German Center for Lung Research (DZL)’s Post

Antibiotics have added a staggering 23 years to the average human lifespan. But bacteria are becoming increasingly resistant to antibiotics, creating a critical global health problem. In this context, this recent paper provides welcome news. Scientists at Uppsala University have discovered a new class of antibiotics that targets the LpxH enzyme involved in lipopolysaccharide synthesis in Gram-negative bacteria. Through in vitro and in vivo tests, they have shown that compounds from this class, called EBL-3599 and EBL-3647, are effective against multidrug-resistant E. coli, K. pneumoniae and P. aeruginosa, all of which have been designated as critical priority pathogens by the WHO. The researchers showed that the antibiotics reduced bacterial loads in a mouse model of bloodstream infection with a single dose, confirming LpxH as an antibiotic target. There is still a lot of work to be done (here I recall the statement by a former colleague of mine: "The fact that it works in mice doesn't tell that much"). But this is certainly a promising new development in a critical area.  #microbiology #antibiotics #globalhealth

🚨 Understanding Phage Resistance in Multi-Drug Resistant Enterococci 🚨 While certain phages can lyse some strains of multi-drug resistant (MDR) enterococci, other strains exhibit high levels of resistance, with the underlying mechanisms remaining poorly understood. 🔬 CRISPRi Screen Unveils Genetic Locus Linked to Phage Resistance 🔬 Researchers used a CRISPR interference (CRISPRi) screen to pinpoint a genetic locus on a mobilizable plasmid from Enterococcus faecalis associated with phage resistance. This locus encodes a putative serine recombinase followed by a Type IV restriction enzyme (TIV-RE), which was shown to restrict the replication of phage phi47 in vancomycin-resistant E. faecalis. Key discoveries include: - The identification of a genetic locus that contributes to phage resistance in MDR enterococci. - The role of TIV-RE in restricting phage replication, with phi47 evolving to overcome this defense by acquiring a missense mutation in a TIV-RE inhibitor protein. - The discovery that this inhibitor, named Type IV Restriction Inhibiting Factor A (tifA), binds to and inactivates diverse TIV-REs. 🔍 Implications for Phage Therapy and Resistance Mechanisms 🔍 These findings significantly advance the understanding of phage defense mechanisms in drug-resistant E. faecalis and provide valuable insight into how phages can evolve to overcome antiphage defense systems. This research could inform future strategies for phage therapy and combatting antibiotic resistance. #PhageTherapy #AntibioticResistance #Microbiology #CRISPRI #EnterococcusFaecalis #InfectiousDiseases #Biotechnology #PhageResearch https://lnkd.in/efwWWGR4

#infectioncontrol https://lnkd.in/gTHUYpDi Researchers designed a #synthetic #drug that shuts down protein production in a range of different bacteria. The #new #antibiotic proved effective against drug-resistant bacterial strains in mice, but hasn’t yet been tested in people. Many antibiotics work by binding to and shutting down #bacterial #ribosomes. Over the last several decades, bacteria have evolved various mechanisms to prevent their ribosomes from being blocked by antibiotics. Often, genetic variants lead to changes in the chemical makeup of the ribosomes that prevent the antibiotics from binding. A research team led by Dr. Andrew Myers from Harvard University, working with Dr. Yury Polikanov from the University of Illinois at Chicago, has been studying ways to tweak antibiotics to beat resistance. In a new study, funded in part by NIH, they examined an older class of antibiotic called lincosamides. Their results were published on February 16, 2024, in Science. Lincosamide antibiotics are based on molecules found in nature, so are called semi-synthetic drugs. Using knowledge of the molecular structure of these antibiotics and how they bind to bacterial ribosomes, the team developed a fully synthetic compound called cresomycin. They chose its building blocks so that it would form the exact shape needed to latch tightly onto ribosomes. The team found that cresomycin worked in both gram-positive and gram-negative bacteria. The latter are especially hard to treat with existing antibiotics. It also worked in strains resistant to other lincosamide antibiotics.

𝗡𝗲𝘄 𝗮𝗽𝗽𝗿𝗼𝗮𝗰𝗵 𝗳𝗼𝗿 #𝗮𝗻𝘁𝗶𝗯𝗶𝗼𝘁𝗶𝗰 𝗱𝗲𝘃𝗲𝗹𝗼𝗽𝗺𝗲𝗻𝘁: The opportunistic bacterial pathogen Pseudomonas aeruginosa is dangerous due to its resistance to multiple antibiotics. A research team from Heinrich Heine University Düsseldorf (HHU) and Jülich Research Center (Forschungszentrum Jülich – FZJ) has now found a mechanism that makes it possible to weaken the virulence of the pathogen. Based on this knowledge, a new approach for antibiotics can be developed, as the authors explain in the scientific journal JACS Au. The editors of the journal have dedicated a cover story to this discovery. The bacterium Pseudomonas aeruginosa often causes a so-called “nosocomial infection” in humans. It is therefore one of the dangerous hospital bacteria that is resistant to several antibiotics. Immunocompromised patients are particularly affected. The World Health Organisation (WHO) has placed P. aeruginosa on the list of “priority pathogens” on which research efforts should focus to find new treatment options. 𝗥𝗲𝘀𝗲𝗮𝗿𝗰𝗵𝗲𝗿𝘀 𝗳𝗶𝗻𝗱 𝗺𝗲𝗰𝗵𝗮𝗻𝗶𝘀𝗺 𝗮𝗴𝗮𝗶𝗻𝘀𝘁 𝗱𝗿𝗲𝗮𝗱𝗲𝗱 𝗵𝗼𝘀𝗽𝗶𝘁𝗮𝗹 𝗴𝗲𝗿𝗺: https://lnkd.in/ev57D-6r Heinrich-Heine-Universität Düsseldorf, Research Center Jülich - Institute 3 for Neuroscience and Medicine, Holger Gohlke, Karl-Erich Jaeger, Rocco Gentile, Matea Modric, Björn Thiele, Filip Kovacic, Stephan Schott Verdugo, Regine Panknin, Arne Claussen

Célio Dias Santos-Júnior et al. Discovery of antimicrobial peptides in the global microbiome with machine learning Open Access Published:June 05,2024 DOI:https://lnkd.in/dT8ZKJ37 "Higlights • Machine learning predicts nearly 1 million new antibiotics in the global microbiome • Out of 100 tested peptides, 79 were active in vitro; 63 of these targeted pathogens • Some peptides may originate from longer sequences through genomic fragmentation • The AMPSphere is an open-access resource to accelerate antibiotic discovery Summary Novel antibiotics are urgently needed to combat the antibiotic-resistance crisis. We present a machine-learning-based approach to predict antimicrobial peptides (AMPs) within the global microbiome and leverage a vast dataset of 63,410 metagenomes and 87,920 prokaryotic genomes from environmental and host-associated habitats to create the AMPSphere, a comprehensive catalog comprising 863,498 non-redundant peptides, few of which match existing databases. AMPSphere provides insights into the evolutionary origins of peptides, including by duplication or gene truncation of longer sequences, and we observed that AMP production varies by habitat. To validate our predictions, we synthesized and tested 100 AMPs against clinically relevant drug-resistant pathogens and human gut commensals both in vitro and in vivo. A total of 79 peptides were active, with 63 targeting pathogens. These active AMPs exhibited antibacterial activity by disrupting bacterial membranes. In conclusion, our approach identified nearly one million prokaryotic AMP sequences, an open-access resource for antibiotic discovery.

🌍🦠 Genomic Insights into Staphylococcus aureus and Atopic Dermatitis 🧬✨ Atopic dermatitis (AD) is the most common chronic inflammatory skin disease globally, and the interplay between AD and the skin microbiota plays a crucial role in its progression. Notably, Staphylococcus aureus is more prevalent in AD patients than in healthy individuals (HE), but the strain-specific differences remain unclear. Our latest research unveils key genomic and functional distinctions between S. aureus strains from AD and HE on both global and local scales: - Global Findings: AD-associated strains have reduced gene content diversity but increased functional variation. We identified two AD-dominant clusters:    - Cluster 1: Enriched with transposases.   - Cluster 2: Containing genes linked to adaptability and antibiotic resistance. - The lantibiotic operon, crucial for biosynthesizing lantibiotics, was acquired through horizontal gene transfer from environmental bacteria. - Local Analysis: Mirrored global trends but highlighted unique functional variations, with local strains exhibiting a strong focus on metal-related genes. This study provides foundational insights into how S. aureus adapts within the AD microenvironment, with implications for understanding antibiotic resistance and guiding future clinical microbiology practices. Another great paper together with Michael Schloter . This great collaboration connects Helmholtz Munich Universität Augsburg and Universitätsklinikum Augsburg. Read more details here https://lnkd.in/d29Jfgdn #AtopicDermatitis #StaphylococcusAureus #Microbiome #Genomics #AntibioticResistance #ClinicalMicrobiology #Research

𝗦𝗲𝗮𝗿𝗰𝗵𝗶𝗻𝗴 𝗳𝗼𝗿 𝘁𝗵𝗲 𝗺𝗶𝗰𝗿𝗼𝗯𝗶𝗮𝗹 𝘁𝗿𝗲𝗮𝘀𝘂𝗿𝗲: Most antibiotics used in human medicine originate from natural products derived from bacteria and other microbes. Novel microorganisms are therefore a promising source of new active compounds - also for the treatment of diseases such as cancer or viral infections. A team from the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) has now been able to isolate a completely new family of bacteria that has particularly high potential for the production of active substances. 𝗡𝗲𝘄 𝗳𝗮𝗺𝗶𝗹𝘆 𝗼𝗳 𝗯𝗮𝗰𝘁𝗲𝗿𝗶𝗮 𝘄𝗶𝘁𝗵 𝗵𝗶𝗴𝗵 𝗽𝗵𝗮𝗿𝗺𝗮𝗰𝗲𝘂𝘁𝗶𝗰𝗮𝗹 𝗽𝗼𝘁𝗲𝗻𝘁𝗶𝗮𝗹 𝗱𝗶𝘀𝗰𝗼𝘃𝗲𝗿𝗲𝗱: https://lnkd.in/dJ-hrDa3 Chantal Bader, Johanna Löhr, Judith Boldt, Boyke B., F.P. Jake Haeckl, Thomas Pietschmann, Helmholtz-Zentrum für Infektionsforschung, Universität des Saarlandes, Susanne Thiele, Charlotte Schwenner (geb. Wermser)

📃Scientific paper: Repurposing carvacrol, cinnamaldehyde, and eugenol as potential anti-quorum sensing agents against uropathogenic Escherichia coli isolates in Alexandria, Egypt Abstract: Background Urinary tract infections represent one of the most frequent hospital and community-acquired infections with uropathogenic Escherichia coli (UPEC) being the main causative agent. The global increase in the emergence of multidrug-resistant (MDR) UPEC necessitates exploring novel approaches. Repurposing natural products as anti-quorum sensing (QS) agents to impede bacterial virulence is gaining momentum nowadays. Hence, this study investigates the anti-QS potentials of carvacrol, cinnamaldehyde, and eugenol against E. coli isolated from urine cultures of Egyptian patients. Results Antibiotic susceptibility testing was performed for 67 E. coli isolates and 94% of the isolates showed MDR phenotype. The usp gene was detected using PCR and accordingly, 45% of the isolates were categorized as UPEC. Phytochemicals, at their sub-inhibitory concentrations, inhibited the swimming and twitching motilities of UPEC isolates, with eugenol showing the highest inhibitory effect. The agents hindered the biofilm-forming ability of the tested isolates, at two temperature sets, 37 and 30 °C, where eugenol succeeded in significantly inhibiting the biofilm formation by > 50% at both investigated temperatures, as compared with untreated controls. The phytochemicals were shown to downregulate the expression of the QS gene ( luxS ) and critical genes related to motility, asserting their anti-QS potential. Further, the combinatory activity of the phytoproducts with five antibiotics... Continued on ES/IODE ➡️ https://etcse.fr/s5b ------- If you find this interesting, feel free to follow, comment and share. We need your help to enhance our visibility, so that our platform continues to serve you.

The battle against Staphylococcus aureus using natural compounds from Ganoderma mushrooms Background: Staphylococcus aureus is a nosocomial pathogen responsible for many serious infectious diseases in humans. Finding the anti- S. aureus agents is a time-consuming and costly process. Recently, computational methods have provided a better understanding of the interactions between herbal medicine drug targets to help clinical practitioners rationally design herbal formulae. Methods: In this study, molecular docking simulation was applied to screen a list of natural secondary metabolites from Ganoderma sp. on the protein target S. aureus sortase A. Molecular dynamics models were used to assess the stability of protein–ligand complexes during the first 100 ns. To validate the computational results, 2 Ganoderma species, G. multiplicatum VNKKK1901 and G. sinense VNKKK1902, were tested for antibacterial activity against S. aureus using the disk diffusion method. Results: The results showed that, among the selected compounds, ganosinensin B and ganosinoside A generated the highest binding energy on S. aureus sortase A, and demonstrated strong and stable binding capacity to proteins. In addition, the extracts of G. sinense VNKKK1902 and G. multiplicatum VNKKK1901 were bactericidal, with minimum bactericidal concentration (MBC)/minimum inhibitory concentration (MIC) ratios of 2. Conclusion: Our findings provide the first scientific report on the antibacterial activity of Ganoderma sp., which contain 2 promising compounds, ganosinensin B and ganosinoside A, as potential hits for developing novel drugs capable of supporting treatment of S. aureus infection. https://lnkd.in/eK5Q5msn

Discovering new sources of antibiotics Antimicrobial resistance is a major public health issue that contributes to the emergence of drug-resistant microorganisms, thereby increasing the risk of nosocomial infections. Short peptide molecules, which have been proposed as novel antibacterial medications, consist of short-length amino acid residues, vast sequence space, and non-specific modes of action. To date, few reported cases of resistance against antimicrobial peptides (AMPs) have been published, which has led researchers to become increasingly interested in their potential clinical applications. Several AMPs, the most common of which include bacitracin, colistin, and polymyxin B, have already been successfully approved for clinical use. Despite the advantages and success of AMPs, the identification of novel AMP candidates remains a challenge due to the time-consuming processes involved in these experiments. Furthermore, although recent advances in machine learning, genetic algorithms, and pattern recognition algorithms have led to the development of novel peptides, few of these approaches have involved mining proteomes and metagenomes. The human microbiome consists of many bacteria species capable of suppressing the growth of pathogens. In fact, recent studies have reported that the human microbiome encodes hundreds of thousands of multiple small-size open reading frames (smORF), few of which have been characterized. Thus, there is tremendous potential to harness the human microbiome to identify unexplored peptide sequences with antimicrobial activity. About the study Using computational techniques, the researchers assessed the antibacterial capabilities of 444,054 peptides from 1,773 human metagenomes listed in the Human Microbiome Project (HMP). To refine the list, 78 peptides were identified and assessed for their antibiotic activity against several high-priority pathogenic and gut commensal bacteria in vitro, following which five peptides were selected for in vivo evaluation. The smORFinder was used to identify genes that encode proteins with high confidence. Antimicrobial peptides were selected based on high AmPEP scores, representation of the peptide's family of origin, effective amino acid composition for chemical synthesis, and absence of hydrophobic clusters. The Database of Antimicrobial Activity and Structure of Peptides (DBAASP) was utilized to examine the physicochemical properties of smORF-encoded peptides (SEPs), including their mechanisms of action, secondary structures, and cytotoxicity.