The pearl jubilee of microcin J25: thirty years of research on an exceptional lasso peptide.

Covering: 1992 up to 2023Since their discovery, lasso peptides went from peculiarities to be recognized as a major family of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products that were shown to be spread throughout the bacterial kingdom. Microcin J25 was first described in 1992, making it one of the earliest known lasso peptides. No other lasso peptide has since then been studied to such an extent as microcin J25, yet, previous review articles merely skimmed over all the research done on this exceptional lasso peptide.

Use of 2,6-diaminopurine as a potent suppressor of UGA premature stop codons in cystic fibrosis.

Nonsense mutations are responsible for around 10% of cases of genetic diseases, including cystic fibrosis. 2,6-diaminopurine (DAP) has recently been shown to promote efficient readthrough of UGA premature stop codons. In this study, we show that DAP can correct a nonsense mutation in the Cftr gene in vivo in a new CF mouse model, in utero, and through breastfeeding, thanks, notably, to adequate pharmacokinetic properties.

Structure of Lacticaseicin 30 and Its Engineered Variants Revealed an Interplay between the N-Terminal and C-Terminal Regions in the Activity against Gram-Negative Bacteria.

Lacticaseicin 30 is one of the five bacteriocins produced by the Gram-positive CNCM I-5369. This 111 amino acid bacteriocin is noteworthy for being active against Gram-negative bacilli including strains resistant to colistin. Prediction of the lacticaseicin 30 structure using the Alphafold2 pipeline revealed a largely helical structure including five helix segments, which was confirmed by circular dichroism.

Impact of microcin J25 on the porcine microbiome in a continuous culture model.

The increased prevalence of spp. resistance in swine spurs the search for alternatives to antibiotics. Microcin J25 (MccJ25), a bacteriocin produced by , is a potent inhibitor of several pathogenic bacteria including .

Evaluating the Potential and Synergetic Effects of Microcins against Multidrug-Resistant .

The advent of multidrug-resistant bacteria has hampered the development of new antibiotics, exacerbating their morbidity and mortality. In this context, the gastrointestinal tract reveals a valuable source of novel antimicrobials. Microcins are bacteriocins produced by members of the family which are endowed with a wide diversity of structures and mechanisms of action, and exert potent antibacterial activity against closely related bacteria.

Gastrointestinal Stability and Cytotoxicity of Bacteriocins From Gram-Positive and Gram-Negative Bacteria: A Comparative Study.

Bacteriocins are receiving increased attention as potent candidates in food preservation and medicine. Although the inhibitory activity of bacteriocins has been studied widely, little is known about their gastrointestinal stability and toxicity toward normal human cell lines. The aim of this study was to evaluate the gastrointestinal stability and activity of microcin J25, pediocin PA-1, bactofencin A and nisin using models.

Ribosomally synthesized peptides, foreground players in microbial interactions: recent developments and unanswered questions.

It is currently well established that multicellular organisms live in tight association with complex communities of microorganisms including a large number of bacteria. These are immersed in complex interaction networks reflecting the relationships established between them and with host organisms; yet, little is known about the molecules and mechanisms involved in these mutual interactions. Ribosomally synthesized peptides, among which bacterial antimicrobial peptides called bacteriocins and microcins have been identified as contributing to host-microbe interplays, are either unmodified or post-translationally modified peptides.

Molecular mechanism of SbmA, a promiscuous transporter exploited by antimicrobial peptides.

Antibiotic metabolites and antimicrobial peptides mediate competition between bacterial species. Many of them hijack inner and outer membrane proteins to enter cells. Sensitivity of enteric bacteria to multiple peptide antibiotics is controlled by the single inner membrane protein SbmA.

Structural Insights from Tandem Mass Spectrometry, Ion Mobility-Mass Spectrometry, and Infrared/Ultraviolet Spectroscopy on Sphingonodin I: Lasso vs Branched-Cyclic Topoisomers.

Lasso peptides form a class of ribosomally synthesized and post-translationally modified peptides (RiPPs) characterized by a mechanically interlocked topology, where the C-terminal tail of the peptide is threaded and trapped within an N-terminal macrolactam ring. Sphingonodin I is a lasso peptide that has not yet been structurally characterized using the traditional structural biology tools (e.g.

Bacteriocins to Thwart Bacterial Resistance in Gram Negative Bacteria.

An overuse of antibiotics both in human and animal health and as growth promoters in farming practices has increased the prevalence of antibiotic resistance in bacteria. Antibiotic resistant and multi-resistant bacteria are now considered a major and increasing threat by national health agencies, making the need for novel strategies to fight bugs and super bugs a first priority. In particular, Gram-negative bacteria are responsible for a high proportion of nosocomial infections attributable for a large part to , such as pathogenic , , and .

New developments in RiPP discovery, enzymology and engineering.

Covering: up to June 2020Ribosomally-synthesized and post-translationally modified peptides (RiPPs) are a large group of natural products. A community-driven review in 2013 described the emerging commonalities in the biosynthesis of RiPPs and the opportunities they offered for bioengineering and genome mining. Since then, the field has seen tremendous advances in understanding of the mechanisms by which nature assembles these compounds, in engineering their biosynthetic machinery for a wide range of applications, and in the discovery of entirely new RiPP families using bioinformatic tools developed specifically for this compound class.

Bacteriocins as a new generation of antimicrobials: toxicity aspects and regulations.

In recent decades, bacteriocins have received substantial attention as antimicrobial compounds. Although bacteriocins have been predominantly exploited as food preservatives, they are now receiving increased attention as potential clinical antimicrobials and as possible immune-modulating agents. Infections caused by antibiotic-resistant bacteria have been declared as a global threat to public health.

Microcin J25 Exhibits Inhibitory Activity Against Newport in Continuous Fermentation Model Mimicking Swine Colonic Conditions.

Microcin J25 (MccJ25), a 21-amino acid bacteriocin produced by (), is a potent inhibitor of Enterobacteriaceae, including pathogenic , , and . Its lasso structure makes it highly stable and therefore of interest as a possible antimicrobial agent in foods or as an alternative to antibiotics in livestock production. In the present study, we aimed to evaluate the inhibitory activity of MccJ25 against subsp.

Phenomic and genomic approaches to studying the inhibition of multiresistant Salmonella enterica by microcin J25.

In livestock production, antibiotics are used to promote animal growth, control infections and thereby increase profitability. This practice has led to the emergence of multiresistant bacteria such as Salmonella, of which some serovars are disseminated in the environment. The objective of this study is to evaluate microcin J25 as an inhibitor of Salmonella enterica serovars of various origins including human, livestock and food.

2,6-Diaminopurine as a highly potent corrector of UGA nonsense mutations.

Nonsense mutations cause about 10% of genetic disease cases, and no treatments are available. Nonsense mutations can be corrected by molecules with nonsense mutation readthrough activity. An extract of the mushroom Lepista inversa has recently shown high-efficiency correction of UGA and UAA nonsense mutations.

The manifold roles of microbial ribosomal peptide-based natural products in physiology and ecology.

The ribosomally synthesized and posttranslationally modified peptides (RiPPs), also called ribosomal peptide natural products (RPNPs), form a growing superfamily of natural products that are produced by many different organisms and particularly by bacteria. They are derived from precursor polypeptides whose modification by various dedicated enzymes helps to establish a vast array of chemical motifs. RiPPs have attracted much interest as a source of potential therapeutic agents, and in particular as alternatives to conventional antibiotics to address the bacterial resistance crisis.

The extremely halophilic archaeon Halobacterium salinarum ETD5 from the solar saltern of Sfax (Tunisia) produces multiple halocins.

The extremely halophilic archaeon Halobacterium salinarum strain ETD5 was previously isolated from the solar saltern of Sfax (Tunisia) and shown to encode and express halocin S8. The Hbt. salinarum ETD5 culture supernatant was shown here to exhibit high antimicrobial activity against several halophilic archaea and bacteria of different genera, showing a cross-domain inhibition.

Multifaceted ABC transporters associated to microcin and bacteriocin export.

Microcins and bacteriocins are ribosomally-synthesized defence peptides produced by Gram-negative and -positive bacteria to target competitors in their niche. Some of them carry posttranslational modifications established by dedicated enzymes. To protect themselves from their own toxic peptides, bacteria use dedicated immunity proteins or expel the toxin using ATP-binding cassette (ABC) transporters.

Evidence of Cis/Trans-Isomerization at Pro7/Pro16 in the Lasso Peptide Microcin J25.

Microcin J25 is a ribosomal synthesized and post-translationally modified peptide (RiPP) characterized by a mechanically interlocked topology called the lasso fold. This structure provides microcin J25 a potent antimicrobial activity resulting from internalization via the siderophore receptor FhuA and further inhibition of the RNA polymerase. In the present work, nuclear magnetic resonance (NMR) and trapped ion mobility spectrometry-mass spectrometry (TIMS-MS) were used to investigate the lasso structure of microcin J25.

Structural signatures of the class III lasso peptide BI-32169 and the branched-cyclic topoisomers using trapped ion mobility spectrometry-mass spectrometry and tandem mass spectrometry.

Lasso peptides are a class of bioactive ribosomally synthesized and post-translationally modified peptides (RiPPs) characterized by a mechanically interlocked topology, where the C-terminal tail of the peptide is threaded and trapped within an N-terminal macrolactam ring. BI-32169 is a class III lasso peptide containing one disulfide bond that further stabilizes the lasso structure. In contrast to its branched-cyclic analog, BI-32169 has higher stability and is known to exert a potent inhibitory activity against the human glucagon receptor.

Haloarcula sebkhae sp. nov., an extremely halophilic archaeon from Algerian hypersaline environment.

A halophilic organism, SWO25, was isolated from water sampled in Algeria at the salt lake (sebkha) of Ouargla. The novel strain stained Gram-negative, and cells were pleomorphic with a red pigmentation. Strain SWO25 grew optimally at 35-45 °C, at pH 6.

Conformational dynamics of the ABC transporter McjD seen by single-molecule FRET.

ABC transporters utilize ATP for export processes to provide cellular resistance against toxins, antibiotics, and harmful metabolites in eukaryotes and prokaryotes. Based on static structure snapshots, it is believed that they use an alternating access mechanism, which couples conformational changes to ATP binding (outward-open conformation) and hydrolysis (inward-open) for unidirectional transport driven by ATP Here, we analyzed the conformational states and dynamics of the antibacterial peptide exporter McjD from using single-molecule Förster resonance energy transfer (smFRET). For the first time, we established smFRET for an ABC exporter in a native-like lipid environment and directly monitor conformational dynamics in both the transmembrane- (TMD) and nucleotide-binding domains (NBD).

Fate and Biological Activity of the Antimicrobial Lasso Peptide Microcin J25 Under Gastrointestinal Tract Conditions.

The bacteriocin microcin J25 (MccJ25) inhibits the growth of Gram-negative pathogens including and species, and . This 21-amino acid peptide has remarkable stability to heat and extreme pH values and resistance to many proteases, thanks to a characteristic lasso structure. In this study, we used the dynamic simulator TIM-1 as gastro-intestinal tract model to evaluate the stability and antibacterial activity of MccJ25 during passage through the proximal portion of the human gastrointestinal tract.

Synthesis, antimicrobial activity and conformational analysis of the class IIa bacteriocin pediocin PA-1 and analogs thereof.

The antimicrobial peptide pediocin PA-1 is a class IIa bacteriocin that inhibits several clinically relevant pathogens including Listeria spp. Here we report the synthesis and characterization of whole pediocin PA-1 and novel analogs thereof using a combination of solid- and solution-phase strategies to overcome difficulties due to instability and undesired reactions. Pediocin PA-1 thus synthesized was a potent inhibitor of Listeria monocytogenes (MIC = 6.