The vast majority of systemic bacterial infections are caused by facultative, often antibiotic-resistant, pathogens colonizing human body surfaces. Nasal carriage of Staphylococcus aureus predisposes ...to invasive infection, but the mechanisms that permit or interfere with pathogen colonization are largely unknown. Whereas soil microbes are known to compete by production of antibiotics, such processes have rarely been reported for human microbiota. We show that nasal Staphylococcus lugdunensis strains produce lugdunin, a novel thiazolidine-containing cyclic peptide antibiotic that prohibits colonization by S. aureus, and a rare example of a non-ribosomally synthesized bioactive compound from human-associated bacteria. Lugdunin is bactericidal against major pathogens, effective in animal models, and not prone to causing development of resistance in S. aureus. Notably, human nasal colonization by S. lugdunensis was associated with a significantly reduced S. aureus carriage rate, suggesting that lugdunin or lugdunin-producing commensal bacteria could be valuable for preventing staphylococcal infections. Moreover, human microbiota should be considered as a source for new antibiotics.
Lugdunin, a novel thiazolidine cyclopeptide, exhibits micromolar activity against methicillin‐resistant Staphylococcus aureus (MRSA). For structure–activity relationship (SAR) studies, synthetic ...analogues obtained from alanine and stereo scanning as well as peptides with modified thiazolidine rings were tested for antimicrobial activity. The thiazolidine ring and the alternating d‐ and l‐amino acid backbone are essential. Notably, the non‐natural enantiomer displays equal activity, thus indicating the absence of a chiral target. The antibacterial activity strongly correlates with dissipation of the membrane potential in S. aureus. Lugdunin equalizes pH gradients in artificial membrane vesicles, thereby maintaining membrane integrity, which demonstrates that proton translocation is the mode of action (MoA). The incorporation of extra tryptophan or propargyl moieties further expands the diversity of this class of thiazolidine cyclopeptides.
Ornament clasp confers function: Synthetic analogues of lugdunin, the first antibiotic from the human nose, reveal essential motifs for conferring antimicrobial activity against methicillin‐resistant Staphylococcus aureus. In addition to an alternating d‐ and l‐configuration, the thiazolidine heterocycle—featured for the first time in a cyclopeptide—is invaluable for the proton translocation mode of action.
Lugdunin is the first reported nonribosomally synthesized antibiotic from human microbiomes. Its production by the commensal
eliminates the pathogen
from human nasal microbiomes. The ...cycloheptapeptide lugdunin is the founding member of the new class of fibupeptide antibiotics, which have a novel mode of action and represent promising new antimicrobial agents. How
releases and achieves producer self-resistance to lugdunin has remained unknown. We report that two ABC transporters encoded upstream of the lugdunin-biosynthetic operon have distinct yet overlapping roles in lugdunin secretion and self-resistance. While deletion of the
transporter genes abrogated most of the lugdunin secretion, the
transporter genes had a dominant role in resistance. Yet all four genes were required for full-level lugdunin resistance. The small accessory putative membrane protein LugI further contributed to lugdunin release and resistance levels conferred by the ABC transporters. Whereas LugIEFGH also conferred resistance to lugdunin congeners with inverse structures or with amino acid exchange at position 6, they neither affected the susceptibility to a lugdunin variant with an exchange at position 2 nor to other cyclic peptide antimicrobials such as daptomycin or gramicidin S. The obvious selectivity of the resistance mechanism raises hopes that it will not confer cross-resistance to other antimicrobials or to optimized lugdunin derivatives to be used for the prevention and treatment of
infections.
Lugdunin, ein neues Thiazolidin‐Cyclopeptid, weist gegenüber Methicillin‐resistentem Staphylococcus aureus (MRSA) antimikrobielle Wirkung im mikromolaren Bereich auf. Für die Untersuchung von ...Struktur‐Aktivitätsbeziehungen (SAR) wurden synthetische Alanin‐ und Stereo‐Derivate sowie Peptide mit modifiziertem Thiazolidinring auf ihre antimikrobielle Aktivität getestet. Sowohl das Thiazolidin als auch die d‐, l‐alternierende Konfiguration stellen essentielle Strukturmotive dar. Bemerkenswert ist die identische Aktivität des Enantiomers, was eine stereospezifische Wechselwirkung mit einem Zielmolekül ausschließt. Die antibakterielle Wirkung korreliert stark mit dem Einbrechen des Membranpotentials von S. aureus. Lugdunin gleicht pH‐Gradienten in künstlichen Membranvesikeln unter Erhalt der Membranintegrität aus. Der Wirkmechanismus (MoA) beruht somit auf Protonentransport. Der Einbau eines zusätzlichen Tryptophans oder einer Propargylfunktion erweitert die Diversität dieser neuen Substanzklasse der Thiazolidin‐Cyclopeptide.
„Gewandspange” verleiht Wirkung: Synthetische Derivate von Lugdunin, dem ersten Antibiotikum aus der menschlichen Nase, enthüllen die essentiellen Strukturmotive für dessen Aktivität gegen Methicillin‐resistenten Staphylococcus aureus. Zusätzlich zur alternierenden d‐, l‐Konfiguration ist der Thiazolidinring – erstmals für ein Cyclopeptid beschrieben – unabdingbar für die protonentransportierende Wirkung.
•An overview of the fast-developing research field of MOF-derived catalysis is presented.•Design and synthesis of highly active MOF-derived catalysts are introduced.•The relation between the ...structure of MOF-derived catalysts and their reactivity is well reviewed.•MOF-derived catalysis for oxidation, epoxidation, reduction, cross-coupling reactions are presented.
Metal-organic frameworks (MOFs) and MOF-derived materials receive growing attention for fine chemical synthesis due to their versatile tunability and high catalytic activity, further, the MOF-derived materials allow high controllability in the design of catalyst systems for organic reactions. This review provides an overview of this fast-developing research field and presents how catalysts can be designed, and synthesis conditions can be adjusted to obtain highly active MOF-derived catalysts. Although diverse reactions are carried out using MOFs and MOF-derived catalysts such as oxidations and reductions of various functional groups, coupling reactions, acid- and base-catalysis, the understanding of the structure–reactivity relation is a major issue which needs to be addressed for the future development of competent MOF-derived catalysts. Especially in terms of sustainable and energy-efficient processes, catalysts are desired to perform under mild reaction conditions with high selectivity and stability. The chemical composition and the structural properties, such as surface area, porosity, and the dispersion of metal species on the MOF-derived support can be modified according to the desired applications. Thus, MOF-derived materials offer a versatile platform for the synthesis of efficient catalysts in the production of fine chemicals and their intermediates. In this review, an overview of contributions in the progress of the applications of MOF-derived materials in the field of fine chemicals and selected key intermediates, are presented and discussed.
Recently our groups discovered lugdunin, a new cyclic peptide antibiotic that inhibits Staphylococcus aureus epithelial colonization in humans and rodents. In this work, we analyzed its ...immuno-modulatory and antimicrobial potential as a single agent or in combination with other microbiota- or host-derived factors. We show that pretreatment of primary human keratinocytes or mouse skin with lugdunin in combination with microbiota-derived factors results in a significant reduction of S. aureus colonization. Moreover, lugdunin increases expression and release of LL-37 and CXCL8/MIP-2 in human keratinocytes and mouse skin, and results in the recruitment of monocytes and neutrophils in vivo, both by a TLR/MyD88-dependent mechanism. Interestingly, S. aureus elimination by lugdunin is additionally achieved by synergistic antimicrobial activity with LL-37 and dermcidin-derived peptides. In summary, our results indicate that lugdunin provides multi-level protection against S. aureus and may thus become a promising treatment option for S. aureus skin infections in the future.
Hyperpolarization‐activated cation (HCN) channels are believed to be involved in the generation of cardiac pacemaker depolarizations as well as in the control of neuronal excitability and plasticity. ...The contributions of the four individual HCN channel isoforms (HCN1—4) to these diverse functions are not known. Here we show that HCN2‐deficient mice exhibit spontaneous absence seizures. The thalamocortical relay neurons of these mice displayed a near complete loss of the HCN current, resulting in a pronounced hyperpolarizing shift of the resting membrane potential, an altered response to depolarizing inputs and an increased susceptibility for oscillations. HCN2‐null mice also displayed cardiac sinus dysrhythmia, a reduction of the sinoatrial HCN current and a shift of the maximum diastolic potential to hyperpolarized values. Mice with cardiomyocyte‐ specific deletion of HCN2 displayed the same dysrhythmia as mice lacking HCN2 globally, indicating that the dysrhythmia is indeed caused by sinoatrial dysfunction. Our results define the physiological role of the HCN2 subunit as a major determinant of membrane resting potential that is required for regular cardiac and neuronal rhythmicity.
Peripheral nerve reconstruction through the employment of nerve guidance conduits with Trichonephila dragline silk as a luminal filling has emerged as an outstanding preclinical alternative to avoid ...nerve autografts. Yet, it remains unknown whether the outcome is similar for silk fibers harvested from other spider species. This study compares the regenerative potential of dragline silk from two orb‐weaving spiders, Trichonephila inaurata and Nuctenea umbratica, as well as the silk of the jumping spider Phidippus regius. Proliferation, migration, and transcriptomic state of Schwann cells seeded on these silks are investigated. In addition, fiber morphology, primary protein structure, and mechanical properties are studied. The results demonstrate that the increased velocity of Schwann cells on Phidippus regius fibers can be primarily attributed to the interplay between the silk's primary protein structure and its mechanical properties. Furthermore, the capacity of silk fibers to trigger cells toward a gene expression profile of a myelinating Schwann cell phenotype is shown. The findings for the first time allow an in‐depth comparison of the specific cellular response to various native spider silks and a correlation with the fibers’ material properties. This knowledge is essential to open up possibilities for targeted manufacturing of synthetic nervous tissue replacement.
Nerve guidance conduits prefilled with silk of Trichonephila spiders offer a promising alternative to autografts. However, the potential of fibers from other spider species remains unexplored. This study compares regenerative effects of silk from Trichonephila inaurata, Nuctenea umbratica, and Phidippus regius, revealing the influence of silk mechanics on cellular response. This offers novel possibilities for the fabrication of artificial nerve replacements.
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