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SpheroBiotics: Re-inventing antibiotic discovery from nature

English title SpheroBiotics: Re-inventing antibiotic discovery from nature
Applicant Schmitt Steven
Number 186286
Funding scheme Bridge - Proof of Concept
Research institution
Institution of higher education ETH Zurich - ETHZ
Main discipline Experimental Microbiology
Start/End 01.08.2019 - 31.10.2020
Approved amount 130'000.00
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Keywords (6)

novel antibiotics; high-throughput screening; nanoFleming; antimicrobial resistance; soil microbiome; microbial dark matter

Lay Summary (German)

Lead
Antibiotika sind Medikamente zur Behandlung von bakteriellen Infektionen. Unsere moderne Medizin wäre ohne Antibiotika unmöglich. Leider werden mehr und mehr bakterielle Krankheitserreger gegen die uns zur Verfügung stehenden Antibiotika resistent. Diese Resistenzen stellen mittlerweile eine ernstzunehmende Gefahr für unser Gesundheitssystem dar. Dieses Projekt hat sich zum Ziel gesetzt, neue und effektive Antibiotika zu entdecken und damit zum Kampf gegen Antibiotikaresistenz beizutragen.
Lay summary
Inhalt und Ziele des Forschungsprojekts
Die meisten unserer heute in den Krankenhäusern verfügbaren Antibiotika stammt von chemischen Substanzen, welche ursprünglich von Mikroorgansimen in der Natur produziert wurden (z.B. im Boden). Es ist allerdings nicht so einfach, diese zu entdecken. Gerade wirklich neuartige und gegen resistente Krankheitserreger effektive Antibiotika sind sehr selten. An der ETH Zürich haben wir eine Technologie entwickelt (der "nanoFleming") welche die Entdeckung von solch seltenen Substanzen wesentlich vereinfacht. Der nanoFleming erlaubt es, Mikroorganismen in ihrem natürlichen Umfeld wachsen zu lassen und sie im gleichen Prozess zu auf die Produktion von neuartigen Antibiotika hin zu untersuchen. Dies bedeutet eine wesentliche Verbesserung und Vereinfachung gegenüber herkömmlichen Entdeckungsprozessen. Im Verlaufe des Projektes werden die entdeckten Antibiotikakandidaten dann weiter charakterisiert und auf ihre Eignung als Medikament hin untersucht, um sie schliesslich der Medikamentenentwicklung zuzuführen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts
Dieses Projekt konzentriert sich auf Antibiotikaentdeckung, ein Bereich der traditionell mit einigen Schwierigkeiten zu kämpfen hat, die mit der nanoFleming Technologie gelöst werden können. Die Erforschung der «dunklen Materie» der natürlichen Mikroorganismen bietet das Potential zur effizienten Bekämpfung der immer problematischer werdenden Antibiotikaresistenzkrise. Die während des Projekts entdeckten Antibiotikakandidaten legen den Grundstein für die Gründung eines Startups mit dem Ziel, diese Substanzen für eine Anwendung im Menschen weiterzuentwickeln.

Resultate des Projekts
Als erstes haben wir die Kultivierung von Mikroorganismen aus dem Erdreich in ihrer natürlichen Umgebung forciert. Dazu entwickelten wir einen Inkubator, welcher es erlaubt, Mikroorgansimen direkt im Erdreich zu kultivieren. Damit können wir wesentlich mehr Mikroorgansimen untersuchen, als dies im Labor möglich ist. Der Inkubator wurde zum Patent angemeldet.
Als nächstes haben wir die Plattform so weiterentwickelt, dass wir die Mikroorgansimen auf Produktion eines Antibiotikums hin testen können. Wir haben dazu neben den natürlichen Mikroorganismen einen bakteriellen Krankheitserreger integriert um so die Interaktion zwischen Millionen von Bodenbakterien und den Krankheitserregern zu beobachten. Wird ein Krankheitserreger von einem Bodenbakterium getötet, so deutet dies auf die Produktion eines Antibiotikums hin. Im Laufe des Projekts haben wir verschiedene Mikroorganismen isoliert, welche antibiotische Substanzen produzieren.
Weiter wurde die Plattform dann in Richtung anderer Habitate ausgeweitet. Eine zunehmend interessante Nische ist dabei das menschliche Mikrobiom. Wir haben erfolgreich Mikroben aus der Mundflora in den nanoFleming eingebettet und die Interaktion zwischen diesen und den Krankheitserregern untersucht.
Direct link to Lay Summary Last update: 24.01.2021

Lay Summary (English)

Lead
Without antibiotic drugs to treat bacterial infections, modern medicine would not exist. However, human pathogens are becoming increasingly resistant to commonly used antibiotics. Moreover, hardly any novel drugs were developed during recent years, which puts our entire healthcare system in peril. This project will contribute to fighting the antimicrobial resistance crisis by providing novel and effective antibiotics.
Lay summary
Content and goals of the project
Chemical substances produced by microorganisms found in nature (e.g., in the soil) have been a valuable source for most of the antibiotics we use in our clinics today. However, truly novel antibiotics that work despite common resistance mechanisms are rare and very hard to find. At ETH Zürich, we have developed a technology (the “nanoFleming”) that allows for the efficient discovery of such scarce, potent antibiotics. The nanoFleming will be used to analyze millions of soil microorganisms for their ability to eliminate antibiotic-resistant pathogens. The nanoFleming makes it possible to grow potential antibiotic producers in their natural environment and provides a shortcut to the antibiotic testing step, a traditionally lengthy and laborious process. During the project, discovered antibiotic candidates will be characterized and their suitability as drugs will be evaluated to afterward feed them into the drug development pipelines of the pharmaceutical industry.

Scientific and societal context of the project
This project focuses on antibiotic drug discovery from natural microorganisms, a discipline that traditionally suffers from several shortcomings, which will be addressed with the technical innovations of the nanoFleming. Exploring the still largely undiscovered and hard to access “dark matter” of nature’s microorganisms will provide solutions to the growing antibiotic resistance crisis. The antibiotic lead molecules derived from this project will lay the foundation for the incorporation of a startup company to develop them further toward their use for human treatment.

Results of the project

Initially, we focused on the cultivation of soil microorganisms in their natural habitat. For this, we developed a special incubator that let us cultivate microorganisms within the nanoFleming and directly in the soil. Using this method, we have access to a tremendously increased number of microorganisms compared to classic laboratory methods. We have applied for a patent protecting the incubator.
Next, the platform was developed further, to test if the microorganisms produce an antibiotic substance. For this, we co-embedded microbial pathogens together with soil microbes and cultivated them within the platform. Using this combination, we are able to probe the interaction between millions of soil microorganism and the pathogens in details. The killing of a pathogen by a soil bacterium indicates the production of an antibiotic substance. In the course of the project, we are able to isolate several microorganisms, that produce an antimicrobial substance.
Furthermore, we wanted to expand the platform towards other natural microbial communities. One resource of increasing interest is the human microbiome. We could successfully integrate microorganisms from the human oral flora into the nanoFleming platform and were able to investigate the interaction between those bacteria and human pathogens.
Direct link to Lay Summary Last update: 24.01.2021

Responsible applicant and co-applicants

Employees

Awards

Title Year
DECHEMA Posterpreis 2020 2020

Use-inspired outputs


Start-ups

Name Year
PepChat 2021

Abstract

Antibiotics, the foundation drugs on which modern medicine relies, are becoming increasingly ineffective as pathogens acquire resistance mechanisms. There is a severe shortage of novel drugs in the discovery and development pipeline, especially against multidrug-resistant (MDR) Gram-negative pathogens. Molecules displaying a truly novel mode of action are urgently needed, and highly valuable. Nature has been the most important source for such novel molecules in the past, but the low-hanging fruits were harvested and discovery is more and more difficult and laborious. I propose a solution to tap the still vastly unexplored treasure trove of nature’s microbial communities, to restock the antibiotics pipeline with highly effective and highly valuable novel compounds that will cure untreatable infections. During my PhD thesis I devised and built the ‘nanoFleming’: a microsphere-based technology that enables discovery of novel antibiotics at an unprecedented rate (>10E6 per batch). It allows for the miniaturized and highly parallelized growth of putative bacterial antibiotic producers, the concomitant testing of their secreted molecules against bacterial pathogens of choice, and the isolation of living producer colonies. In its first iteration, the nanoFleming has allowed me to isolate over 100 novel antimicrobial peptides. In a next step, the nanoFleming is currently being adapted to the discovery of novel antibiotic classes from soil microbiomes. The robust microspheres are suited to cultivation of previously inaccessible bacteria and for enrichment of slow-growing and rare strains. Combined with a smart selection of targets (antibiotic resistant clinical isolates and bioengineered strains), the technology will provide the necessary critical improvements in the rate of discovery of new antimicrobial lead compounds. These efforts are enabled by an ETH Pioneer fellowship. However, their completion will not be sufficient to cross the large gap toward ability to secure customers/industrial development partners and investors. To convincingly demonstrate the power of the nanoFleming, the platform needs to reliably provide novel antimicrobial lead compounds. This I plan to achieve with the here proposed BRIDGE Proof of Concept project. To this end, I will run large scale discovery campaigns from soil microbiomes against drug-resistant target human pathogens, isolate promising drug candidates, and advance at least one of them to pre-clinical testing. My goal is to take the project to the implementation of the first in vivo tests in a mouse model. The expected outcome is an up and running nanoFleming platform tuned to natural product drug discovery, which has yielded the first promising candidate compounds. Furthermore, I intend to adapt the nanoFleming for screening campaigns in human microbiomes. Therewith I expect to uncover the first commensal microbial defender strains to pave the way for microbiome therapy applications. Microbiome therapies are a future new medical treatment paradigm, and complement the fight against antibiotic resistance.
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