40 research outputs found
Zirconyl Clindamycinphosphate Antibiotic Nanocarriers for Targeting Intracellular Persisting Staphylococcus aureus
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A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms
Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) â a crucial transcriptional regulator serving major functions in PA virulence â can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry-driven hit-to-lead optimization and in-depth biological profiling of a new QSI generation is reported. The QSI possess excellent activity in inhibiting pyocyanin production and PqsR reporter-gene with IC50 values as low as 200 and 11Â Ă 10â9 m, respectively. Drug metabolism and pharmacokinetics (DMPK) as well as safety pharmacology studies especially highlight the promising translational properties of the lead QSI for pulmonary applications. Moreover, target engagement of the lead QSI is shown in a PA mucoid lung infection mouse model. Beyond that, a significant synergistic effect of a QSI-tobramycin (Tob) combination against PA biofilms using a tailor-made squalene-derived nanoparticle (NP) formulation, which enhance the minimum biofilm eradicating concentration (MBEC) of Tob more than 32-fold is demonstrated. The novel lead QSI and the accompanying NP formulation highlight the potential of adjunctive pathoblocker-mediated therapy against PA infections opening up avenues for preclinical development
Naturstoffe als Pathoblocker gegen Streptokokken-Infektionen
Worldwide millions of people are affected by streptococcal diseases ranging from mild to severe. Lethality rates up to 30 % for invasive diseases and recurrent infections often leading to post-infection sequelae like rheumatic heart disease show that current antibiotic treatment is not sufficient. Therefore, a new concept has to be applied: It is assumed that resistance will not arise if conserved virulence mechanisms are targeted. To influence them small molecules are needed. Myxobacteria are proven producers of small molecules offering new chemical scaffolds and unknown modes-of-action.
Consequently, by combining microbiological, cell-biological and analytical methods myxobacterial extracts and compounds were screened for activity with regard to two virulence mechanisms of S.pyogenes: invasion into epithelial cells and exploitation of the hostâs plasmin(ogen) system. Active compounds were identified by linking a bioactivity-guided isolation strategy with analytical methods.
This work demonstrates that myxobacterial compounds interfere successfully with two virulence mechanisms of S.pyogenes: (1) Two compounds inhibit streptococcal invasion by targeting a protein not known to be involved in this process so far. (2) Several compounds can serve as new inhibitors of plasmin(ogen) showing better inhibitory activity than known antifibrinolytics. Moreover, two of these compounds significantly prolonged survival in an in vivo skin infection model usually leading to systemic severity.
There is rising evidence that the new class of anti-infectives targeting virulence - the âpathoblockersâ -will be enriched by myxobacterial compounds and improve the therapy of diseases caused by S.pyogenes.Millionen Menschen weltweit sind von Krankheiten betroffen, die durch Streptokokken verursacht werden und bisweilen schwere Verlaufsformen aufweisen. LetalitĂ€tsraten von bis zu 30 % fĂŒr schwere VerlĂ€ufe und wiederkehrende Infektionen, die oft zu SpĂ€tkomplikationen wie der rheumatischen Herzkrankheit fĂŒhren, zeigen, dass die derzeitigen antibiotischen Möglichkeiten nicht ausreichen. Daher wird nun ein neuer Ansatz verfolgt: Diesem liegt die These zugrunde, dass das Angreifen an konservierten Virulenzmechanismen das Auftreten von Resistenzen vermeidet. FĂŒr diesen Ansatz werden so genannte âkleine MolekĂŒleâ benötigt. Myxobakterien haben sich als verlĂ€ssliche Produzenten solcher âkleinen MolekĂŒleâ erwiesen, wobei sie zudem oft neu chemische Grundstrukturen und neuartige Wirkmechanismen bieten.
Daher wurden myxobakterielle Extrakte und Substanzen auf ihre AktivitÀt in Bezug auf zwei Virulenzmechanismen von S.pyogenes untersucht: die Invasion in Epithelzellen und die Ausnutzung des menschlichen Plasmin(ogen)-Systems. Dabei wurden mikro-, zellbiologische und analytische Methoden kombiniert. Aktive Substanzen wurden mittels einer bioaktivitÀtsgeleiteten Isolierungsstrategie in Verbindung mit analytischen Methoden identifiziert.
Diese Arbeit zeigt, dass myxobakterielle Substanzen erfolgreich mit zwei Virulenzmechanismen von S.pyogenes interferieren können: (1) Zwei Substanzen hemmen die Invasion, indem sie an einem Protein angreifen, dessen Rolle in diesem Prozess bisher unbekannt war. (2) Mehrere Substanzen können als neue Hemmstoffe des Plasmin(ogen)s dienen und zeigen zudem eine bessere AktivitĂ€t als bisher bekannte Antifibrinolytika. Des Weiteren verlĂ€ngerten zwei dieser Substanzen signifikant das Ăberleben in einem Maus-Hautinfektionsmodell, welches (sonst) zu einer Sepsis fĂŒhrt.
Diese Ergebnisse zeigen, dass diese neue Klasse von Anti-Infektiva, die Virulenzmechanismen angreift - die âPathoblockerâ - durch die myxobakteriellen Substanzen bereichert und die Therapiemöglichkeiten von durch Streptokokken hervorgerufenen Krankheiten verbessern wird
Natural compounds as pathoblockers of streptococcal infections
Worldwide millions of people are affected by streptococcal diseases ranging from mild to severe. Lethality rates up to 30 % for invasive diseases and recurrent infections often leading to post-infection sequelae like rheumatic heart disease show that current antibiotic treatment is not sufficient. Therefore, a new concept has to be applied: It is assumed that resistance will not arise if conserved virulence mechanisms are targeted. To influence them small molecules are needed. Myxobacteria are proven producers of small molecules offering new chemical scaffolds and unknown modes-of-action.
Consequently, by combining microbiological, cell-biological and analytical methods myxobacterial extracts and compounds were screened for activity with regard to two virulence mechanisms of S.pyogenes: invasion into epithelial cells and exploitation of the hostâs plasmin(ogen) system. Active compounds were identified by linking a bioactivity-guided isolation strategy with analytical methods.
This work demonstrates that myxobacterial compounds interfere successfully with two virulence mechanisms of S.pyogenes: (1) Two compounds inhibit streptococcal invasion by targeting a protein not known to be involved in this process so far. (2) Several compounds can serve as new inhibitors of plasmin(ogen) showing better inhibitory activity than known antifibrinolytics. Moreover, two of these compounds significantly prolonged survival in an in vivo skin infection model usually leading to systemic severity.
There is rising evidence that the new class of anti-infectives targeting virulence - the âpathoblockersâ -will be enriched by myxobacterial compounds and improve the therapy of diseases caused by S.pyogenes.Millionen Menschen weltweit sind von Krankheiten betroffen, die durch Streptokokken verursacht werden und bisweilen schwere Verlaufsformen aufweisen. LetalitĂ€tsraten von bis zu 30 % fĂŒr schwere VerlĂ€ufe und wiederkehrende Infektionen, die oft zu SpĂ€tkomplikationen wie der rheumatischen Herzkrankheit fĂŒhren, zeigen, dass die derzeitigen antibiotischen Möglichkeiten nicht ausreichen. Daher wird nun ein neuer Ansatz verfolgt: Diesem liegt die These zugrunde, dass das Angreifen an konservierten Virulenzmechanismen das Auftreten von Resistenzen vermeidet. FĂŒr diesen Ansatz werden so genannte âkleine MolekĂŒleâ benötigt. Myxobakterien haben sich als verlĂ€ssliche Produzenten solcher âkleinen MolekĂŒleâ erwiesen, wobei sie zudem oft neu chemische Grundstrukturen und neuartige Wirkmechanismen bieten.
Daher wurden myxobakterielle Extrakte und Substanzen auf ihre AktivitÀt in Bezug auf zwei Virulenzmechanismen von S.pyogenes untersucht: die Invasion in Epithelzellen und die Ausnutzung des menschlichen Plasmin(ogen)-Systems. Dabei wurden mikro-, zellbiologische und analytische Methoden kombiniert. Aktive Substanzen wurden mittels einer bioaktivitÀtsgeleiteten Isolierungsstrategie in Verbindung mit analytischen Methoden identifiziert.
Diese Arbeit zeigt, dass myxobakterielle Substanzen erfolgreich mit zwei Virulenzmechanismen von S.pyogenes interferieren können: (1) Zwei Substanzen hemmen die Invasion, indem sie an einem Protein angreifen, dessen Rolle in diesem Prozess bisher unbekannt war. (2) Mehrere Substanzen können als neue Hemmstoffe des Plasmin(ogen)s dienen und zeigen zudem eine bessere AktivitĂ€t als bisher bekannte Antifibrinolytika. Des Weiteren verlĂ€ngerten zwei dieser Substanzen signifikant das Ăberleben in einem Maus-Hautinfektionsmodell, welches (sonst) zu einer Sepsis fĂŒhrt.
Diese Ergebnisse zeigen, dass diese neue Klasse von Anti-Infektiva, die Virulenzmechanismen angreift - die âPathoblockerâ - durch die myxobakteriellen Substanzen bereichert und die Therapiemöglichkeiten von durch Streptokokken hervorgerufenen Krankheiten verbessern wird
All Roads Lead to Rome: Enhancing the Probability of Target Attainment with Different Pharmacokinetic/Pharmacodynamic Modelling Approaches
In light of rising antimicrobial resistance and a decreasing number of antibiotics with novel modes of action, it is of utmost importance to accelerate development of novel treatment options. One aspect of acceleration is to understand pharmacokinetics (PK) and pharmacodynamics (PD) of drugs and to assess the probability of target attainment (PTA). Several in vitro and in vivo methods are deployed to determine these parameters, such as time-kill-curves, hollow-fiber infection models or animal models. However, to date the use of in silico methods to predict PK/PD and PTA is increasing. Since there is not just one way to perform the in silico analysis, we embarked on reviewing for which indications and how PK and PK/PD models as well as PTA analysis has been used to contribute to the understanding of the PK and PD of a drug. Therefore, we examined four recent examples in more detail, namely ceftazidime-avibactam, omadacycline, gepotidacin and zoliflodacin as well as cefiderocol. Whereas the first two compound classes mainly relied on the âclassicalâ development path and PK/PD was only deployed after approval, cefiderocol highly profited from in silico techniques that led to its approval. Finally, this review shall highlight current developments and possibilities to accelerate drug development, especially for anti-infectives
Aerosolized delivery of ESKAPE pathogens for murine pneumonia models
Abstract Murine pneumonia models for ESKAPE pathogens serve to evaluate novel antibacterials or to investigate immunological responses. The majority of published models uses intranasal or to a limited extent the intratracheal instillation to challenge animals. In this study, we propose the aerosol delivery of pathogens using a nebulizer. Aerosol delivery typically results in homogeneous distribution of the inoculum in the lungs because of lower particle size. This is of particular importance when compounds are assessed for their pharmacokinetic and pharmacodynamic (PK/PD) relationships as it allows to conduct several analysis with the same sample material. Moreover, aerosol delivery has the advantage that it mimics the ânatural routeâ of respiratory infection. In this short and concise study, we show that aerosol delivery of pathogens resulted in a sustained bacterial burden in the neutropenic lung infection model for five pathogens tested, whereas it gave a similar result in immunocompetent mice for three out of five pathogens. Moreover, a substantial bacterial burden in the lungs was already achieved 2 h post inhalation. Hence, this study constitutes a viable alternative for intranasal administration and a refinement of murine pneumonia models for PK/PD assessments of novel antibacterial compounds allowing to study multiple readouts with the same sample material
CO2-Emissions From Personal Consumption of Goods and Services: Development and Validation of a Footprint Calculator
Lectin-Targeted Prodrugs Activated by Pseudomonas aeruginosa for Self-Destructive Antibiotic Release
Chronic Pseudomonas aeruginosa infections are characterized by biofilm formation, a major virulence factor of P. aeruginosa and cause of extensive drug resistance. Fluoroquinolones are effective antibiotics but are linked to severe side effects. The two extracellular P. aeruginosa-specific lectins LecA and LecB are key structural biofilm components and can be exploited for targeted drug delivery. In this work, several fluoroquinolones were conjugated to lectin probes by cleavable peptide linkers to yield lectin-targeted prodrugs. Mechanistically, these conjugates therefore remain non-toxic in the systemic distribution and will be activated to kill only once they have accumulated at the infection site. The synthesized prodrugs proved stable in the presence of host blood plasma and liver metabolism but rapidly released the antibiotic cargo in the presence of P. aeruginosa in a self-destructive manner in vitro. Furthermore, the prodrugs showed good absorption, distribution, metabolism, and elimination (ADME) properties and reduced toxicity in vitro, thus establishing the first lectin-targeted antibiotic prodrugs against P. aeruginosa