CV

• Research focus

Reduced antibiotic efficacy against infections has broad health, social and economic impacts, including severely constrained therapy options for people undergoing state of the art medical procedures. For more than 30 years, I have been developing a new type of antimicrobial drug paradigm that can mitigate the impact of antimicrobial resistance on the prevailing antibiotic therapies.

• EDUCATION

1983  Master of Cell Biology (Cand. Scient), University of Southern Denmark

1988  PhD in Microbiology, University of Copenhagen (UCPH), Denmark

2006  Doctor of Technical Sciences (Dr. Techn)Technical University of Denmark (DTU)

• CURRENT POSITION(S)

2008 – Present    Professor of Biomedical Microbiology ISIM, UCPH, Denmark

2013 – Present   Managing Director and Founder, Costerton Biofilm Center, UCPH, Denmark

2020 – Present    Consultant for SCELSE, Singapore

• PREVIOUS POSITIONS

1984-1988    Scientific Assistant – PhD student Dept. of Microbiology, DTU, Denmark

1989-1995    Post-Doc, Dept. of Microbiology, DTU, Denmark

1996-2004    Associate Professor of Microbiology, Dept. of Microbiology, DTU, Denmark

2002-2006    Vice-president and Founder QSI-Pharma A/S, a DTU - LEOPharma spin-out

2003-2008    Head of Center of Biomedical Microbiology, BioCentrum, DTU, Denmark

2004-2008    Professor of Biomedical Microbiology, BioCentrum, DTU, Denmark

2009-2014    Director, DSF Center for Antimicrobial Research, ISIM, SUND, UCPH, Denmark

2011-2020    Research Director and co-founder, Singapore Centre of Environmental Life Science (SCELSE), Nanyang Technological University (NTU), Singapore

• SCIENTIFIC PUBLICATIONS

Total number of peer-reviewed publications: 306 (PubMed)

Total number of publications (incl. patents): 480 (Google Scholar)

Number of citations:  Total 60.500  Annual 3.900

H-index: 126

Complete publication lists: https://scholar.google.dk/citations?hl=en&user=lrRJ1moAAAAJ&view_op=list_works&sortby=pubdate

https://pubmed.ncbi.nlm.nih.gov/?term=Givskov+M&timeline=expanded&sort=date

Rankings:

I am among the World's Top 2% Scientists and rank as 8^th  best Scientist in University of Copenhagen https://www.adscientificindex.com/university/University+of+Copenhagen/

https://www.adscientificindex.com/scientist/michael-givskov/1522784

SELECTED PUBLICATIONS

1. A genetic switch controls Pseudomonas aeruginosa surface colonization. Manner C, Teixeira R, Saha D, Kaczmarczyk A, Zemp R, Wyss F, Jaeger T, Laventie BJ, BoyerS, Malone J, Qvortrup K, Andersen JB, Givskov M, Tolker-Nielsen T, Hiller S, Drescher K, Jenal U. Publication spring 2023 Nature Microbiol., IF 30.9
2. Identification of small molecules that interfere with c-di-GMP signaling and induce dispersal of Pseudomonas aeruginosabiofilms Andersen JB, Hultqvist LD, Jansen CU, Jakobsen TH, Nilsson M,  Rybtke M, Uhd J, Fritz BG, Seifert R, Berthelsen J, Nielsen TE, Qvortrup K,  Givskov M, Tolker-Nielsen T. Nature Biofilms Microbiomes. 2021 7(1)59. 8 https://doi.org/10.1038/s41522-021-00225-4   IF 8.5
3. Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma. Lindahl LM, Willerslev-Olsen A, Gjerdrum LMR, Nielsen PR, Blümel E, Rittig AH, Celis P, Herpers B, Becker JC, Stausbøl-Grøn B, Wasik MA, Gluud M, Fredholm S, Buus TB, Johansen C, Nastasi C, Peiffer L, Kubat L, Bzorek M, Eriksen JO, Kejsgaard T, Bonefeld CM, Geisler C, Mustelin T, Langhoff E, Givskov M, Woetmann A, Kilian M, Litman T, Iversen L, Odum N. 2019 Sep 26;134(13):1072-1083. doi: 10.1182/blood.2018888107. IF 25.7
4. Small Molecule Anti-biofilm Agents Developed on the Basis of Mechanistic Understanding of Biofilm Formation. Qvortrup K, Hultqvist LD, Nilsson M, Jakobsen TH, Jansen CU, Uhd J, Andersen JB, Nielsen TE, Givskov M, Tolker-Nielsen T. Front Chem. 2019 Nov 1;7:742. doi: 10.3389/fchem.2019.00742. eCollection 2019.PMID: 31737611. IF 5.5
5. Reactivity and Synthetic Applications of Multicomponent Petasis Reactions. Wu P, Givskov M, Nielsen TE. Chem Rev. 2019 Oct 23;119(20):11245-11290. doi: 10.1021/acs.chemrev.9b00214. Epub 2019 Aug 27.PMID: 31454230 IF 60.6
6. Metagenomic and metatranscriptomic analysis of saliva reveals disease-associated microbiota in patients with periodontitis and dental caries. Belstrøm D, Constancias F, Liu Y, Yang L, Drautz-Moses DI, Schuster SC, Kohli GS, Jakobsen TH, Holmstrup P, Givskov M. Nature Biofilms Microbiomes. 2017 Oct 2;3:23. doi: 10.1038/s41522-017-0031-4. eCollection 2017.PMID: 28979798 IF 8.5
7. Detection of Pathogenic Biofilms with Bacterial Amyloid Targeting Fluorescent Probe, CDy11. Kim JY, Sahu S, Yau YH, Wang X, Shochat SG, Nielsen PH, Dueholm MS, Otzen DE, Lee J, Delos Santos MM, Yam JK, Kang NY, Park SJ, Kwon H, Seviour T, Yang L, Givskov M, Chang YT. J Am Chem Soc. 2016 Jan 13;138(1):402-7. doi: 10.1021/jacs.5b11357. Epub 2016 Jan 4.PMID: 26684612 4
8. In silico analyses of metagenomes from human atherosclerotic plaque samples. Mitra S, Drautz-Moses DI, Alhede M, Maw MT, Liu Y, Purbojati RW, Yap ZH, Kushwaha KK, Gheorghe AG, Bjarnsholt T, Hansen GM, Sillesen HH, Hougen HP, Hansen PR, Yang L, Tolker-Nielsen T, Schuster SC, Givskov M.  Microbiome. 2015 Sep 3;3:38. doi: 10.1186/s40168-015-0100-y.PMID: 26334731  IF 14.4
9. Dispersed cells represent a distinct stage in the transition from bacterial biofilm to planktonic lifestyles. Chua SL, Liu Y, Yam JK, Chen Y, Vejborg RM, Tan BG, Kjelleberg S, Tolker-Nielsen T, Givskov M, Yang L. Nat Commun. 2014 Jul 21;5:4462. doi: 0.1038/ncomms5462.PMID: 25042103 IF 18
10. First case of E anophelis outbreak in an intensive-care unit. Teo J, Tan SY, Tay M, Ding Y, Kjelleberg S, Givskov M, Lin RT, Yang L. 2013 Sep 7;382(9895):855-6. doi: 10.1016/S0140-6736(13)61858-9. PMID: 24012265  IF 203

• Competitive grants AND AWARDS

While at DTU             S:  69.4 mill DKK

1. Involvement of cell-cell communication in the pathogenesis of chronic Pseudomonas aeruginosa lung infection in cystic fibrosis. Supported by SSVF with 5 mill DKK, 01-Aug-1997 to 01-Aug-2000. PI: M. Givskov.
2. Involvement of cell-cell communication in the pathogenesis of chronic Pseudomonas aeruginosa lung infection in cystic fibrosis. PI: M. Givskov. A DTU PhD grant 2 mill DKK.
3. Involvement of cell-cell communication systems in coordinated behavior of bacteria. PI: M. Givskov. Supported by SSVF with 36 mill DKK, 01-Jan-1997 31-Dec-1999.
4. Role of bacterial cell-to-cell communication in food quality deterioration and food quality preservation. Financed by STVF with 2 mill DKK, 01-Jul-1997 to 01-Jul-2001.
5. Impact of small molecule mediated cell-cell communication on the efficacy of inoculant bacteria in the rhizosphere. Financed by EU with 4 mill DKK, 01-Sep-1996 to 31-Aug-1999.
6. Effect of manure spreading on horizontal transmission of bacterial resistance genes. 2 mill DKK financed by the Ministry for Food and Agriculture for a PhD grant.
7. Molecular analysis and characterization of pH and stationary phase inducible promoters from Lactococcus lactis. PhD grant, 2 mill DKK financed by ATV.
8. Cell communication and food deterioration, financed by STVF 2 mill DKK. Jan-2000 to 31-Dec-2002. PI's Lone gram and Givskov
9. A new approach to the control of microbial activity. PI: M. Givskov. Financed by STVF with 5 mill DKK (five-year frame program, prolongation for three additional years optional) from 01-Jan-2001 to 31-Dec-2005.
10. A new approach to the control of microbial activity. PI: M. Givskov. Financed by The Villum-Kann Rasmussen Foundation 5 mill DKK., 01-May-2001 to 01-Oct-2004.
11. Pseudomonas: pathogenicity and biotechnology. European elite PhD school denoted "Pseudomonas: pathogenicity and biotechnology" granted by Deutsche Forshungsgemeinshaft and the Danish Research Council to Givskov, Molin and Hoiby. 01-Jan-2001 to 31-Dec-2003. PhD grant to Givskov 2 mill DKK.
12. Leo-incubator finances the establishment of QSI-Pharma Spin out for the design of novel, anti-microbial drugs: 14 mill DKK plus free administrative support. Jan-2002 to 01-Oct-2005.
13. Center for elimination of biofilms on medical equipment. Jan-2004 to 31-Dec-2006. Innovation consortium in collaboration with The Technological Institute, The University of Aalborg, Coloplast Research A/S, Egalet A/S, Melitek A/S, PBN Medicals A/S and Radiometer Medical A/S. Givskov part 5 mill DKK.
14. Drug hunting at the Great Barrier Reef, PI Givskov, fieldwork 15 mill DKK support from private foundations, August 2004.
15. Microbial opportunistic Pathogens; a severe problem to human health. Danish Research Center. 25 mill DKK Jan-2004 to 31-Dec-2007. PI Søren Molin CBM, BioCentrum (DTU). Members: Michael Givskov, CBM, BioCentrum (DTU), Lone Gram Danish Institute for Fisheries Research (DFU), Niels Høiby, Rigshospitalet (RH), Hanne Ingmer, Dept of Veterinary Microbiology (KVL), Per Klemm, BioCentrum (DTU), Karen A. DKKogfelt, Statens Serum Institut(SSI) & CBM BioCentrum (DTU), Niels B. Larsen, The Danish Polymer Centre (RISØ), Tim Tolker-Nielsen, CBM, BioCentrum (DTU),Bjarke B. Christensen, Danish Food Administration (IFSE). Givskov part 7 mill DKK.
16. Garlic derived antimicrobials for treatment of CF patients. Marts-2006 to April-2008. PI Givskov. Supported by The German Mukoviszidose ev with 6 mill DKK.
17. Confocal microscope 2006. PI Givskov. Danish Research Council FNU 2 mill DKK.
18. 2006 Res. Collab. grant from Mölnlycke Health Care to PI Givskov 1 mill DKK.
19. Bacterial infections on implants and in the lungs of experimental animals. October 2006 to June 2007. Grant from UNSW Sydney to PI Givskov 35 mill DKK.
20. Food constituents and impact on chronic infections. Jan-2007 to Jan-2011. PI Givskov. Supported by the Danish Strategic Research Council (Food and Health) with 14 mill DKK.
21. Discovery of marine bioactive bacteria and natural products and their use to promote human health and safety. Supported by the Danish Strategic Research Council (Food and Health) with 13.9 mill DKK and the Lundbeck foundation with 1.5 mill DKK. Jan-2008 to Jan-2012. PI Lone Gram. Givskov part 7 mill DKK.           

While at UCPH      S:  76.4 mill DKK 

1. FTP 2009-2012:  5 mill DKK. Computer-based development of anti-pathogenic drugs.
2. DSF 2009-2015: 29 mill DKK Center for Antimicrobial Research.
3. Villum-Kann Rasmussen Foundation 2010-2013: 7 mill DKK.  Biofilms a common course of Chronic   infections.
4. Novoseed 2011-2015: 0 mill DKK. Biofilm 1: Identification of compounds that inhibit c-di-GMP synthesis in Pseudomonas aeruginosa. 
5. Kemira 2013-2017: 8 mill DKK Research collab. Development of biofilm controlling chemistry to prevent biofilm formation in paper manufacturing machines.
6. FNU 2013-2016:  3 mill DKK. Danish Council for Independent Research.  Mechanisms involved in bacterial biofilm formation and antimicrobial tolerance.
7. Lundbeck Foundation 2016-2021: 10 mill DKK. Identification of antimicrobials that can dismantle biofilms
8. FTP 2016-2019: 9 mill DKK.  Danish Council for Independent Research. Antimicrobials designed to dismantle antibiotic resistant biofilms.
9. Research and Innovation Fund 2017-2022: 3 mill DKK. DK-Openscreen
10. Novoseed 2018-2021: 5 mill DKK. Biofilm 2: A procedure to dismantle and eradicate bacterial biofilms.
11. Cystic Fibrosis Trust UK 2021: 25 mill DKK. Co-therapy of a novel P. aeruginosa biofilm disruptor with standard of care antibiotics
12. Innoexplorer 2021: 5 mill DKK. A drug for biofilm dissolution and clearance
13. Sygeforsikring (Health Insurance) Danmark 2022-2024: 62 mill DKK. High-potency solution against biofilms – expanding the global arsenal against antibiotic resistance.

1. While in Singapore (on a part-time contract approved by UCPH and NTU) S:  ~  100 mill DKK 

In 2010, Co-recipient (with 4 other applicants incl. PI Prof. Staffan Kjelleberg) of a 150 mill SGD SCELSE 10 years grant + 5 years extension 50 mill SGD from the Singaporean National Research Council (SCELSE core-funding 200 mill SGD ~ 1 billion DKK). SCELSE became organized as four scientific Clusters.  My Cluster (operational for 10 years) was financed with ~ 2 mill SGD annually as core funding.

2004 Statoil research award 0.1 mill DKK

2014 Kirsten and Freddy Johansen’s Medical Science & Preclinical Research Award 1.5 mill DKK

• SUPERVISION

Postdocs and A/Profs (no track record available), PhD’s 29, Master Students 38.

• INSTITUTIONAL RESPONSIBILITIES

2001 –  2006      Member of the faculty board, Biocentrum DTU, Denmark

2003 – 2008    Head of Centre of Biomedical Microbiology, BioCentrum, DTU, Denmark

2005 – 2008      Member of the Academic Advisory Board, DTU, Denmark

2011 – 2021      Member of the Directorate, SCELSE, NTU, Singapore

2013 – Present   Head of Costerton Biofilm Center, ISIM, UCPH, Denmark

• REVIEWING ACTIVITIES

1996 – 2000  Consultant for GX Biosystems A/S, Denmark

2003 – 2006  Member of the editorial board of Applied and Environmental Microbiology, USA

2000 – 2008  Consultant for Biosignal Pty. ltd., Australia

2017 – 2020  Member of the Scientific Advisory Board, Neem Biotech

• MAJOR COLLABORATIONS

Major Domestic Partners (presently)

Prof. Tim Tolker-Nielsen and his team at CBC :: Assoc. Prof. Katrin Qvortrup and her team at the Chemical Biology Group at DTU :: Prof. Claus Moser and his team at CBC and the Clinical Microbiology Department Rigshospitalet :: Assoc. Prof. Daniel Midjord-Belstrøm at Department of Odontology :: Prof. Klaus Qvortrup Core Facility for Integrated Microscopy Department of Biomedical Sciences.

Major International partners (presently)

Prof Urs Jenal, Biocentrum, University of Basel, Switzerland :: Prof Alain Filloux, Director of SCELSE, Singapore :: Dr Florentin Constancias, Department of Health Sciences and Technology, ETH Zürich, Switzerland :: Prof Roland Seifert, Hannover Medical School, Germany :: Prof Liang Yang, (former SCELSE) presently Southern University of Science and Technology, Shenzhen, China :: Prof Paul Williams, University of Nottingham, United Kingdom :: Prof Leo Eberl, University of Zürich, Switzerland

• INNOVATION AND OUTREACH

TV documentaries (selected few)

Viden om TV DR2. - Bakteriekrigen i kroppen. 24 februar 2009 :: Urt. SVTV1. Hvidløgs helbredende virkning Juli 2007 :: Viden om TV DR2. Skræddersyet medicin Oktober 2006 :: Dags Dato TV2 Søndag Afløseren for pennicillin. 20-03-2005 :: Viden om TV DR2 Antibiotika resitens. 15-10- 2005 :: TV2 News. Garlic., top story 12-06-2004 :: BBC World Service News Programme Feb 2002

Patents (selection of most important)

DK-606085-D0, DK-210085-D0 and US-5173418-A, (1985)  Production in Escherichia coli of extracellular Serratia spp. hydrolases ,"Benzon Pharma, A/S","Soren Molin, Michael Givskov, Erik Riise” Research collaboration between Benzon Pharma and the Molin lab. One of the enzymes went into production in mid-nineties and is sold as Benzonase® Nuclease by Merck. As an inventor, I received royalty payments for 15 years. This invention was part of my PhD Thesis.

EP-0635061-B1 (1992) A method of limiting the survival of genetically engineered microorganisms in their environment. GX BioSystems A/S, Soren Molin, Michael Givskov et al.  The spin out GX Biosystems A/S owned the invention. I was engaged as a consultant for several years.

AU-708962-B2, US-6555356-B2 (1995) Methods for microbial regulation, Unisearch Limited,"Michael Givskov, Staffan Kjelleberg et al. The spin out Biosignal Pty Ltd was formed 1999 in Australia out of this invention. I was engaged as a consultant for the following 10 years.

WO-03106445-A1 (2002) Compounds and methods for controlling bacterial virulence. Qsi Pharma A/S,"John Nielsen, Michael Givskov. Based on the patent and underlying research, Leo Incubator financed formation of the spin-out Qsi Pharma A/S at DTU. QSI Pharma CVR-26444071 was owned by LEO Pharma (85%) and DTU (15%) and dissolved 2013. My position was as Vice-director until LEO in 2007 terminated the company.

US-10603289-B2 (2010) Process for the manufacture of ajoene derivatives. “Givskov et al”. The patent was licensed to Neem Biotech UK, a subsidiary of Zaluvida (https://www.zaluvida.com/human-health/). From 2015 on, I worked with Neem Biotech (in particular Medical Director Michael Graz) to develop Ajoene, a small anti-microbial molecule from garlic that was able to achieve US FDA Orphan Drug Designation for the treatment of Pseudomonas and Staph biofilm-infections in Cystic Fibrosis patients.  I functioned as a consultant and member of the advisory board. License agreement with UCPH and DTU. Dr Graz is now involved in the Disperazol project.

Patent: US-20210127677-A1 (2018, 2020) Method for controlling growth of microorganisms and/or biofilms in an industrial process "Kemira Oyj, UCPH ","Jaakko Simell, Marko Kolari, Michael Givskov, et al. Translation of an Environmental Biofilm Biology project which started as a collaboration project with Kemira in 2013 aiming at chemical biofilm control in paper manufacturing processes. The compound B11, that we identified with our Chemical Biology Platform, has performed extremely well in industrial test settings and we are currently collaborating with Kemira to identify the molecular target and MoA. This is required for regulatory purposes aiming at approval for usage and market introduction of this “environmentally greener solution”. Kemira has presently established a worldwide IPR protection and has signed a license agreement with UCPH. Givskov M, Tolker Nielsen T, Andersen JB.

Patent application: WO 2022/043503 A1 Jurisdictions: Application No: 2021073753 Filed: Aug 27, 2021 Published: Mar 3, 2022, entering National Phase spring 2023. Earliest Priority: Aug 27, 2020. Owned by UCPH and DTU. Givskov and Tolker-Nielsen are the main inventors who started the project in 2010. The invention relates to c-di-GMP lowering chemical compounds having anti-biofilm properties. In particular, anti-biofilm compounds or salts or tautomers thereof for use in treatment and/or prevention of bacterial biofilm infection in human subjects caused by biofilm-forming bacteria of the genus Pseudomonas. The name Disperazol is protected. The majority of the funding I attracted with affiliation UCPH has financed the development of Disperazol. The formation of a new spin-out company “Disperazol” is pending, refer to https://www.disperazol.dk/. Currently interacting with Boehringer Ingelheim Venture Fund with the aim of raising up to 10 mill EURO (in dilutive funding) to progress through Clinical one phase and develop similar assets to control other ESKAPE pathogens.

Full patent / patent application list available at

https://www.lens.org/lens/search/patent/list?q=michael%20givskov&p=0&n=10&s=_score&d=%2B&f=false&e=false&l=en&authorField=author&dateFilterField=publishedDate&orderBy=%2B_score&presentation=false&preview=true&stemmed=true&useAuthorId=false&inventor.must=GIVSKOV%20MICHAEL

Primære forskningsområder

Good health is a key factor of our life and we live with an increasing life expectancy. Despite technological and medical progression, life threatening infections are returning as a serious threat even in well developed countries like Denmark and the societal costs of infectious diseases are considerable. Over the next decades our society will go through changes that greatly affect our sensitivity to microbial pathogens where the most pronounced will be the increase in elderly, immuno-compromised and hospitalized people. Such citizens are susceptible to chronic infections caused by well known bacteria such as Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. In Denmark, ~100.000 hospitalized patients acquire infections, often in connection with the use of medical devises such as arteriovenous shunts, pacemakers, urinary and other types of catheters, orthopedic devices and mechanical heart valves with an estimated 200-300 annual fatalities. Skin ulcers that develop into chronic wounds are also a significant and partly neglected problem, which affects patients with impaired blood circulation in particular diabetes patients. It is assumed that ~ 50.000 patients suffer from wounds that require special treatment and medical attention because of bacterial infections. This is an important socioeconomic burden, which includes patient suffering, lost employment and reduced life quality. The problem is growing in pace with the increasing emergence of multidrug-resistant bacteria.

In the golden age of antibiotics discovery, potent antibiotics such as penicillin, tetracycline, and vancomycin were discovered and brought to the clinic during the 1940s-1950s. These medicines have saved millions of lives but the backside of the coin is that they by their mode of action (killing the bacteria) strongly promote development of resistant bacterial variants, which rapidly outmatch the original sensitive strains. Infectious diseases that were once treatable with antibiotics will with time become incurable. In order to identify new antimicrobial drug targets, it is imperative to broaden our understanding of the molecular basis of infection, rather than just going in for the kill.

My working hypothesis is the following. The biofilm lifestyle dominates in the above mentioned chronic bacterial infections. Consequently, they share similar characteristics; they tolerate the highest deliverable doses of antibiotics and resist the action of the immune system as well as controlling the infectious process by cell-to-cell communication and internal signal transmission.

Biofilms are agglomerates of microorganisms surrounded by a self-produced extracellular matrix. For example, in the biofilm mode, P. aeruginosa uses "quorum sensing" communication to inform its fellow bacteria that it is time to launch a shield against attaching white blood cells. However, quorum sensing is only the tip of the iceberg of factors governing control over progression of the infectious processes which suggests multiple targets for efficient disease control. In the present project, I intend to generate information about genes at play during infection with particular emphasis on those that are differentially expressed in the biofilm state. Based on this, new anti-biofilm measures can be identified which efficiently decrease the biofilm forming capability or persistence of the infectious bacteria.

So far the majority of biofilm research has been carried out by means of in vitro systems. Much important information regarding gene expression, organization, structural development, antibiotic tolerance and interaction with neutrophiles (PMNs) has been generated this way (see for example refs 95*, 101*, 117*, 124*, 145*). Available data does not support the presence of a unique biofilm program i.e. a collection of genes that is expressed during development and maturation of biofilms (ref 124*).  However, transcending traditional biofilm research into in vivo conditions for example by use of the implant model recently developed by my research team (ref 148*) in combination with transcriptomics will likely promote the discovery new bacterial genes and key proteins. Focus will be on those that are involved in the control mechanisms of the infectious processes. The classical approach is bacterial genetics which employs mutations to perturb the function of gene products. I will also follow a complementary approach, namely "chemical genetics", which uses libraries of natural and synthetic small molecules to perturb expression and function of gene products. My ongoing collaboration with organic and natural products chemists at DTU will provide a diversity of active small molecules, and thereby develop a deeper understanding of the complex biology of bacterial infections.

This in vivo experimental approach will make it possible to identify a collection of infection relevant genes; those that we already are familiar with (for example quorum sensing controlled genes) but importantly, those among the 50% whose function is presently unknown. Selected bacterial genes are then genetically engineered to construct screens for chemical genetics purposes. This will then in turn assists in the identification of bioactive small molecules capable of reducing expression of whole gene collections relevant to infection, in particular those involved in the temporal progression of infection and biofilm tolerance to the immune system.  In other words, by controlling the multiple lines of command, disease-causing bacteria may be disarmed and the biofilms eradicated by the action of the host's defenses. It is important to emphasize that this approach seeks to target genes encoding non-essential phenotypes such as those involved in bacterial adhesion, intercellular signaling (c-di-GMP) and cell to cell signaling (quorum sensing). Blocking those functions does not hamper growth per se and consequently does not create a harsh selection pressure for development of insensitivity as we see with conventional antibiotics.

Chemical genetics approaches are inherently steps closer to drug development than classical genetics; however, it is not the my mission to develop new drugs per se. Small molecule hits may very well have the potential to be drug candidates, but it is naive (and an unrealistic success criterion for university based research funded by public grants) to expect that clinical candidates can be provided. The identification of novel small molecules as powerful tools for biological investigation and proof-of-concept of novel anti-microbial mechanisms (which transcend the past setbacks of resistance/tolerance) defines the meaning of success. At this stage industry must take over (based on shared intellectual properties) and cover the cost of further drug development and clinical trials. Many pharmaceutical companies no longer have antibiotic drugs in the pipeline or, even more worryingly, research activities in the field. The responsibility of uncovering novel antibacterial targets and potent small molecule probes therefore more than ever resides in the academic sector. In addition to creating new and exciting science, these initiatives will also educate a new, strong generation of young scientists, prepared for the multidisciplinary research efforts increasingly demanded by both academia and industry.

My aim is to continuously develop and combine research in molecular infectious biology with chemistry. My ultimate ambition is a paradigm shift in future anti-microbial treatment, fundamentally different from the traditional strategies of directly killing the bacteria with antibiotics, which have prevailed ever since the discovery of penicillin.

What are the structural features of small molecules most likely to yield specific modulation of protein functions involved in the control of infectious processes? It remains difficult to predict which small molecules will best modulate these biological processes and disease states, especially with limited prior knowledge, e.g. protein crystal structures, of the macromolecular targets. It is therefore necessary to systematically screen thousands of small molecules to find a successful match between a chemical and its target. As with the previous screens I have developed (refs 59*, 95*, 117*) for QS regulated gene expression, transcriptomic based analysis mentioned above will provide target genes for construction of those new screens.

Small molecules come in a variety of different shapes, e.g. they may be flat, rod-like, or spherical, and they may contain a variety of atoms with many functions. Natural products are small molecules that tend to be complex, highly three-dimensional in structure, and very different from one to another, whereas compounds made by traditional medicinal chemistry tend to be simple, flat, and alike. Natural products represent a prime source of "chemical diversity", and the hit rates of screening natural product libraries for novel antibiotics by far exceed those of prevalent compound libraries in the pharmaceutical industry. An example of this is my work with garlic (ref 129*). Garlic contains a variety of small molecule chemistry capable of blocking quorum sensing in P. aeruginosa. Previous support from the Strategic Research Council and the German Mukoviszidose  e.V. has enabled us to identify and synthesize QS blocker chemistry and we have used this to successfully treat lung infection in our infectious, pulmonary mouse model.

Much of the medicinal chemistry practiced in industry has failed to provide compounds suitable for antimicrobial drug development, imparted by the strategic mistake of focusing on quantity rather than quality (or chemical diversity). However, given their track record in antimicrobial discovery, there is little reason to assume that natural products could not continue to play an important role in this process. Consequently, in collaboration I will engage in a two-pronged approach for providing novel small molecule libraries for drug discovery: natural products, and synthetic small molecules mimicking the structural features of potent natural products.  "Diversity-oriented synthesis" (DOS) offers the potential to meet structural demands. Unlike traditional strategies for chemical synthesis, the DOS approach enables chemists to rapidly and efficiently synthesize libraries of complex and structurally diverse small molecules in a small number of synthetic steps. Rapid optimization of small molecule properties by structural modification in follow-up studies requires synthetic routes that are as short as possible. Keeping the number of synthetic steps to an absolute minimum ensures that all critical aspects of the small molecule discovery process are met, including optimization, and scale-up.