A Bioorganometallic Journey from Peptide Bioconjugates to Novel Metal-based Antibiotics Nils Metzler-Nolte* Inorganic Chemistry I – Bioinorganic Chemistry, Ruhr University Bochum, 44801 Bochum, Germany E-mail: [email protected]

Since the discovery of modern antibiotics such as the penicillins in the first half of the last century, bacterial infections that would have been fatal only 100 years ago can be successfully treated for a relatively small cost. On the other hand, even in developed countries with excellent healthcare facilities, the fight against bacterial infections is a continuous one. Resistance against many common antibiotics develops rapidly and in fact often quicker than novel antibiotics reach the market. Therefore, there is an urgent need for new classes of antibiotics.

To match this need, metal-containing compounds hold particular promise.[1] On the one hand, a metal complex alone might enhance the activity of an established drug. Alternatively, addition of a metal complex might alter the specificity of a given (organic) drug, e.g. by making it active not only against Gram-positive but also against Gram-negative bacteria. In our group, we have successfully modified the activity of two classes of antibiotics by substitution with metal complexes, namely anti-microbial peptides (AMPs) and a novel lead structure named platensimycin. Derivatization of a short AMP with a primary sequence consisting of three arginine and three tryptophane residues by metallocenes (e.g. ferrocene and ruthenocene carboxlic acid derivatives) yielded not only more active derivatives. Also, depending on the nature of the metallocene and its place within the peptide sequence, we could extend the activity of the conjugate to otherwise resistant strains.[2] In collaboration with microbiologists, the mechanism of action of our new metal-containing AMPs was elucidated,[3, 4] and the lead structures improved to reach an activity that matches that of vancomycin, often a drug of last resort in bacterial infections.[5]

In a different project, we have synthesized numerous derivatives of the antibiotic lead structure platensimycin,[6] a newly discovered inhibitor of bacterial fatty acid biosynthesis. These derivatives are not easily accessible by common organic synthesis and yield valuable insight into the mode of action of platensimycin.[7] These results will be related to earlier work in our group on medicinal organometallic chemistry.[8, 9]

REFERENCES

[1] M. Patra, G. Gasser, N. Metzler-Nolte, Dalton Trans. 2012, 41, 6350. [2] J. T. Chantson, M. V. Varga Falzacappa, S. Crovella, N. Metzler-Nolte, ChemMedChem 2012, 1, 1268. [3] H. Bauke Albada, A.-I. Chiriac, M. Wenzel, M. Penkova, J. E. Bandow, H.-G. Sahl, N. Metzler-Nolte, Beilstein J. Org. Chem. 2012, 8, 1753. [4] M. Wenzel, A. I. Chiriac, ..., N. Metzler-Nolte, S. K. Straus, E. Bremer, D. Becher, H. Brötz-Oesterhelt, H.-G. Sahl, J. E. Bandow PNAS 2014, 111, E1409. [5] H. B. Albada, P. Prochnow, S. Bobersky, J. E. Bandow, N. Metzler-Nolte, Chem. Sci. 2014, 5, 4453. [6] M. Patra, G. Gasser, A. Pinto, K. Merz, I. Ott, J. E. Bandow, N. Metzler-Nolte, ChemMedChem 2012, 4, 1930. [7] M. Wenzel, M. Patra, D. Albrecht, D. Y.-K. Chen, K. C. Nicolaou, N. Metzler-Nolte, J. E. Bandow, Antimicrob. Agents Chemother. 2012, 55, 2590. [8] G. Gasser, I. Ott, N. Metzler-Nolte, J. Med. Chem. 2011, 54, 3. [9] G. Gasser, N. Metzler-Nolte, Curr. Opinion Chem. Biol. 2012, 16, 84.

Prof. Dr. Nils Metzler-Nolte

Academic Career: PhD (Dr. rer. nat.), University of Munich, Inorganic Chemistry, 1994 Postdoc (with M. L. H. Green), University of Oxford, UK, 1995 - 1996 Associate Professor, University of Heidelberg, 2000 - 2006 Full Professor (W3), Chair of Inorganic Chemistry I, Ruhr-University Bochum, 2006 -

Honors, Awards, Functions, Professional Activities: Karl-Ziegler-Fellowship of the German Chemical Society, 2001 Visiting Professor at the Universities of Milan (Italy), Stellenbosch (South Africa) and Paris 6 (France) Julius van Haast Award of the Royal Society of New Zealand, 2016 Chairman of Third German Ferrocene Colloquium, Heidelberg, 2005 Chairman of the Fifth International Symposium on Bioorganometallic Chemistry (ISBOMC’10), Bochum, 2010 Chair of the 2016 Gordon Conference "Metals in Medicine" Speaker of DFG Research Unit (Forschergruppe) FOR 630, 2006-2013 Dean of the Ruhr-University Research School for Graduate Studies (funded by the German Research Foundation, DFG), 2009 - 2012 Vice-President for Early Career Researchers and International Affairs of Ruhr University Bochum, 2010 - 2012 Councillor of the Society of Biological Inorganic Chemistry (SBIC) 2012 - 2015 Associate Editor for Bioinorganic Chemistry Dalton Transactions, 2013 - International Editorial Advisory Boards: Eur. J. Inorg. Chem. 2007 – 2013; Appl. Organomet. Chem. 2009 – present; Chemical Science 2010 – present; J. Biol. Inorg. Chem. 2012 – present; Metallodrugs 2013 – 2016.

Publications > 180 papers in international peer reviewed journals, > 10 Reviews and Highlight articles (with peer- review), 8 book chapters. Total > 6500 citations, average 35 citations per paper, h-Index = 41 (April 2016). 1 Book (with U. Schatzschneider "Bioinorganic Chemistry: A Practical Course", W. de Gruyter, 2009) 2 Edited books (with H.-B. Kraatz “Concepts and models in bioinorganic chemistry”, Wiley-VCH, 2006); G. Jaouen, N. Metzler-Nolte (Eds.) "Medicinal Organometallic Chemistry", Vol. 32 in the Series Topics in Organometallic Chemistry (Springer, 2010)