Rolf Müller

Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)/Helmholtz Centre for Infection Research (HZI) · Department of Microbial Natural Products (MINS)

Coronatine (COR) represents a phytotoxin produced by several pathovars of Pseudomonas syringae. It mediates multiple virulence activities by mimicking the plant stress hormone jasmonoyl-l-isoleucine. Structurally, COR consists of a bicyclic polyketide moiety, coronafacic acid (CFA), which is linked via an amide bond to an unusual ethylcyclopropyl a...

The development of antiviral drugs against the Severe Acute Respiratory Syndrome coronavirus 2 (SARS‐CoV‐2) responsible for the recent Covid‐19 pandemic is crucial, as treatment options remain limited and vaccination does not prevent (re)infection. Two relatively underexplored targets of this virus are the 3′‐5′ exoribonuclease (ExoN) and the 2’‐O‐...

The transmission of antibiotic-resistance genes, comprising mobilization and relocation events, orchestrates the dissemination of antimicrobial resistance. Inspired by this evolutionarily successful paradigm, we developed ACTIMOT, a CRISPR-Cas9–based approach to unlock the vast chemical diversity concealed within bacterial genomes. ACTIMOT enables...

Research into new antibiotics is becoming increasingly important as antibiotic resistance increases worldwide. The genus Streptomyces in particular is able to produce a wide range of antimicrobial products due to the large number of biosynthetic gene clusters (BGCs) in its genome. However, not all BGCs are expressed under laboratory conditions. In...

Myxoquaterines represent a recently discovered class of natural products with intriguing biological properties. They were isolated from Pendulasporacea albinea MSr 11954 and display a unique structure combining heterocyclic (pyrrole, oxazoline), hexaene, and 2‐amino‐1,3‐diol subunits. We have now synthesized the first example of a myxoquaterine nat...

Sphingoid bases are important bioactive lipids found in a variety of organisms, serving as the backbone of sphingolipids, which regulate essential physiological processes. Here we describe the total synthesis and structure revision of halisphingosine A, a sphingoid base initially isolated from marine sponges. To address inconsistencies in the NMR i...

Plasmids are extrachromosomal DNA molecules in bacteria and archaea, playing critical roles in horizontal gene transfer, antibiotic resistance, and pathogenicity. Since its first release in 2018, our database on plasmids, PLSDB, has significantly grown and enhanced its content and scope. From 34 513 records contained in the 2021 version, PLSDB now...

Background High levels of the polyunsaturated fatty acid arachidonic acid (AA) within the ovarian carcinoma (OC) microenvironment correlate with reduced relapse-free survival. Furthermore, OC progression is tied to compromised immunosurveillance, partially attributed to the impairment of natural killer (NK) cells. However, potential connections bet...

Submission Trajectory for the research article "Thermo-amplifier circuit in probiotic E. coli for stringently temperature-controlled release of a novel antibiotic"

Peptide drugs have seen rapid advancement in biopharmaceutical development, with over 80 candidates approved globally. Despite their therapeutic potential, the clinical translation of peptide drugs is hampered by challenges in production yields and stability. Engineered bacterial therapeutics is a unique approach being explored to overcome these is...

Myxoquaterines represent a recently discovered class of natural products with intriguing biological properties. They were isolated from Pendulasporacea albinea MSr 11954 and display a unique structure combining heterocyclic (pyrrole, oxazoline), hexa­ene, and 2‐amino‐1,3‐diol subunits. We have now synthesized the first example of a myxoquaterine na...

Novel scaffolds for broad-spectrum antibiotics are rare and in strong demand because of the increase in antimicrobial resistance. The cystobactamids, discovered from myxobacterial sources, have a unique hexapeptidic scaffold with five arylamides and possess potent, resistance-breaking properties. This study investigates the role of the central D-ri...

Aging is a multifactorial and complex physiological process, affecting every organ with characteristic manifestations. Understanding the molecular mechanisms that drive aging processes is crucial to targeting age-related disorders. Recent reports suggest that severe post-infection syndromes can partially accelerate aging. However, the underlying ge...

Natural products have proven themselves as a valuable resource for antibiotics. However, in view of increasing antimicrobial resistance, there is an urgent need for new, structurally diverse agents that have the potential to overcome resistance and treat Gram‐negative pathogens in particular. Historically, the search for new antibiotics was strongl...

Sphingoid bases are important bioactive lipids found in a variety of organisms, serving as the backbone of sphingolipids, which regulate essential physiological processes. Here we describe the total synthesis and structure revision of halisphingosine A, a sphingoid base initially isolated from marine sponges. To address inconsistencies in the NMR i...

Fluoroquinolones (FQs) are an important class of potent broad-spectrum antibiotics. However, their general use is more and more limited by adverse side effects. While general mechanisms for the fluoroquinolone-associated disability (FQAD) have been identified, the underlying molecular targets of toxicity remain elusive. In this study, focusing on t...

Fluoroquinolones (FQs) are an important class of potent broad-spectrum antibiotics. However, their general use is more and more limited by adverse side effects. While general mechanisms for the fluoroquinolone-associated disability (FQAD) have been identified, the underlying molecular targets of toxicity remain elusive. In this study, focusing on t...

Antimicrobial resistance (AMR) is escalating globally at an alarming rate, posing a severe threat to public health and modern medicine. A substantial strategy to combat AMR and ensure safe and efficient antimicrobial therapies in the future is the development of antimicrobial agents based on novel scaffolds exerting an innovative mode of action. Th...

The human microbiome emerges as a promising reservoir for diagnostic markers and therapeutics. Since host-associated microbiomes at various body sites differ and diseases do not occur in isolation, a comprehensive analysis strategy highlighting the full potential of microbiomes should include diverse specimen types and various diseases. To ensure r...

Understanding human, animal, and environmental microbiota is essential for advancing global health and combating antimicrobial resistance (AMR). We investigate the oral and gut microbiota of 48 animal species in captivity, comparing them to those of wildlife animals. Specifically, we characterize the microbiota composition, metabolic pathways, AMR...

The ubiquitous opportunistic pathogen Pseudomonas aeruginosa is responsible for severe infections and notoriously known for acquiring antimicrobial resistance. Inhibiting the bacterium’s extracellular elastase, LasB – a zinc-dependent protease – presents a promising strategy to mitigate its virulence. Within this medicinal chemistry–driven hit-to-l...

Cystobactamids have a unique oligoarylamide structure and exhibit broad-spectrum activity against Gram-negative and Gram-positive bacteria. In this study, the central α-amino acid of the cystobactamid scaffold was modified to address the relevance of stereochemistry, hydrogen bonding and polarity by 33 derivatives. As demonstrated by three matched...

Novel scaffolds for broad-spectrum antibiotics are rare and in strong demand because of the increase in antimicrobial resistance. The cystobactamids, discovered from myxobacterial sources, have a unique hexapeptidic scaffold with five arylamides and possess potent, resistance-breaking properties. This study investigates the role of the central D-ri...

Innovative discovery approaches such as genome-mining and metabolomics-inspired methods have reshaped the natural product research field, complementing traditional bioactivity-based screens and allowing hitherto unseen compounds to be uncovered from previously investigated producers. In line with these trends, we report here imidacins, a novel clas...

Background Tumor cells release extracellular vesicles (EVs) that contribute to the polarization of macrophages towards tumor-associated macrophages (TAMs). High expression levels of the RNA binding protein IGF2BP2/IMP2 are correlated with increased tumor cell proliferation, invasion, and poor prognosis in the clinic. However, there is a lack of und...

Virus inactivation is a prerequisite for safe handling of high-risk infectious samples. β-Propiolactone (BPL) is an established reagent with proven virucidal efficacy. BPL primarily reacts with DNA, RNA, and amino acids. The latter may modify antigenic protein epitopes interfering with binding properties of affinity reagents such as antibodies and...

The Klebsiella oxytoca species complex is part of the human microbiome, especially during infancy and childhood. K. oxytoca species complex strains can produce enterotoxins, namely, tilimycin and tilivalline, while also contributing to colonization resistance (CR). The relationship between these seemingly contradictory roles is not well understood....

Lysophosphatidic acid (LPA) species, prevalent in the tumor microenvironment (TME), adversely impact various cancers. In ovarian cancer, the 18:0 and 20:4 LPA species are selectively associated with shorter relapse-free survival, indicating distinct effects on cellular signaling networks. Macrophages represent a cell type of high relevance in the T...

Quantifying microbiome species and composition from metagenomic assays is often challenging due to its time-consuming nature and computational complexity. In Bioinformatics, k-mer-based approaches were long established to expedite the analysis of large sequencing data and are now widely used to annotate metagenomic data. We make use of k-mer counti...

The natural product chlorotonil displays high potency against multidrug‐resistant Gram‐positive bacteria and Plasmodium falciparum. Yet, its scaffold is characterized by low solubility and oral bioavailability, but progress was recently made to enhance these properties. Applying late‐stage functionalization, we aimed to further optimize the molecul...

Background Different production systems of livestock animals influence various factors, including the gut microbiota. Methods We investigated whether changing the conditions from barns to free-range chicken farming impacts the microbiome over the course of three weeks. We compared the stool microbiota of chicken from industrial barns after introdu...

The rapid development of antibiotic resistance, especially among difficult-to-treat Gram-negative bacteria, is recognized as a serious and urgent threat to public health. The detection and characterization of novel resistance mechanisms are essential to better predict the spread and evolution of antibiotic resistance. Corramycin is a novel and modi...

The natural product chlorotonil displays high potency against multidrug‐resistant Gram‐positive bacteria and Plasmodium falciparum. Yet, its scaffold is characterized by low solubility and oral bioavailability but progress was recently made to enhance these properties. Applying late‐stage functionalization, we aimed to further optimize the molecule...

Engineered bacterial therapeutics is a rapidly emerging field in which bacteria are genetically engineered to produce and deliver therapeutic compounds at the body site of use. They offer the advantages of being able to produce biopharmaceutical drugs on the spot and control drug release time and dosage through genetic switches to treat a variety o...

The authors would like to make the following corrections to the original publication [...]

Designing novel candidates as potential antibacterial scaffolds has become crucial due to the lack of new antibiotics entering the market and the persistent rise in multidrug resistance. Here, we describe a new class of potent antibacterial agents based on a 5-aryl-N 2 ,N 4-dibutylpyrimidine-2,4-diamine scaffold. Structural optimization focused on...

In the past century, microbial natural products have proven themselves to be substantial and fruitful sources of anti-infectives. In addition to the well-studied Actinobacteria, understudied bacterial taxa like the Gram-negative myxobacteria have increasingly gained attention in the ongoing search for novel and biologically active natural products....

Cystobacamids are aromatic oligoamides that exert their natural antibacterial properties by inhibition of bacterial gyrases. Such aromatic oligoamides were proposed to inhibit a‐helix‐mediated protein‐protein interactions and may serve for specific recognition of DNA. Based on this suggestion, we designed new derivatives that have duplicated cystob...

Chronic lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis are incurable. Epithelial senescence, a state of dysfunctional cell cycle arrest, contributes to the progression of such diseases. Therefore, lung epithelial cells are a valuable target for therapeutic intervention. Here, we present a 3D airway lung organoid pla...

Antimicrobial resistance is one of the major health threats of the modern world. Thus, new structural classes of antimicrobial compounds are needed in order to overcome existing resistance. Cystobactamids as such a new compound class inhibit the well-established target bacterial type II topoisomerases while exhibiting superior antibacterial and res...

Nitroxoline (NTX) is an antibiotic approved for the treatment of uncomplicated urinary tract infections (UTIs) caused by Enterobacteriaceae like Escherichia coli , and it has been on the market for more than 50 years. Despite being in use longer than several other clinically relevant antibiotics, the resistance of clinical isolates against NTX has...

The quest for novel anti-infectives against drug-resistant pathogens of the so-called ESKAPE panel is accompanied by intensive research aiming to find treatment options for the future. In this study, we evaluated the pharmacokinetics and pharmacodynamics of the two atypical tetracyclines: chelocardin (CHD) and amidochelocardin (CDCHD). Although CHD...

The human microbiome has emerged as a rich source of diverse and bioactive natural products, harboring immense potential for therapeutic applications. To facilitate systematic exploration and analysis of its biosynthetic landscape, we present ABC-HuMi: the Atlas of Biosynthetic Gene Clusters (BGCs) in the Human Microbiome. ABC-HuMi integrates data...

Biosynthetic engineering of bicyclic darobactins, selectively sealing the lateral gate of the outer membrane protein BamA, leads to active analogues, which are up to 128-fold more potent against Gram-negative pathogens compared to native counterparts. Because of their excellent antibacterial activity, darobactins represent one of the most promising...

The 3rd international conference of the Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.

Background Pamamycins are a family of highly bioactive macrodiolide polyketides produced by Streptomyces alboniger as a complex mixture of derivatives with molecular weights ranging from 579 to 705 Daltons. The large derivatives are produced as a minor fraction, which has prevented their isolation and thus studies of chemical and biological propert...

A crucial requirement for metastasis formation in ovarian high-grade serous carcinoma (HGSC) is the disruption of the protective peritoneal mesothelium. Using co-culture systems of primary human cells, we discovered that tumor-associated NK cells induce TRAIL-dependent apoptosis in mesothelial cells via death receptors DR4 and DR5 upon encounter wi...

Infections caused by the Gram-negative pathogen Pseudomonas aeruginosa are emerging worldwide as a major threat to human health. Conventional antibiotic monotherapy suffers from rapid resistance development, underlining urgent need for novel treatment concepts. Here, we report on a nontraditional approach to combat P. aeruginosa-derived infections...

The resolution of 3D electron diffraction (ED) data of small-molecule crystals is often relatively poor, due to either electron-beam radiation damage during data collection or poor crystallinity of the material. Direct methods, used as standard for crystal structure determination, are not applicable when the data resolution falls below the commonly...

Listeria monocytogenes is a foodborne bacterium that naturally occurs in the soil. Originating from there, it contaminates crops and infects farm animals and their consumption by humans may lead to listeriosis, a systemic life‐threatening infectious disease. The adaptation of L. monocytogenes to such contrastive habitats is reflected by the presenc...

The discovery pipeline for novel antibiotics runs dry, while antimicrobial resistances increase, causing 1.3 million deaths per year globally. Even in the European Economic Area with generally intact health care, more than 35,000 people die per year with numbers expected to rise. Especially certain pathogenic Gram-negative bacteria are to blame. Op...

The human microbiome has emerged as a rich source of diverse and bioactive natural products, harboring immense potential for therapeutic applications. To facilitate systematic exploration and analysis of its biosynthetic landscape, we present ABC-HuMi: the Atlas of Biosynthetic Gene Clusters (BGCs) in the Human Microbiome. ABC-HuMi integrates data...

Developments in computational omics technologies have provided new means to access the hidden diversity of natural products, unearthing new potential for drug discovery. In parallel, artificial intelligence approaches such as machine learning have led to exciting developments in the computational drug design field, facilitating biological activity...

Biosynthetic engineering of bi–cyclic darobactins, which selectively seal the lateral gate of the outer membrane pro-tein BamA, lead to highly active analogues which are up to 128–fold more potent against critical and clinically relevant Gram–negative pathogens compared to their native counterparts. Because of their excellent antibacterial activity...

Even with the aid of the available methods, the configurational assignment of natural products can be a challenging task that is prone to errors, and it sometimes needs to be corrected after total synthesis or single‐crystal X‐ray diffraction (XRD) analysis. Herein, the absolute configuration of amidochelocardin is revised using a combination of XR...

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded 'mycobacterial mutasome' - minimally comprising DnaE2 polymerase and ImuA' and ImuB accessory proteins - rema...

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded ‘mycobacterial mutasome’ – minimally comprising DnaE2 polymerase and ImuA′ and ImuB accessory proteins – rema...

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded ‘mycobacterial mutasome’ – minimally comprising DnaE2 polymerase and ImuA′ and ImuB accessory proteins – rema...

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded ‘mycobacterial mutasome’ – minimally comprising DnaE2 polymerase and ImuA′ and ImuB accessory proteins – rema...