An international research group led by the Helmholtz Centre for Infection Research (HZI) has discovered a promising new drug candidate against severe lung infections caused by the hospital germ Staphylococcus aureus. The study, which has just been published in Cell Host & Microbe, describes for the first time how small molecules from the quinoxalinedione class specifically block the bacterial toxin α-hemolysin – a key trigger of tissue damage and inflammation.

Pneumonia caused by the bacterium Staphylococcus aureus is one of the most dangerous infections that can occur in hospital. Particularly worrying are multi-resistant strains, against which many antibiotics are no longer effective. These pathogens are widespread worldwide and pose a major challenge even for modern healthcare systems. Despite intensive therapy, mortality among affected patients is over 20 percent.

“Even with effective antibiotics, infections with Staphylococcus aureus are often difficult to treat,” says Prof. Mark Brönstrup, senior author of the study and head of the “Chemical Biology” department at the HZI. “Our novel strategy therefore does not attack the bacterium itself, but specifically neutralizes a toxin it produces. This opens up a new therapeutic perspective – especially for critically ill people at high risk.”

The new research approach is aimed at the targeted inhibition of the key virulence factor α-hemolysin. Hemolysin is a protein that forms pores in cell membranes in the lungs, leading to the destruction of lung tissue and immune cells, inflammation and ultimately to a worsening of the disease. The researchers developed a miniaturized test system that allowed them to screen over 180,000 compounds for their ability to block the effect of α-hemolysin. Drug candidates from the quinoxalinedione class, in particular the compound H052, proved to be highly effective, both in cell culture and in animal models.

“Our goal was to develop a small molecule that neutralizes the toxin before it causes damage – and that is exactly what the quinoxalindiones do,” says Dr. Aditya Shekhar, first author of the study. ”It was particularly impressive that we were not only able to protect cells, but also significantly improve survival in infected mice.”

In the mouse model, the active substance was able to increase the survival rate in the case of an acute lung infection with the highly virulent S. aureus USA300 strain, both when administered preventively or therapeutically. At the same time, inflammatory markers and the bacterial load in the lungs of immunocompetent mice were reduced. The combination of H052 with the antibiotic linezolid was also effective.

New approaches in the fight against antibiotic resistance

The concept of so-called “pathoblockers”, i.e. agents that target bacterial virulence mechanisms rather than the bacterium itself, is considered a promising approach. Since no selective pressure is exerted on the bacterium, the risk of development of resistance is significantly lower.

“Our results show that even large bacterial toxins can be specifically inhibited by small molecules – this opens doors for a completely new class of anti-infectives,” adds Shekhar. Thanks to good manufacturing options and tolerability, the drug candidate H052 could be used in particular as an infusion preparation in hospitals – for example to prevent severe pneumonia in high-risk patients.

The research was carried out mainly at the HZI in Braunschweig and as part of the German Center for Infection Research (DZIF) in close partnership with the Lead Discovery Center (LDC) in Dortmund. The research team received milestone-dependent funding of 4.9 million US dollars to date from the non-profit organization Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X); CARB-X has indicated that further funding may be provided through the end of Phase 1 of the clinical trial based on project progress.

Background: Responsible approach to animal testing

The animal experiments with mice used in this study were carried out in strict compliance with the applicable legal requirements and ethical standards. The aim was to generate meaningful data with as few animals as possible that could contribute to the development of new therapeutic options for seriously ill patients. The insights gained represent an important step towards developing animal-free models and clinical applications in the long term.

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About CARB-X:

The “Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator” (CARB-X) is a global, non-profit funding initiative of Boston University that aims to accelerate the development of innovative antibiotics and develop novel therapeutics, vaccines and diagnostics to combat drug-resistant bacterial infections. It supports companies and research institutions that are developing such products in the early phases up to clinical phase I. CARB-X focuses on the dangerous bacteria listed in the priority lists of the World Health Organization (WHO) and the US Centers for Disease Control and Prevention (CDC). Germany, represented by the Federal Ministry of Education and Research (BMBF), has been funding CARB-X since the beginning of 2019 and will continue to support the partnership with a further 40 million euros in the second funding phase starting in 2023. In total, CARB-X has invested approximately 400 million US dollars in 92 projects worldwide since its inception, supporting the largest and most innovative pipeline of preclinical and early-stage products against antibiotic-resistant infections in the world. The work of CARB-X and the portfolio companies it supports is supported by local accelerators. The German Center for Infection Research (DZIF) and its partners, the Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI), have established themselves as a CARB-X accelerator within the CARB-X Global Accelerator Network (CARB-X GAN).

https://carb-x.org/

The research described in this press release is supported by ASPR/BARDA Cooperative Agreement No. IDSEP160030 and by funding from the Wellcome Trust, the German Federal Ministry of Education and Research, and the UK Global Antimicrobial Resistance Innovation Fund (GAMRIF), managed by CARB-X. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response, any other funding body or CARB-X.

Helmholtz Centre for Infection Research:

Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig and its other sites in Germany are engaged in the study of bacterial and viral infections and the body’s defence mechanisms. They have a profound expertise in natural compound research and its exploitation as a valuable source for novel anti-infectives. As member of the Helmholtz Association and the German Center for Infection Research (DZIF) the HZI performs translational research laying the ground for the development of new treatments and vaccines against infectious diseases.

http://www.helmholtz-hzi.de/en

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Contact:
Susanne Thiele, Spokesperson
susanne.thiele@helmholtz-hzi.de
Dr Andreas Fischer, Editor
andreas.fischer@helmholtz-hzi.de

Helmholtz Centre for Infection Research
Press and Communications
Inhoffenstr. 7
D-38124 Braunschweig
Germany
Phone: +49 531 6181-1400; -1405

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As limited partners of KHAN-II, the European Investment Fund (EIF, Luxembourg), Akros Pharma Inc. (USA), the Max Planck Foundation (Germany), the Thyssen’sche Handelsgesellschaft (Germany), and KHAN-II Vermögensverwaltung committed in a first closing to invest a total of EUR 51 million for early-stage drug discovery investments. Khanu was established as general partner. An additional closing is planned this year to target a total of EUR 100 million.

Assets will be sourced predominantly from academia in Germany (such as Max Planck Institutes, among others) and Europe, focusing on innovative therapeutic opportunities in indications with high unmet medical need. Project investments will be made and executed at the Lead Discovery Center GmbH, Dortmund (LDC), a professional drug discovery and translational research incubator with a proven track record (www.lead-discovery.de). KHAN-II will also invest opportunistically into early-stage companies and spin-offs, providing structuring of the founding process if needed.

Very significantly – and building on the preferred partnership with the Max Planck Society (MPG) , Germany’s largest basic research organisation – KHAN-II has signed a co-investment agreement with MPG, adding EUR 18 million of co-funding for drug discovery projects originating from the world-class biomedical research of the Max Planck Institutes.

“Based on the first closing, we are now inviting other investors to meet KHAN-II’s target of EUR 100 million, for which an additional public commitment is already in place, to be matched with private capital. With their commitments, our trusted KHAN-II limited partners continuously contribute to the high-quality and successful performance of our powerful translational ecosystem. All of these financial efforts will accelerate our drug discovery and development ambitions to provide future medications for patients in need,” states Bert Klebl, Managing Director of Khanu and LDC. “We are highly motivated and excited that KHAN-II will enable the transfer of further promising early-stage drug discovery assets into translation, thereby creating new treatment options for patients,” adds Michael Hamacher, also Managing Director of Khanu and LDC.

“We are delighted to see the launch of KHAN-II, which builds upon the solid foundation laid by KHAN-I, and further strengthens the commitment to advancing early-stage drug discovery for the benefit of society and patients. This new fund will drive cutting-edge projects, particularly from the world-class research of the Max Planck Institutes, to bring transformative innovations closer to clinical application,” says Bram Wijlands, Managing Director of Max Planck Innovation, the technology transfer organization of the MPG.

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Contact: pr@lead-discovery.de (For KHAN-II)

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About KHAN Technology Transfer Fund II (KHAN-II) and Khanu Fondsverwaltung GmbH (Khanu)

KHAN Technology Transfer Fund II (KHAN-II) is an early-stage life sciences venture fund. Our mission is to create value through cooperative drug development partnerships with academic innovators in Europe. KHAN-II focuses on first-in-class therapies for attractive markets with a high unmet medical need. KHAN-II has unique access to cutting-edge scientific research at Max Planck and leading European academia. KHAN-II is managed by Khanu Fondsverwaltung GmbH, a world class drug discovery and fund team, having access to the state-of-the-art drug discovery incubator Lead Discovery Center GmbH, achieving an exceptional low attrition rate and effective investments.

For more information, please contact info@khanu.de

About the European Investment Fund (EIF)

The fund is supported by an investment from the EIF, with the support of:

• InvestEU Equity, with the financial backing of the European Union. InvestEU Fund supports private and public investments in four policy areas that represent important priorities for the Union and bring high EU added value: sustainable infrastructure; research, innovation and digitisation; small and medium-sized businesses; and social investment and skills.
• The ERP-EIF Facility, with the financial backing of the German Federal Government. The ERP-EIF Facility is a partnership between the German Federal Government and the EIF, managed by the EIF, providing venture and growth capital financing with a focus on high-tech early- and later-stage companies in Germany.

Further information available at:

InvestEU – European Union

The ERP-EIF Facility

About Max Planck Foundation

The Max Planck Foundation is a private, independent and non-profit organization with the sole purpose of providing funds for excellent, innovative and forward-looking research projects of the Max Planck Society. As additional support for scientists from the Max Planck Society the Foundation also facilitates the transfer from knowledge to application. The foundation was established in 2006 and the assets of the foundation are currently around EUR 725 million.

Further information available at: www.maxplanckfoundation.org

About Akros Pharma Inc.

Akros Pharma Inc. is a wholly owned subsidiary of JT America, which is, in turn, a wholly owned subsidiary of Japan Tobacco Inc., headquartered in Tokyo, Japan. Akros Pharma Inc. is recognized in the pharmaceutical industry for its innovative drug discovery and development. The company is committed to developing new pharmaceutical products for the U.S. and global markets.

Further information available at: www.akrospharma.com

About Thyssen’sche Handelsgesellschaft

Thyssen’sche Handelsgesellschaft (THG) is a German single-family office and a highly renowned investor with roots in the Julius Thyssen family. THG is located in Muelheim an der Ruhr, follows a long-term investment approach and owns a highly diversified set of portfolio companies in different industry segments.

About Lead Discovery Center

Lead Discovery Center GmbH (LDC) was established in 2008 by the technology transfer organization Max Planck Innovation, as a novel approach to capitalize on the potential of excellent basic research for the discovery of new therapies for diseases with high medical need. LDC takes on promising early-stage projects from academia and transforms them into innovative pharmaceutical leads and antibodies that reach initial proof-of-concept in animals as well as candidate nomination. In close collaboration with high-profile partners from research and industry, LDC is building a strong and growing portfolio of small molecule and antibody leads with exceptional medical and commercial potential.

LDC sustains a long-term partnership with the Max Planck Society as well as with the KHAN Technology Transfer Funds I + II. It has formed alliances with AstraZeneca, Bayer, Boehringer Ingelheim, Merck KGaA, Qurient, invIOS, Cumulus Oncology, Nodus Oncology, JT Pharmaceuticals, KinSea Lead Discovery AS, HLB Life Science, the Helmholtz Center for Infection Research, etc. In addition, LDC also works with leading translational drug discovery centres and with various investors to provide its assets for company creation.

Further information available at: www.lead-discovery.de

About Max Planck Innovation

Max Planck Innovation (MI) is responsible for the technology transfer of the Max Planck Society and, as such, the link between industry and basic research. With an interdisciplinary team, MI advises and supports scientists at Max Planck Institutes in evaluating their inventions, filing patents and founding companies. MI offers industry unique access to the innovations of the Max Planck Institutes. Thus, MI performs an important task: the transfer of basic research results into products that contribute to economic and social progress.

Further information available at: www.max-planck-innovation.com

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CasInvent Pharma, a university spin-off focused on developing anti-cancer compounds, has successfully closed the Pre-Series A funding round, raising a total of € 1.6 million from both existing and new investors. Founded in 2020 as a spin-off from Masaryk University in Brno and with the support of i&i Prague, CasInvent Pharma specializes in the development of highly selective inhibitors targeting the casein kinase 1 enzyme family. These enzymes play an important role in several disease-related processes, including the migration of leukaemia cells into lymphoid organs. The small-molecule inhibitors are designed to target individual isoforms of CK1 and thereby selectively eradicate leukemic cells.

„It’s gratifying to have convinced both new and existing partners to support our quest in developing effective treatment options and giving hope to patients suffering from these cancers with a very low survival rate,“ says Alexander Scheer, CEO of CasInvent Pharma. He believes these inhibitors have the potential to treat patients with conditions like acute myeloid leukaemia, pancreatic cancer, certain types of breast cancer (TNBC), and other diseases with limited treatment options.

„The company’s ability to attract new investors reaffirms not just the project’s quality, but also the combined expertise of the team at CasInvent Pharma,“ says Ivan Vohlmuth, a partner at i&i Bio. „The team has worked really hard over the past 18 months and achieved promising data in the development of their CK1 inhibitor portfolio. We are pleased to continue to support the company,“ add Michael Krebs and Peter Nussbaumer from KHAN-I.

Joining the investment round, alongside i&i Bio, KHAN-I and i&i Prague, are two new partners: the Holeček Family Foundation and BIOINVESTIMED a. s. „Supporting this innovative project allows us to participate in the important development of new treatment methods and therapeutic strategies in the field of oncological diseases. At the same time, we are impressed that a Czech entity has embarked on this difficult and financially demanding path. With our engagement, we would like to motivate other investors to fund promising life science companies in the Czech Republic,“ says Ondřej Novák, Director of the Holeček Family Foundation.

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About CasInvent Pharma
CasInvent Pharma is a drug discovery spin-off company established in 2020 by Masaryk University and Bio-Innovation Centre i&i Prague, s.r.o. (Ltd). The mission of the company is to develop new therapeutic options for the treatment of resistant tumours. The CasInvent platform is based on the use of proprietary, best-in-class, highly selective inhibitors of enzymes belonging to the casein kinase 1 (CK1) family that are responsible for the regulation of different cellular mechanisms leading to resistance to targeted therapies.
Further information available at: www.casinvent.com

About i&i Biotech Fund (i&i Bio)
i&i Bio is a Luxembourg-based venture capital firm that invests in innovative European life science companies focused on drug discovery, medical devices, diagnostics, and digital health. The Fund was created thanks to the cooperation of the biotech incubator i&i Prague and the European Investment Fund (see below). With over € 53 million under management, i&i Bio plans to invest in about 20 early-stage companies. i&i Bio is led by an experienced team of professionals with backgrounds in private equity, healthcare and venture capital, supporting entrepreneurs on their journey to global success. Thanks to close cooperation with the fund’s main sponsor, the biotech academic incubator i&i Prague, i&i Bio is supporting and advancing transformative Central European technology companies.
Further information available at: www.inibio.eu

About the European Investment Fund (EIF)
The Fund is supported by an investment from the EIF, with the support of

• lnnovFin Equity, with the financial backing of the European Union under Horizon 2020 Financial Instruments and the European Fund for Strategic Investments (EFSI) set up under the Investment Plan for Europe. The purpose of the EFSI is to help support financing and implementing productive investments in the European Union and to ensure increased access to financing; and
• the Pan-European Guarantee Fund (EGF), implemented by the EIF with the financial support of the Participating Member States. The objective of the EGF is to respond to the economic impact of the COVID-19 pandemic by ensuring that companies in the Participating Member States have sufficient short-term liquidity available to weather the crisis and can continue their growth and development in the medium to long term.

Further information available at: EIF to invest €25 million to support biomedical tech transfer in Central Europe

About KHAN-I
KHAN Technology Transfer Fund I GmbH & Co KG (KHAN-I) is an early-stage life sciences venture fund with € 70 million under management. Their mission is to create value through cooperative drug development partnerships with academic innovators in Europe. KHAN-I focuses on first-in-class therapies for attractive markets with a high unmet medical need. The fund is managed by Khanu Management GmbH, an experienced team of professionals with proven track records in early-stage
drug development and academic spin-offs as well as pharma licensing and partnering. KHAN-I received an investment from the European Investment Fund (EIF) with the support of InnovFin Equity, and with the financial backing of the European Union under Horizon 2020 Financial Instruments and the European Fund for Strategic Investments (EFSI) under the Investment Plan for Europe.
KHAN-I is also supported by Austria Wirtschaftsservice GmbH (AWS with funds provided by the Austrian Federal Ministry for Digital and Economic Affairs and the Austrian Foundation for Research, Technology, and Development), Max Planck Foundation, and Thyssen’sche Handelsgesellschaft mbH. In addition, KHAN-I sustains a preferred partnership with the Max Planck Society (Max-Planck-Gesellschaft e.V.).
Further information available at: www.khanu.de

About i&i Prague
i&i Prague focuses on the transfer of new technologies into practice. It was established at the Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences and is dedicated to innovations in the field of drug development, diagnostics and medical devices originating from academic institutions. It supports the creation of spin-off companies and the sale of licenses. So far, the company has participated in the creation of or otherwise supported 15 spin-off companies from 5 countries, has an equity stake in 9 of them and has invested over CZK 70 million. Overall, the spin-offs in i&i Prague’s portfolio have raised more than CZK 1.8 billion from other investors. In 2021, i&i Prague established the i&i Bio Investment Fund in cooperation with the European Investment Fund.
Further information available at: www.iniprague.com

Holeček Family Foundation
We support people with knowledge, experience and vision in areas we consider important for the development of our society. We provide support in the form of an open opportunity to receive funding from the Foundation and we leave it up to the beneficiaries to decide how to best use the support we grant. We would like to inspire others with our actions, because we believe that giving back to society brings value to us all.
Our main area of focus is the Czech educational system. Educated people are a prerequisite for the development of any society and there is therefore a close focus on educational projects in the Foundation’s activities. Good health is a prerequisite for a full and active life for all of us. Therefore, the quality of health care, social care and the health care system is also in the Foundation’s focus. Last but not least, the Foundation supports science and research projects as the main drivers of progress and development in any society. The Foundation mainly supports organisations such as universities or hospitals, which already have a strong potential in the fields mentioned above, but their funding does not always allow them to fully develop their potential. In addition to these main areas of focus, the Board of Trustees also looks at specific innovative projects with the potential of bringing new discoveries or practices.
Further information available at: www.holecekfoundation.cz

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Contact: pr@lead-discovery.de (for KHAN-I)

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Ian Waddell, CEO of Nodus Oncology said: “This is an exciting time for Nodus Oncology; this additional investment will help us to fast-track the development of our current DDR inhibitor programmes and grow our pipeline with exciting new first-in-class assets.”

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About Nodus Oncology
Nodus Oncology is a biotech company developing first- and best-in-class molecules focused on the DNA damage response (DDR) in patient sub-groups where molecular vulnerabilities exist. Founded by Cumulus Oncology, which contributes capital and oncology discovery as well as development expertise to the creation of new biotech companies, Nodus has received seed investment from both Cumulus Oncology and additional investors.
For more information visit: www.nodusoncology.com.

About KHAN-I
KHAN Technology Transfer Fund I GmbH & Co KG (KHAN-I) is an early-stage life sciences venture fund with € 70 million under management. Their mission is to create value through cooperative drug development partnerships with academic innovators in Europe. KHAN-I focuses on first-in-class therapies for attractive markets with a high unmet medical need. The fund is managed by Khanu Management GmbH, an experienced team of professionals with proven track records in early-stage drug development and academic spin-offs as well as pharma licensing and partnering. KHAN-I received an investment from the European Investment Fund (EIF) with the support of InnovFin Equity, and with the financial backing of the European Union under Horizon 2020 Financial Instruments and the European Fund for Strategic Investments (EFSI) under the Investment Plan for Europe. KHAN-I is also supported by Austria Wirtschaftsservice GmbH (AWS with funds provided by the Austrian Federal Ministry for Digital and Economic Affairs and the Austrian Foundation for Research, Technology, and Development), Max Planck Foundation, and Thyssen’sche Handelsgesellschaft mbH. In addition, KHAN-I sustains a preferred partnership with the Max Planck Society (Max-Planck-Gesellschaft e.V.).
For more information visit: www.khanu.de

About Cumulus Oncology
From securing pre-seed investment in 2020, Cumulus has continued to develop a capitally efficient business model. The company sources novel oncology assets from academic institutes, commercial drug discovery groups and biopharmaceutical companies. The Cumulus scientific and commercial team members identify novel targets for drug discovery programmes which the company funds, supports, and collaborates on. Following rigorous due diligence and market assessment activities, negotiations on deal terms and in-depth feasibility on the investment case, selected assets are spun out into newly created companies. An early focus on molecularly selected patient sub-groups, is a key aspect of the business model. The company incorporates the use of artificial intelligence (AI) and machine learning (ML) platforms into its decision-making process to prioritise targets and assets.
Cumulus contributes both early-stage capital and oncology drug development expertise and manages each spinout company to achieve key development milestones and value inflections. The companies created by Cumulus represent valuable investment opportunities for VCs that focus on the biotech sector. These VCs are important partners for Cumulus when the spinout companies reach key inflection points. The founding team at Cumulus consists of successful life science entrepreneurs, scientists and a range of oncology drug development and pharma sector business professionals.
Further information available at: www.cumulusoncology.com

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Contact: pr@lead-discovery.de (for KHAN-I)

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