of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products

RSC Chemical Biology, Journal Year: 2023, Volume and Issue: 5(2), P. 90 - 108

Published: Nov. 21, 2023

The major approaches ( i.e. bioactivity-guided screening, genome mining, and biosynthetic engineering) employed in the exploration of RiPP (ribosomally synthesized post-translationally modified peptides) natural products are discussed this review.

Language: Английский

---

Genome mining of sulfonated lanthipeptides reveals unique cyclic peptide sulfotransferases

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(6), P. 2773 - 2785

Published: Feb. 26, 2024

Although sulfonation plays crucial roles in various biological processes and is frequently utilized medicinal chemistry to improve water solubility chemical diversity of drug leads, it rare underexplored ribosomally synthesized post-translationally modified peptides (RiPPs). Biosynthesis RiPPs typically entails modification hydrophilic residues, which substantially increases their stability bioactivity, albeit at the expense reducing solubility. To explore sulfonated that may have improved solubility, we conducted co-occurrence analysis RiPP class-defining enzymes sulfotransferase (ST), discovered two distinctive biosynthetic gene clusters (BGCs) encoding both lanthipeptide synthetase (LanM) ST. Upon expressing these BGCs, characterized structures novel lanthipeptides determined catalytic details LanM We demonstrate SslST-catalyzed leader-independent but relies on presence A ring formed by LanM. Both ST are promiscuous towards residues ring, displays strict regioselectivity toward Tyr5. The recognition cyclic peptide was further discussed. Bioactivity evaluation underscores significance ST-catalyzed sulfonation. This study sets up starting point engineering STs as biocatalysts for hydrophobic improvement.

Language: Английский

---

Discovery of phosphorylated lantibiotics with proimmune activity that regulate the oral microbiome

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(22)

Published: May 22, 2023

Lantibiotics are ribosomally synthesized and posttranslationally modified peptides (RiPPs) that produced by bacteria. Interest in this group of natural products is increasing rapidly as alternatives to conventional antibiotics. Some human microbiome–derived commensals produce lantibiotics impair pathogens’ colonization promote healthy microbiomes. Streptococcus salivarius one the first commensal microbes colonize oral cavity gastrointestinal tract, its biosynthesis RiPPs, called salivaricins, has been shown inhibit growth pathogens. Herein, we report on a phosphorylated class three related collectively referred salivaricin 10, exhibit proimmune activity targeted antimicrobial properties against known pathogens multispecies biofilms. Strikingly, immunomodulatory activities observed include upregulation neutrophil-mediated phagocytosis, promotion antiinflammatory M2 macrophage polarization, stimulation neutrophil chemotaxis—these have attributed phosphorylation site identified N-terminal region peptides. Salivaricin 10 were determined be S. strains found subjects, their dual bactericidal/antibiofilm immunoregulatory may provide new means effectively target infectious while maintaining important microbiota.

Language: Английский

---

Heterologous Expression and Characterization of Estercin A, a Class II Lanthipeptide Derived from Clostridium estertheticum CF016, with Antimicrobial Activity against Clinically Relevant Pathogens

Journal of Natural Products, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Recent genome mining work revealed that unexplored habitats exhibit great potential for discovering new nonribosomal peptides (NRPs) and ribosomally synthesized post-translationally modified (RiPPs). Lanthipeptides are a group of RiPPs exhibiting variety biological functions. They characterized by the presence thioether-containing bis-amino acids lanthionine and/or methyllanthionine. In this study, we heterologously expressed structurally estercin A, an unprecedented class II lanthipeptide derived from Clostridium estertheticum CF016 in Escherichia coli. Comprising 27 amino acids, A features three overlapping (methyl-)lanthionine rings, with shorter C-terminal part compared to most reported lanthipeptides. Estercin exhibited selective antimicrobial properties against methicillin-resistant Staphylococcus aureus, bowel infection-associated perfringens tetani. The mode action was determined as binding lipid on cell membrane. stability across range pH values temperatures showed resistance degradation trypsin. Our findings highlight novel stable peptide significant combating clinically relevant pathogens.

Language: Английский

---

Marine Metagenome Mining Reveals Lanthipeptides Colwesin A–C, Exhibiting Novel Ring Topology and Anti-inflammatory Activity

ACS Synthetic Biology, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Marine natural products are promising sources for drug discovery due to their unique structures and diverse biological activities. The establishment of the Global Microbiome Genome Catalogue (GOMC) has significantly expanded repository derived from marine-associated bacteria. In this study, we identified Class I lanthipeptide biosynthetic gene cluster col Colwellia_A sp. based on GOMC database. Through heterologous expression in Escherichia coli subsequent structural analysis, characterized three novel lanthipeptides, colwesins A-C, which possess cyclic by an exceptionally large number thioether rings. To best our knowledge, colwesin C is first simultaneously containing locked, nonoverlapped, nested ring topologies. These findings highlight robust ring-forming capacity synthetases. Colwesins A-C were found exhibit anti-inflammatory activity lipopolysaccharide-induced mouse macrophage RAW264.7 cell lines without detectable cytotoxicity. Overall, results broaden understanding diversity marine-derived lanthipeptides.

Language: Английский

---

Do Bacteria Provide an Alternative to Cancer Treatment and What Role Does Lactic Acid Bacteria Play?

Microorganisms, Journal Year: 2022, Volume and Issue: 10(9), P. 1733 - 1733

Published: Aug. 27, 2022

Cancer is one of the leading causes mortality and morbidity worldwide. According to 2022 statistics from World Health Organization (WHO), close 10 million deaths have been reported in 2020 it estimated that number cancer cases world-wide could increase 21.6 by 2030. Breast, lung, thyroid, pancreatic, liver, prostate, bladder, kidney, pelvis, colon, rectum cancers are most prevalent. Each year, approximately 400,000 children develop cancer. Treatment between countries vary, but usually includes either surgery, radiotherapy, or chemotherapy. Modern treatments such as hormone-, immuno- antibody-based therapies becoming increasingly popular. Several recent reports published on toxins, antibiotics, bacteriocins, non-ribosomal peptides, polyketides, phenylpropanoids, phenylflavonoids, purine nucleosides, short chain fatty acids (SCFAs) enzymes with anticancer properties. Most these molecules target cells a selective manner, directly indirectly through specific pathways. This review discusses role bacteria, including lactic acid their metabolites treatment

Language: Английский

---

In Silico Identification of Potential Clovibactin-like Antibiotics Binding to Unique Cell Wall Precursors in Diverse Gram-Positive Bacterial Strains

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1724 - 1724

Published: Feb. 18, 2025

The rise in multidrug-resistant bacteria highlights the critical need for novel antibiotics. This study explores clovibactin-like compounds as potential therapeutic agents targeting lipid II, a crucial component bacterial cell wall synthesis, using silico techniques. A total of 2624 clovibactin analogs were sourced from PubChem database and screened ProTox 3.0 software based on their ADME-Tox properties, prioritizing candidates with favorable pharmacokinetic profiles minimal toxicity. Molecular docking protocols then employed to assess binding interactions selected II. Our analysis identified Compound 22 particularly promising candidate, exhibiting strong affinity, stable complex formation, high selectivity target. Binding energy analysis, conducted via molecular dynamics simulations, revealed highly negative value -25.50 kcal/mol 22, surpassing that underscoring its efficacy. In addition, was prioritized due exceptional affinity II suggesting lower likelihood adverse effects. These characteristics position candidate further pharmacological development. While our computational results are encouraging, experimental validation is essential confirm efficacy safety these compounds. not only advances understanding but also contributes ongoing efforts combat antimicrobial resistance through innovative antibiotic

Language: Английский

---