Summary: A synthetic version of a peptide produced by human-associated bacteria shows promise against antibiotic-resistant pathogens. The molecule, derived from a naturally occurring compound called lugdunin, disrupts bacterial energy processes and is active against MRSA. These results point toward a new class of antibiotics that could treat infections resistant to current drugs.
Source: German Center for Infection Research
Researchers from the Universities of Tübingen and Göttingen together with the German Center for Infection Research have clarified how a novel class of antibiotics, known as fibupeptides, kills multidrug-resistant bacteria. By interfering with the bacterial membrane potential and enabling proton translocation, these compounds shut down the cell’s energy supply and cause bacterial death. The study was published in the journal Angewandte Chemie.
In 2016, a team led by Prof. Andreas Peschel at the University of Tübingen reported the discovery of lugdunin, the first fibupeptide identified. Lugdunin is produced by Staphylococcus lugdunensis, a member of the human nasal microbiome. Its unique thiazolidine cyclopeptide structure makes it a promising prototype for an entirely new family of antibiotics. Importantly, lugdunin has demonstrated activity against methicillin-resistant Staphylococcus aureus (MRSA), a clinically important pathogen responsible for severe and hard-to-treat infections, especially in hospital settings.
The spread of multidrug-resistant bacteria poses a growing threat to public health. A 2018 review estimated hundreds of thousands of infections and thousands of deaths across Europe associated with resistant pathogens, underscoring the urgent need for antibiotics with novel structures and mechanisms. Unlike many recently developed antibiotics that are only modestly different from older drugs and therefore vulnerable to existing resistance mechanisms, lugdunin and related fibupeptides represent a structurally distinct alternative.
The research team synthesized a series of lugdunin analogues to map which molecular features are essential for antimicrobial activity and to reveal the compound’s mechanism of action. Their structure–activity relationship (SAR) work showed that the thiazolidine ring and an alternating d- and l-amino acid backbone are critical for activity. In contrast to many peptide antibiotics that act by binding specific chiral targets, lugdunin’s non-natural enantiomer retained full activity, indicating the absence of a stereospecific biological target.
Functional testing revealed the mechanism: fibupeptides dissipate the bacterial membrane potential by transporting protons (positive hydrogen ions) across the cell membrane. Bacterial cells depend on an electrochemical gradient between the inside and outside of the membrane to power essential processes. By equalizing this gradient, lugdunin and effective synthetic analogues produce an energy collapse that prevents the cell from sustaining life and leads to death. Experiments using artificial membrane vesicles confirmed that lugdunin equalizes pH gradients without destroying membrane integrity, demonstrating proton translocation as the mode of action.
Because the antibiotic effect does not depend on a chiral interaction with a specific protein target, it may be harder for bacteria to evolve resistance through simple target modifications. Indeed, researchers report that resistance to lugdunin could not be induced in the laboratory under tested conditions. This property, together with a new chemical scaffold and a distinct mechanism—proton translocation and membrane-potential dissipation—makes fibupeptides an attractive lead for future antibiotic development.
The team used systematic modification of lugdunin’s structure—replacing amino acids, altering stereochemistry, and modifying the thiazolidine ring—to determine which motifs are required for activity. Their findings identify essential structural features and also show that the molecular class can be diversified, for example by adding tryptophan or propargyl groups, which may aid future optimization for potency, stability, or pharmacological properties.
While these preclinical results are encouraging, extensive further testing is needed before fibupeptides can be considered therapeutic candidates. The researchers plan additional studies to evaluate safety, efficacy, and pharmacokinetics in appropriate preclinical models, and to explore whether lugdunin analogues can be advanced toward clinical development. Ongoing investigations are supported by collaborative networks including the Tübingen excellence cluster “Controlling Microbes to Fight Infections,” launched in 2019.
Source:
German Center for Infection Research
Media Contacts:
Nadine Schilling – German Center for Infection Research
Image Source:
University of Tübingen / Sebastian N. Wirtz.
Original Research: Closed access
“Synthetic Lugdunin Analogues Reveal Essential Structural Motifs for Antimicrobial Action and Proton Translocation Capability.” Nadine Schilling et al., Angewandte Chemie. DOI: 10.1002/anie.201901589
Abstract
Synthetic Lugdunin Analogues Reveal Essential Structural Motifs for Antimicrobial Action and Proton Translocation Capability
Lugdunin, a thiazolidine cyclopeptide, shows micromolar activity against methicillin-resistant Staphylococcus aureus (MRSA). Synthetic analogues produced by alanine and stereo scanning and peptides with modified thiazolidine rings were tested for antimicrobial activity. The thiazolidine ring and alternating d- and l-amino acid backbone are essential. The non-natural enantiomer displays equal activity, indicating the absence of a chiral target. Antibacterial activity correlates strongly with dissipation of the membrane potential in S. aureus. Lugdunin equalizes pH gradients in artificial membrane vesicles while preserving membrane integrity, demonstrating that proton translocation is its mode of action. Introducing additional tryptophan or propargyl moieties expands the chemical diversity of thiazolidine cyclopeptides.