Publications by authors named "Jennifer Herrmann"

93 Publications

Zebrafish: An Attractive Model to Study Infection and Its Use as a Drug Discovery Tool.

Pharmaceuticals (Basel) 2021 Jun 21;14(6). Epub 2021 Jun 21.

Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research, Saarland University Campus, 66123 Saarbrücken, Germany.

Non-mammalian in vivo disease models are particularly popular in early drug discovery. Zebrafish ( is an attractive vertebrate model, the success of which is driven by several advantages, such as the optical transparency of larvae, the small and completely sequenced genome, the small size of embryos and larvae enabling high-throughput screening, and low costs. In this review, we highlight zebrafish models of infection, which are used in drug discovery and for studying disease pathogenesis and virulence. Further, these infection models are discussed in the context of other relevant zebrafish models for pharmacological and toxicological studies as part of early drug profiling. In addition, we examine key differences to commonly applied models of infection based on invertebrate organisms, and we compare their frequency of use in academic research covering the period of January 2011 to January 2021.
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http://dx.doi.org/10.3390/ph14060594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235121PMC
June 2021

The antibiotic sorangicin A inhibits promoter DNA unwinding in a rifampicin-resistant RNA polymerase.

Proc Natl Acad Sci U S A 2020 12 16;117(48):30423-30432. Epub 2020 Nov 16.

Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY 10065;

Rifampicin (Rif) is a first-line therapeutic used to treat the infectious disease tuberculosis (TB), which is caused by the pathogen (). The emergence of Rif-resistant (Rif) presents a need for new antibiotics. Rif targets the enzyme RNA polymerase (RNAP). Sorangicin A (Sor) is an unrelated inhibitor that binds in the Rif-binding pocket of RNAP. Sor inhibits a subset of Rif RNAPs, including the most prevalent clinical Rif RNAP substitution found in infected patients (S456>L of the β subunit). Here, we present structural and biochemical data demonstrating that Sor inhibits the wild-type RNAP by a similar mechanism as Rif: by preventing the translocation of very short RNAs. By contrast, Sor inhibits the Rif S456L enzyme at an earlier step, preventing the transition of a partially unwound promoter DNA intermediate to the fully opened DNA and blocking the template-strand DNA from reaching the active site in the RNAP catalytic center. By defining template-strand blocking as a mechanism for inhibition, we provide a mechanistic drug target in RNAP. Our finding that Sor inhibits the wild-type and mutant RNAPs through different mechanisms prompts future considerations for designing antibiotics against resistant targets. Also, we show that Sor has a better pharmacokinetic profile than Rif, making it a suitable starting molecule to design drugs to be used for the treatment of TB patients with comorbidities who require multiple medications.
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http://dx.doi.org/10.1073/pnas.2013706117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720108PMC
December 2020

Metabolic Profiling to Determine Bactericidal or Bacteriostatic Effects of New Natural Products using Isothermal Microcalorimetry.

J Vis Exp 2020 10 29(164). Epub 2020 Oct 29.

Helmholtz Institute for Pharmaceutical Research Saarland, Department of Microbial Natural Products, Helmholtz Centre for Infection Research and Department of Pharmacy, Saarland University; Partner Site Hannover-Braunschweig, German Centre for Infection Research (DZIF);

Due to the global threat of rising antimicrobial resistance, novel antibiotics are urgently needed. We investigate natural products from Myxobacteria as an innovative source of such new compounds. One bottleneck in the process is typically the elucidation of their mode-of-action. We recently established isothermal microcalorimetry as part of a routine profiling pipeline. This technology allows for investigating the effect of antibiotic exposure on the total bacterial metabolic response, including processes that are decoupled from biomass formation. Importantly, bacteriostatic and bactericidal effects are easily distinguishable without any user intervention during the measurements. However, isothermal microcalorimetry is a rather new approach and applying this method to different bacterial species usually requires pre-evaluation of suitable measurement conditions. There are some reference thermograms available of certain bacteria, greatly facilitating interpretation of results. As the pool of reference data is steadily growing, we expect the methodology to have increasing impact in the future and expect it to allow for in-depth fingerprint analyses enabling the differentiation of antibiotic classes.
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http://dx.doi.org/10.3791/61703DOI Listing
October 2020

Drug Administration Routes Impact the Metabolism of a Synthetic Cannabinoid in the Zebrafish Larvae Model.

Molecules 2020 Sep 29;25(19). Epub 2020 Sep 29.

Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy, Saarland University, Campus E8 1, 66123 Saarbrücken, Germany.

Zebrafish () larvae have gained attention as a valid model to study in vivo drug metabolism and to predict human metabolism. The microinjection of compounds, oligonucleotides, or pathogens into zebrafish embryos at an early developmental stage is a well-established technique. Here, we investigated the metabolism of zebrafish larvae after microinjection of methyl 2-(1-(5-fluoropentyl)-1-pyrrolo[2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7'-5F-ADB) as a representative of recently introduced synthetic cannabinoids. Results were compared to human urine data and data from the in vitro HepaRG model and the metabolic pathway of 7'-5F-ADB were reconstructed. Out of 27 metabolites detected in human urine samples, 19 and 15 metabolites were present in zebrafish larvae and HepaRG cells, respectively. The route of administration to zebrafish larvae had a major impact and we found a high number of metabolites when 7'-5F-ADB was microinjected into the caudal vein, heart ventricle, or hindbrain. We further studied the spatial distribution of the parent compound and its metabolites by mass spectrometry imaging (MSI) of treated zebrafish larvae to demonstrate the discrepancy in metabolite profiles among larvae exposed through different administration routes. In conclusion, zebrafish larvae represent a superb model for studying drug metabolism, and when combined with MSI, the optimal administration route can be determined based on in vivo drug distribution.
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http://dx.doi.org/10.3390/molecules25194474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582563PMC
September 2020

Amidochelocardin Overcomes Resistance Mechanisms Exerted on Tetracyclines and Natural Chelocardin.

Antibiotics (Basel) 2020 Sep 18;9(9). Epub 2020 Sep 18.

Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), and Department of Pharmacy, Saarland University Campus E8.1, 66123 Saarbrücken, Germany.

The reassessment of known but neglected natural compounds is a vital strategy for providing novel lead structures urgently needed to overcome antimicrobial resistance. Scaffolds with resistance-breaking properties represent the most promising candidates for a successful translation into future therapeutics. Our study focuses on chelocardin, a member of the atypical tetracyclines, and its bioengineered derivative amidochelocardin, both showing broad-spectrum antibacterial activity within the ESKAPE (, and species) panel. Further lead development of chelocardins requires extensive biological and chemical profiling to achieve favorable pharmaceutical properties and efficacy. This study shows that both molecules possess resistance-breaking properties enabling the escape from most common tetracycline resistance mechanisms. Further, we show that these compounds are potent candidates for treatment of urinary tract infections due to their in vitro activity against a large panel of multidrug-resistant uropathogenic clinical isolates. In addition, the mechanism of resistance to natural chelocardin was identified as relying on efflux processes, both in the chelocardin producer and in the pathogen Resistance development in led primarily to mutations in , causing increased expression of the efflux pump. Most importantly, amidochelocardin overcomes this resistance mechanism, revealing not only the improved activity profile but also superior resistance-breaking properties of this novel antibacterial compound.
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http://dx.doi.org/10.3390/antibiotics9090619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559539PMC
September 2020

How to Study the Metabolism of New Psychoactive Substances for the Purpose of Toxicological Screenings-A Follow-Up Study Comparing Pooled Human Liver S9, HepaRG Cells, and Zebrafish Larvae.

Front Chem 2020 17;8:539. Epub 2020 Jul 17.

Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany.

The new psychoactive substances (NPS) market continues to be very dynamic. A large number of compounds belonging to diverse chemical groups continue to emerge. This makes their detection in biological samples challenging for clinical and forensic toxicologists. Knowledge of the metabolic fate of NPS is crucial for developing comprehensive screening procedures. As human studies are not feasible due to ethical concerns, the current study aimed to compare the NPS' metabolic pattern in incubations with pooled human liver S9 fraction (pHLS9), human liver HepaRG cells, and zebrafish larvae. The latter model was recently shown to be a promising preclinical surrogate for human hepatic metabolism of a synthetic cannabinoid. However, studies concerning other NPS classes are still missing and therefore an amphetamine-based -methoxybenzyl (NBOMe) compound, a synthetic cathinone, a pyrrolidinophenone analog, a lysergamide, as well as another synthetic cannabinoid were included in the current study. Liquid chromatography coupled to Orbitrap-based high-resolution tandem mass spectrometry was used to analyze metabolic data. Zebrafish larvae were found to produce the highest number of phase I but also phase II metabolites (79 metabolites in total), followed by HepaRG cells (66 metabolites). Incubations with pHLS9 produced the least metabolites (57 metabolites). Furthermore, the involvement of monooxygenases and esterases in the metabolic phase I transformations of 4F-MDMB-BINACA was elucidated using single-enzyme incubations. Several cytochrome P450 (CYP) isozymes were shown to contribute, and CYP3A5 was involved in all CYP-catalyzed reactions, while amide and ester hydrolysis were catalyzed by the human carboxylesterase (hCES) isoforms hCES1b and/or hCES1c. Finally, metabolites were compared to those present in human biosamples if data were available. Overall, the metabolic patterns in HepaRG cells provided the worst overlap with that in human biosamples. Zebrafish larvae experiments agreed best with data found in human plasma and urine analysis. The current study underlines the potential of zebrafish larvae as a tool for elucidating the toxicokinetics of NPS in the future.
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http://dx.doi.org/10.3389/fchem.2020.00539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380166PMC
July 2020

Protein-Templated Hit Identification through an Ugi Four-Component Reaction*.

Chemistry 2020 Nov 30;26(64):14585-14593. Epub 2020 Sep 30.

Department for Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-, Helmholtz Centre for Infection Research (HZI), Campus Building E8.1, 66123, Saarbrücken, Germany.

Kinetic target-guided synthesis represents an efficient hit-identification strategy, in which the protein assembles its own inhibitors from a pool of complementary building blocks via an irreversible reaction. Herein, we pioneered an in situ Ugi reaction for the identification of novel inhibitors of a model enzyme and binders for an important drug target, namely, the aspartic protease endothiapepsin and the bacterial β-sliding clamp DnaN, respectively. Highly sensitive mass-spectrometry methods enabled monitoring of the protein-templated reaction of four complementary reaction partners, which occurred in a background-free manner for endothiapepsin or with a clear amplification of two binders in the presence of DnaN. The Ugi products we identified show low micromolar activity on endothiapepsin or moderate affinity for the β-sliding clamp. We succeeded in expanding the portfolio of chemical reactions and biological targets and demonstrated the efficiency and sensitivity of this approach, which can find application on any drug target.
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http://dx.doi.org/10.1002/chem.202002250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756422PMC
November 2020

Toxicokinetics and toxicodynamics of the fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine and furanoyl-1-benzyl-4-anilinopiperidine.

Arch Toxicol 2020 06 5;94(6):2009-2025. Epub 2020 Apr 5.

Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, 66421, Homburg, Germany.

The two fentanyl homologs cyclopropanoyl-1-benzyl-4´-fluoro-4-anilinopiperidine (4F-Cy-BAP) and furanoyl-1-benzyl-4-anilinopiperidine (Fu-BAP) have recently been seized as new psychoactive substances (NPS) on the drugs of abuse market. As their toxicokinetic and toxicodynamic characteristics are completely unknown, this study focused on elucidating their in vitro metabolic stability in pooled human liver S9 fraction (pHLS9), their qualitative in vitro (pHLS9), and in vivo (zebrafish larvae) metabolism, and their in vitro isozyme mapping using recombinant expressed isoenzymes. Their maximum-tolerated concentration (MTC) in zebrafish larvae was studied from 0.01 to 100 µM. Their µ-opioid receptor (MOR) activity was analyzed in engineered human embryonic kidney (HEK) 293 T cells. In total, seven phase I and one phase II metabolites of 4F-Cy-BAP and 15 phase I and four phase II metabolites of Fu-BAP were tentatively identified by means of liquid chromatography high-resolution tandem mass spectrometry, with the majority detected in zebrafish larvae. N-Dealkylation, N-deacylation, hydroxylation, and N-oxidation were the most abundant metabolic reactions and the corresponding metabolites are expected to be promising analytical targets for toxicological analysis. Isozyme mapping revealed the main involvement of CYP3A4 in the phase I metabolism of 4F-Cy-BAP and in terms of Fu-BAP additionally CYP2D6. Therefore, drug-drug interactions by CYP3A4 inhibition may cause elevated drug levels and unwanted adverse effects. MTC experiments revealed malformations and changes in the behavior of larvae after exposure to 100 µM Fu-BAP. Both substances were only able to produce a weak activation of MOR and although toxic effects based on MOR activation seem unlikely, activity at other receptors cannot be excluded.
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http://dx.doi.org/10.1007/s00204-020-02726-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303074PMC
June 2020

Squalenyl Hydrogen Sulfate Nanoparticles for Simultaneous Delivery of Tobramycin and an Alkylquinolone Quorum Sensing Inhibitor Enable the Eradication of P. aeruginosa Biofilm Infections.

Angew Chem Int Ed Engl 2020 06 11;59(26):10292-10296. Epub 2020 May 11.

Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Center for Infection Research, 66123, Saarbrücken, Germany.

Elimination of pulmonary Pseudomonas aeruginosa (PA) infections is challenging to accomplish with antibiotic therapies, mainly due to resistance mechanisms. Quorum sensing inhibitors (QSIs) interfering with biofilm formation can thus complement antibiotics. For simultaneous and improved delivery of both active agents to the infection sites, self-assembling nanoparticles of a newly synthesized squalenyl hydrogen sulfate (SqNPs) were prepared. These nanocarriers allowed for remarkably high loading capacities of hydrophilic antibiotic tobramycin (Tob) and a novel lipophilic QSI at 30 % and circa 10 %, respectively. The drug-loaded SqNPs showed improved biofilm penetration and enhanced efficacy in relevant biological barriers (mucin/human tracheal mucus, biofilm), leading to complete eradication of PA biofilms at circa 16-fold lower Tob concentration than Tob alone. This study offers a viable therapy optimization and invigorates the research and development of QSIs for clinical use.
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http://dx.doi.org/10.1002/anie.202001407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317969PMC
June 2020

The glucocorticoid-induced leucine zipper mediates statin-induced muscle damage.

FASEB J 2020 03 6;34(3):4684-4701. Epub 2020 Feb 6.

Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany.

Statins, the most prescribed class of drugs for the treatment of hypercholesterolemia, can cause muscle-related adverse effects. It has been shown that the glucocorticoid-induced leucine zipper (GILZ) plays a key role in the anti-myogenic action of dexamethasone. In the present study, we aimed to evaluate the role of GILZ in statin-induced myopathy. Statins induced GILZ expression in C2C12 cells, primary murine myoblasts/myotubes, primary human myoblasts, and in vivo in zebrafish embryos and human quadriceps femoris muscle. Gilz induction was mediated by FOXO3 activation and binding to the Gilz promoter, and could be reversed by the addition of geranylgeranyl, but not farnesyl, pyrophosphate. Atorvastatin decreased Akt phosphorylation and increased cleaved caspase-3 levels in myoblasts. This effect was reversed in myoblasts from GILZ knockout mice. Similarly, myofibers isolated from knockout animals were more resistant toward statin-induced cell death than their wild-type counterparts. Statins also impaired myoblast differentiation, and this effect was accompanied by GILZ induction. The in vivo relevance of our findings was supported by the observation that gilz overexpression in zebrafish embryos led to impaired embryonic muscle development. Taken together, our data point toward GILZ as an essential mediator of the molecular mechanisms leading to statin-induced muscle damage.
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http://dx.doi.org/10.1096/fj.201902557RRRDOI Listing
March 2020

Cystobactamid 507: Concise Synthesis, Mode of Action, and Optimization toward More Potent Antibiotics.

Chemistry 2020 Jun 28;26(32):7219-7225. Epub 2020 Apr 28.

Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland, Saarland University, Campus E8.1, 66123, Saarbrücken, Germany.

Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids-a novel natural class of antibiotics with broad-spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure-activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor-groove binding as part of the drug-target interaction without showing significant intercalation. By designing a new analogue of cystobactamid 919-2, we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram-negative bacteria.
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http://dx.doi.org/10.1002/chem.202000117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317206PMC
June 2020

Semisynthesis and biological evaluation of amidochelocardin derivatives as broad-spectrum antibiotics.

Eur J Med Chem 2020 Feb 20;188:112005. Epub 2019 Dec 20.

Department of Chemical Biology, Helmholtz Centre for Infection Research (HZI), Inhoffenstrasse 7, 38124, Braunschweig, Germany; German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 38124, Braunschweig, Germany. Electronic address:

To address the global challenge of emerging antimicrobial resistance, the hitherto most successful strategy to new antibiotics has been the optimization of validated natural products; most of these efforts rely on semisynthesis. Herein, we report the semisynthetic modification of amidochelocardin, an atypical tetracycline obtained via genetic engineering of the chelocardin producer strain. We report modifications at C4, C7, C10 and C11 by the application of methylation, acylation, electrophilic substitution, and oxidative C-C coupling reactions. The antibacterial activity of the reaction products was tested against a panel of Gram-positive and Gram-negative pathogens. The emerging structure-activity relationships (SARs) revealed that positions C7 and C10 are favorable anchor points for the semisynthesis of optimized derivatives. The observed SAR was different from that known for tetracyclines, which underlines the pronounced differences between the two compound classes.
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http://dx.doi.org/10.1016/j.ejmech.2019.112005DOI Listing
February 2020

Synthetic and Biological Studies on New Urea and Triazole Containing Cystobactamid Derivatives.

Chemistry 2020 Apr 11;26(19):4289-4296. Epub 2020 Mar 11.

Institut für Organische Chemie und Biomolekulares Wirkstoffzentrum (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167, Hannover, Germany.

Cystobactamids belong to the group of arene-based oligoamides that effectively inhibit bacterial type IIa topoisomerases. Cystobactamid 861-2 is the most active member of these antibiotics. Most amide bonds present in the cystobactamids link benzoic acids with anilines and it was found that some of these amide bonds undergo chemical and enzymatic hydrolysis, especially the one linking ring C with ring D. This work reports on the chemical synthesis and biological evaluation of thirteen new cystobactamids that still contain the methoxyaspartate hinge. However, we exchanged selected amide bonds either by the urea or the triazole groups and modified ring A in the latter case. While hydrolytic stability could be improved with these structural substitutes, the high antibacterial potency of cystobactamid 861-2 could only be preserved in selected cases. This includes derivatives, in which the urea group is positioned between rings A and B and where the triazole is found between rings C and D.
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http://dx.doi.org/10.1002/chem.201904073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186842PMC
April 2020

Synthetic studies of cystobactamids as antibiotics and bacterial imaging carriers lead to compounds with high efficacy.

Chem Sci 2019 Dec 10;11(5):1316-1334. Epub 2019 Dec 10.

Department of Chemical Biology, Helmholtz Centre for Infection Research Inhoffenstrasse 7 38124 Braunschweig Germany

There is an alarming scarcity of novel chemical matter with bioactivity against multidrug-resistant Gram-negative bacterial pathogens. Cystobactamids, recently discovered natural products from myxobacteria, are an exception to this trend. Their unusual chemical structure, composed of oligomeric -aminobenzoic acid moieties, is associated with a high antibiotic activity through the inhibition of gyrase. In this study, structural determinants of cystobactamid's antibacterial potency were defined at five positions, which were varied using three different synthetic routes to the cystobactamid scaffold. The potency against could be increased ten-fold to an MIC (minimum inhibitory concentration) of 0.06 μg mL, and the previously identified spectrum gap of could be closed compared to the natural products (MIC of 0.5 μg mL). Proteolytic degradation of cystobactamids by the resistance factor AlbD was prevented by an amide-triazole replacement. Conjugation of cystobactamid's N-terminal tetrapeptide to a Bodipy moiety induced the selective localization of the fluorophore for bacterial imaging purposes. Finally, a first proof of concept was obtained in an infection mouse model, where derivative led to the reduction of bacterial loads (cfu, colony-forming units) in muscle, lung and kidneys by five orders of magnitude compared to vehicle-treated mice. These findings qualify cystobactamids as highly promising lead structures against infections caused by Gram-positive and Gram-negative bacterial pathogens.
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http://dx.doi.org/10.1039/c9sc04769gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148378PMC
December 2019

Setting Our Sights on Infectious Diseases.

ACS Infect Dis 2020 01 6;6(1):3-13. Epub 2019 Dec 6.

Global Health Institute of Merck, Ares Trading S.A. , a subsidiary of Merck KGaA Darmstadt Germany , Route de Crassier 1 , 1262 Eysins , Switzerland.

In May 2019, the Wellcome Centre for Anti-Infectives Research (CAIR) at the University of Dundee, UK, held an international conference with the aim of discussing some key questions around discovering new medicines for infectious diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new drugs to treat most infectious diseases. We were keen to see if there were lessons that we could learn across different disease areas and between the preclinical and clinical phases with the aim of exploring how we can improve and speed up the drug discovery, translational, and clinical development processes. We started with an introductory session on the current situation and then worked backward from clinical development to combination therapy, pharmacokinetic/pharmacodynamic (PK/PD) studies, drug discovery pathways, and new starting points and targets. This Viewpoint aims to capture some of the learnings.
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http://dx.doi.org/10.1021/acsinfecdis.9b00371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958537PMC
January 2020

PLGA nanocapsules improve the delivery of clarithromycin to kill intracellular Staphylococcus aureus and Mycobacterium abscessus.

Nanomedicine 2020 02 18;24:102125. Epub 2019 Nov 18.

Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University, Saarbrücken, Germany; Department of Pharmacy, Saarland University, Saarbrücken, Germany. Electronic address:

Drug delivery systems are promising for targeting antibiotics directly to infected tissues. To reach intracellular Staphylococcus aureus and Mycobacterium abscessus, we encapsulated clarithromycin in PLGA nanocapsules, suitable for aerosol delivery by nebulization of an aqueous dispersion. Compared to the same dose of free clarithromycin, nanoencapsulation reduced 1000 times the number of intracellular S. aureus in vitro. In RAW cells, while untreated S. aureus was located in acidic compartments, the treated ones were mostly situated in non-acidic compartments. Clarithromycin-nanocapsules were also effective against M. abscessus (70-80% killing efficacy). The activity of clarithromycin-nanocapsules against S. aureus was also confirmed in vivo, using a murine wound model as well as in zebrafish. The permeability of clarithromycin-nanocapsules across Calu-3 monolayers increased in comparison to the free drug, suggesting an improved delivery to sub-epithelial tissues. Thus, clarithromycin-nanocapsules are a promising strategy to target intracellular S. aureus and M. abscessus.
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http://dx.doi.org/10.1016/j.nano.2019.102125DOI Listing
February 2020

A Randomized, Controlled, Split-Face Study of the Efficacy of a Picosecond Laser in the Treatment of Melasma

J Drugs Dermatol 2019 Nov;18(11):1104-1107

Introduction: Melasma is a common disorder where patients develop hyperpigmented macules and patches on the face and is thought to be the result of sun exposure and hormonal contributions, although the pathogenesis is not completely understood. Lasers have been used for melasma treatment with varying degrees of success. Objectives: The objective of this study was to examine the safety and efficacy of a novel picosecond laser for the treatment of melasma. Materials and Methods: Ten subjects received nine weekly laser treatments with a picosecond laser to a randomized half of their face. A lightening cream was applied to the entire face to serve as a control. The primary outcome measure was clinical efficacy measured by a patient-reported outcome survey, the Melasma Quality of Life (MELASQOL) questionnaire, and physician assessment with the Global Aesthetic Improvement Scale (GAIS). The secondary outcome measure was safety, which was assessed by monitoring for adverse events. Photos were taken before every treatment and at a 1-week follow-up. Results: Ninety percent of subjects rated their melasma as at least slightly better, and 90% percent of subjects would recommend this laser treatment to others with melasma. MELASQoL questionnaire scores improved by an average of 5.7 points after laser treatment. Assessments by two board-certified dermatologists using the GAIS revealed an overall improvement in 80% of patients on the laser treatment side versus 20% on the control side. Side effects, including erythema and discomfort, were minimal and transient post-treatment. Conclusions: This study suggests that picosecond laser treatments are a safe and efficacious way to treat melasma. J Drugs Dermatol. 2019;18(11):1104-1107.
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November 2019

Scalable Syntheses of Methoxyaspartate and Preparation of the Antibiotic Cystobactamid 861-2 and Highly Potent Derivatives.

Org Lett 2019 10 10;21(20):8369-8372. Epub 2019 Oct 10.

Institut für Organische Chemie und Biomolekulares Wirkstoffzentrum (BMWZ) der Leibniz Universität Hannover , Schneiderberg 1B , 30167 Hannover , Germany.

An improved scalable synthesis of orthogonally functionalized methoxyaspartate, the chiral hinge region element in cystobactamids, is reported. This improvement sets the stage for the total synthesis of four new cystobactamids along with cystobactamid 861-2, whose antibacterial properties are determined and compared. The cyano derivative of cystobactamide 861-2 shows superior antibacterial activity against Gram-negative bacteria to any natural cystobactamide tested so far.
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http://dx.doi.org/10.1021/acs.orglett.9b03143DOI Listing
October 2019

Perquinolines A-C: Unprecedented Bacterial Tetrahydroisoquinolines Involving an Intriguing Biosynthesis.

Angew Chem Int Ed Engl 2019 09 21;58(37):12930-12934. Epub 2019 Aug 21.

Department of Pharmacy, Pharmaceutical Biotechnology, University of Saarland, Campus, Bld. C2 3, Saarbrucken, 66123, Germany.

Metabolic profiling of Streptomyces sp. IB2014/016-6 led to the identification of three new tetrahydroisoquinoline natural products, perquinolines A-C (1-3). Labelled precursor feeding studies and the cloning of the pqr biosynthetic gene cluster revealed that 1-3 are assembled by the action of several unusual enzymes. The biosynthesis starts with the condensation of succinyl-CoA and l-phenylalanine catalyzed by the amino-7-oxononanoate synthase-like enzyme PqrA, representing rare chemistry in natural product assembly. The second condensation and cyclization events are conducted by PqrG, an enzyme resembling an acyl-CoA ligase. Last, ATP-grasp RimK-type ligase PqrI completes the biosynthesis by transferring a γ-aminobutyric acid or β-alanine moiety. The discovered pathway represents a new route for assembling the tetrahydroisoquinoline cores of natural products.
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http://dx.doi.org/10.1002/anie.201905538DOI Listing
September 2019

DNA Repair Enzyme Containing Lip Balm for the Treatment of Actinic Cheilitis: A Pilot Study

J Drugs Dermatol 2019 06;18(6):576

Background: DNA repair enzymes have been shown to reduce actinic keratoses and non-melanoma skin cancers, but their use for the treatment of actinic cheilitis has not been studied. Objective: The purpose of this pilot study was to examine the efficacy of a DNA repair enzyme lip balm containing T4 endonuclease in reducing the severity of actinic cheilitis in patients who applied the lip balm twice daily for 3 months. Methods: We performed a prospective study in which 29 patients with a diagnosis of actinic cheilitis underwent a 3-month trial using a topical DNA repair enzyme lip balm containing T4 endonuclease applied to the lips twice daily. The primary, objective outcome was percent of actinic lip involvement, measured using computer software by dividing the calculated affected surface area by the calculated total surface area. Additional outcomes included pre- and post-intervention determination of an actinic cheilitis score on the Actinic Cheilitis Scale, which visually and tactilely quantifies the percentage of lip involvement, amount of roughness, erythema, and tenderness as well as a physician assessment using the Global Aesthetic Improvement Scale. Results: Twenty-five of the 29 enrolled patients completed the trial. The lip balm significantly decreased the percentage of affected lip surface area (P<0.0001). According to the Actinic Cheilitis Scale, data demonstrate that the lip balm significantly decreased the percentage of lip involvement (P=0.002), amount of roughness (P=0.0012)), erythema (P=0.0020), and tenderness (P=0.0175). The total Actinic Cheilitis Scale score also significantly improved after the 3-month treatment period (P<0.0001). According to the Global Aesthetic Improvement Scale, the average score for all 26 patients was 1.04. Conclusion: This study suggests that topical DNA repair enzyme lip balm containing T4 Endonuclease could potentially be a safe and efficacious way to improve and treat actinic cheilitis. J Drugs Dermatol. 2019;18(6):576-579
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June 2019

Hydrochlorothiazide-induced photosensitivity in a psoriasis patient following exposure to narrow-band ultraviolet B excimer therapy.

Photodermatol Photoimmunol Photomed 2019 Sep 6;35(5):369-371. Epub 2019 Jun 6.

Research Department, Moy-Fincher-Chipps Facial Plastics & Dermatology, Beverly Hills, California.

Drug-induced photosensitivity develops when the use of oral or topical photosensitizing medications creates a rash after exposure to ultraviolet (UV) radiation. Medications most commonly implicated in photosensitive drug reactions include amiodarone, nonsteroidal anti-inflammatories, thiazides, tetracycline antibiotics, chlorpromazine, and fluoroquinolones. It is generally believed that drug-induced photosensitivity is an UVA phenomenon, caused by UV wavelengths between 315 and 400 nm. Here, we present a case of hydrochlorothiazide (HCTZ)-induced photosensitivity following exposure to 308-nm narrow-band (nb) UVB light emitted from an excimer laser in a patient undergoing treatment for plaque psoriasis. This patient had received biweekly treatments with the excimer laser for years prior without any history of adverse reactions. We believe that our patient suffered an acute photosensitivity to UVB due to new-onset HCTZ. Because nb UVB-emitting lasers are used to treat many dermatologic conditions, physicians should be aware of potential photosensitivity reactions, review medication lists and counsel patients accordingly.
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http://dx.doi.org/10.1111/phpp.12471DOI Listing
September 2019

Treatment of Moderate-to-severe Facial Acne Vulgaris with Solid-state Fractional 589/1,319-nm Laser.

J Clin Aesthet Dermatol 2019 Mar 1;12(3):28-31. Epub 2019 Mar 1.

Drs. Kang and Herrmann are with the Division of Dermatology, Harbor-UCLA Medical Center in Torrance, California.

The objectives of this study were to evaluate the efficacy, safety and patient satisfaction of a unique combination of wavelengths 589nm and 1,319nm for the treatment of facial acne vulgaris. This was a small, randomized, prospective, split-face, single-blinded study of patients with moderate-to-severe acne vulgaris. The study took place at a single outpatient center study in Torrance, California. Nine patients underwent four treatment sessions at 2- to 3-week intervals. Each patient received one pass with the 1,319nm laser followed by one pass with the 589nm laser only to the randomized treatment side of the face. A blinded, board-certified dermatologist reviewed photographs and counted acne lesions on treated and nontreated sides. Of the nine patients, eight were Fitzpatrick Skin Type IV. At the final visit, inflammatory acne lesions were reduced by 2.5 (-23.1%) on the treatment side and increased by 1.1 (+11.1%) on the control side. No patients experienced bruising, edema, hyperpigmentation or scarring. At the conclusion of the study, 77.8 percent of the patients reported overall satisfaction. This unique combination of lasers appears to be safe in patients with Fitzpatrick Skin Type IV, and might be useful in treating moderate-to-severe acne vulgaris.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440707PMC
March 2019

Starch-Chitosan Polyplexes: A Versatile Carrier System for Anti-Infectives and Gene Delivery.

Polymers (Basel) 2018 Mar 1;10(3). Epub 2018 Mar 1.

Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Center for Infection Research (HZI), Saarland University, D-66123 Saarbrücken, Germany.

Despite the enormous potential of nanomedicine, the search for materials from renewable resources that balance bio-medical requirements and engineering aspects is still challenging. This study proposes an easy method to make nanoparticles composed of oxidized starch and chitosan, both isolated from natural biopolymers. The careful adjustment of C/N ratio, polymer concentration and molecular weight allowed for tuning of particle characteristics. The system's carrier capability was assessed both for anti-infectives and for nucleic acid. Higher starch content polyplexes were found to be suitable for high encapsulation efficiency of cationic anti-infectives and preserving their bactericidal function. A cationic carrier was obtained by coating the anionic polyplex with chitosan. Coating allowed for a minimal amount of cationic polymer to be employed and facilitated plasmid DNA loading both within the particle core and on the surface. Transfection studies showed encouraging result, approximately 5% of A549 cells with reporter gene expression. In summary, starch-chitosan complexes are suitable carriers with promising perspectives for pharmaceutical use.
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http://dx.doi.org/10.3390/polym10030252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415184PMC
March 2018

Engineering Atypical Tetracycline Formation in Amycolatopsis sulphurea for the Production of Modified Chelocardin Antibiotics.

ACS Chem Biol 2019 03 12;14(3):468-477. Epub 2019 Feb 12.

Department of Microbial Natural Products , Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) , Helmholtz Centre for Infection Research (HZI), and Department of Pharmacy, Saarland University, Campus E8.1 , 66123 Saarbrücken , Germany.

To combat the increasing spread of antimicrobial resistance and the shortage of novel anti-infectives, one strategy for the development of new antibiotics is to optimize known chemical scaffolds. Here, we focus on the biosynthetic engineering of Amycolatopsis sulphurea for derivatization of the atypical tetracycline chelocardin and its potent broad-spectrum derivative 2-carboxamido-2-deacetyl-chelocardin. Heterologous biosynthetic genes were introduced into this chelocardin producer to modify functional groups and generate new derivatives. We demonstrate cooperation of chelocardin polyketide synthase with tailoring enzymes involved in biosynthesis of oxytetracycline from Streptomyces rimosus. An interesting feature of chelocardin, compared with oxytetracycline, is the opposite stereochemistry of the C4 amino group. Genes involved in C4 transamination and N,N-dimethylation of oxytetracycline were heterologously expressed in an A. sulphurea mutant lacking C4-aminotransferase. Chelocardin derivatives with opposite stereochemistry of the C4 amino group, as N,N-dimethyl- epi-chelocardin and N,N-dimethyl-2-carboxamido-2-deacetyl- epi-chelocardin, were produced only when the aminotransferase from oxytetracycline was coexpressed with the N-methyltransferase OxyT. Surprisingly, OxyT exclusively accepted intermediates carrying an S-configured amino group at C4 in chelocardin. Applying medicinal chemistry approaches, several 2-carboxamido-2-deacetyl- epi-chelocardin derivatives modified at C4 were produced. Analysis of the antimicrobial activities of the modified compounds demonstrated that the primary amine in the R configuration is a crucial structural feature for activity of chelocardin. Unexpectedly, C10 glycosylated chelocardin analogues were identified, thus revealing the glycosylation potential of A. sulphurea. However, efficient glycosylation of the chelocardin backbone occurred only after engineering of a dimethylated amino group at the C4 position in the opposite S configuration, which suggests some evolutionary remains of chelocardin glycosylation.
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http://dx.doi.org/10.1021/acschembio.8b01125DOI Listing
March 2019

Tools for studying the metabolism of new psychoactive substances for toxicological screening purposes - A comparative study using pooled human liver S9, HepaRG cells, and zebrafish larvae.

Toxicol Lett 2019 May 22;305:73-80. Epub 2019 Jan 22.

Department of Experimental and Clinical Toxicology, Institute of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany. Electronic address:

New psychoactive substances (NPS) are an emerging topic amongst abused compounds. New varieties appear constantly on the market, without any knowledge about their toxicodynamic and/or -kinetic properties and knowledge of their metabolism is crucial for the development of analytical methods employed for their detection. Controlled human studies would of course be best suited but due to ethical reasons and lack of preclinical safety data, they are usually not available. Often, in vitro models are used to evaluate similarities to human in vivo hepatic phase I and II metabolism and systems explored include primary human hepatocytes, pooled human S9 fraction, and HepaRG, a human hepatic cell line. All these in vitro models have considerable limitations and drug distribution, reabsorption, enterohepatic circulation, and renal elimination cannot be studied. In the recent years, zebrafish (Danio rerio) larvae (embryos) were discussed as a potential in vivo model to overcome these limitations. To date, no studies demonstrating its suitability for studying NPS metabolism in the context of analytical toxicology are available. The aim of this study was to elucidate whether zebrafish larvae can serve as a surrogate for human hepatic metabolism of NPS to develop toxicological screening procedures. Here, we used methyl 2-(1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7'N-5F-ADB), a new synthetic cannabinoid, whose human metabolism was recently described in the literature, as a model compound to evaluate zebrafish larvae as a new tool for metabolism studies. Different conditions for zebrafish larvae and HepaRG protocols were tested. As zebrafish larvae and HepaRG cell incubations provided the highest number of metabolites and the most authentic spectrum of human metabolites. The most suitable larvae protocol was the incubation via medium and the analysis of the extracted zebrafish larvae. The zebrafish larvae model might be a promising preclinical surrogate for human hepatic metabolism of NPS.
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http://dx.doi.org/10.1016/j.toxlet.2019.01.010DOI Listing
May 2019

Aurantimycin resistance genes contribute to survival of Listeria monocytogenes during life in the environment.

Mol Microbiol 2019 04 27;111(4):1009-1024. Epub 2019 Feb 27.

FG11 Division of Enteropathogenic Bacteria and Legionella, Robert Koch Institute, Burgstrasse 37, Wernigerode, 38855, Germany.

Bacteria can cope with toxic compounds such as antibiotics by inducing genes for their detoxification. A common detoxification strategy is compound excretion by ATP-binding cassette (ABC) transporters, which are synthesized upon compound contact. We previously identified the multidrug resistance ABC transporter LieAB in Listeria monocytogenes, a Gram-positive bacterium that occurs ubiquitously in the environment, but also causes severe infections in humans upon ingestion. Expression of the lieAB genes is strongly induced in cells lacking the PadR-type transcriptional repressor LftR, but compounds leading to relief of this repression in wild-type cells were not known. Using RNA-Seq and promoter-lacZ fusions, we demonstrate highly specific repression of the lieAB and lftRS promoters through LftR. Screening of a natural compound library yielded the depsipeptide aurantimycin A - synthesized by the soil-dwelling Streptomyces aurantiacus - as the first known naturally occurring inducer of lieAB expression. Genetic and phenotypic experiments concordantly show that aurantimycin A is a substrate of the LieAB transporter and thus, lftRS and lieAB represent the first known genetic module conferring and regulating aurantimycin A resistance. Collectively, these genes may support the survival of L. monocytogenes when it comes into contact with antibiotic-producing bacteria in the soil.
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http://dx.doi.org/10.1111/mmi.14205DOI Listing
April 2019

An endothelial cell line infected by Kaposi's sarcoma-associated herpes virus (KSHV) allows the investigation of Kaposi's sarcoma and the validation of novel viral inhibitors in vitro and in vivo.

J Mol Med (Berl) 2019 03 4;97(3):311-324. Epub 2019 Jan 4.

Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124, Braunschweig, Germany.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), a tumor of endothelial origin predominantly affecting immunosuppressed individuals. Up to date, vaccines and targeted therapies are not available. Screening and identification of anti-viral compounds are compromised by the lack of scalable cell culture systems reflecting properties of virus-transformed cells in patients. Further, the strict specificity of the virus for humans limits the development of in vivo models. In this study, we exploited a conditionally immortalized human endothelial cell line for establishment of in vitro 2D and 3D KSHV latency models and the generation of KS-like xenograft tumors in mice. Importantly, the invasive properties and tumor formation could be completely reverted by purging KSHV from the cells, confirming that tumor formation is dependent on the continued presence of KSHV, rather than being a consequence of irreversible transformation of the infected cells. Upon testing a library of 260 natural metabolites, we selected the compounds that induced viral loss or reduced the invasiveness of infected cells in 2D and 3D endothelial cell culture systems. The efficacy of selected compounds against KSHV-induced tumor formation was verified in the xenograft model. Together, this study shows that the combined use of anti-viral and anti-tumor assays based on the same cell line is predictive for tumor reduction in vivo and therefore allows faithful selection of novel drug candidates against Kaposi's sarcoma. KEY MESSAGES: Novel 2D, 3D, and xenograft mouse models mimic the consequences of KSHV infection. KSHV-induced tumorigenesis can be reverted upon purging the cells from the virus. A 3D invasiveness assay is predictive for tumor reduction in vivo. Chondramid B, epothilone B, and pretubulysin D diminish KS-like lesions in vivo.
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http://dx.doi.org/10.1007/s00109-018-01733-1DOI Listing
March 2019

-Acylated amino acid methyl esters from marine group bacteria.

Beilstein J Org Chem 2018 3;14:2964-2973. Epub 2018 Dec 3.

Institute of Organic Chemistry, Technische Universität Braunschweig, Hagenring 30, 38106 Braunschweig, Germany.

Bacteria of the group (Rhodobacteraceae) are important members of many marine ecosystems. Similar to other Gram-negative bacteria many roseobacters produce -acylhomoserine lactones (AHLs) for communication by quorum sensing systems. AHLs regulate different traits like cell differentiation or antibiotic production. Related -acylalanine methyl esters (NAMEs) have been reported as well, but so far only from EL-164. While screening various roseobacters isolated from macroalgae we encountered four strains, sp. D12_1.68, sp. F13, F14 and D3 that produced new derivatives and analogs of NAMEs, namely -acyl-2-aminobutyric acid methyl esters (NABME), -acylglycine methyl esters (NAGME), -acylvaline methyl esters (NAVME), as well as for the first time a methyl-branched NAME, -(13-methyltetradecanoyl)alanine methyl ester. These compounds were detected by GC-MS analysis, and structural proposals were derived from the mass spectra and by derivatization. Verification of compound structures was performed by synthesis. NABMEs, NAVMEs and NAGMEs are produced in low amounts only, making mass spectrometry the method of choice for their detection. The analysis of both EI and ESI mass spectra revealed fragmentation patterns helpful for the detection of similar compounds derived from other amino acids. Some of these compounds showed antimicrobial activity. The structural similarity of -acylated amino acid methyl esters and similar lipophilicity to AHLs might indicate a yet unknown function as signalling compounds in the ecology of these bacteria, although their singular occurrence is in strong contrast to the common occurrence of AHLs. Obviously the structural motif is not restricted to spp. and occurs also in other genera.
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http://dx.doi.org/10.3762/bjoc.14.276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296433PMC
December 2018

BAX/BAK-Induced Apoptosis Results in Caspase-8-Dependent IL-1β Maturation in Macrophages.

Cell Rep 2018 11;25(9):2354-2368.e5

Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany. Electronic address:

IL-1β is a cytokine of pivotal importance to the orchestration of inflammatory responses. Synthesized as an inactive pro-cytokine, IL-1β requires proteolytic maturation to gain biological activity. Here, we identify intrinsic apoptosis as a non-canonical trigger of IL-1β maturation. Guided by the discovery of the immunomodulatory activity of vioprolides, cyclic peptides isolated from myxobacteria, we observe IL-1β maturation independent of canonical inflammasome pathways, yet dependent on intrinsic apoptosis. Mechanistically, vioprolides inhibit MCL-1 and BCL2, which in turn triggers BAX/BAK-dependent mitochondrial outer membrane permeabilization (MOMP). Induction of MOMP results in the release of pro-apoptotic factors initiating intrinsic apoptosis, as well as the depletion of IAPs (inhibitors of apoptosis proteins). IAP depletion, in turn, operates upstream of ripoptosome complex formation, subsequently resulting in caspase-8-dependent IL-1β maturation. These results establish the ripoptosome/caspase-8 complex as a pro-inflammatory checkpoint that senses the perturbation of mitochondrial integrity.
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http://dx.doi.org/10.1016/j.celrep.2018.10.087DOI Listing
November 2018

Expressing cytotoxic compounds in Escherichia coli Nissle 1917 for tumor-targeting therapy.

Res Microbiol 2019 Mar 14;170(2):74-79. Epub 2018 Nov 14.

Shandong University - Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, Shandong University, No. 72 Binhai Road, Qingdao 266237, PR China. Electronic address:

Abnormal blood vessels and hypoxic and necrotic regions are common features of solid tumors and related to the malignant phenotype and therapy resistance. Certain obligate or facultative anaerobic bacteria exhibit inherent ability to colonize and proliferate within solid tumors in vivo. Escherichia coli Nissle 1917 (EcN), a non-pathogenic probiotic in European markets, has been known to proliferate selectively in the interface between the viable and necrotic regions of solid tumors. The objective of this study was to establish a tumor-targeting therapy system using the genetically engineered EcN for targeted delivery of cytotoxic compounds, including colibactin, glidobactin and luminmide. Biosynthetic gene clusters of these cytotoxic compounds were introduced into EcN and the corresponding compounds were detected in the resultant recombinant EcN strains. The recombinant EcN showed significant cytotoxic activity in vitro and in vivo as well, and significantly suppressed the tumor growth. Together, this study confirmed efficient tumor-targeting colonization of EcN and demonstrated its potentiality in the tumor-specific delivery of cytotoxic compounds as a new tumor-targeting therapy system.
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http://dx.doi.org/10.1016/j.resmic.2018.11.001DOI Listing
March 2019