Antimicrobial Resistance & Microbial Pathogenicity

Prof. Dr. Dr. Thomas A. Wichelhaus

PD Dr. Dr. Silke Besier
Denia Frank (MTA)


Antimicrobial Resistance

Staphylococcus aureus
The evolution of increasingly antimicrobial-resistant strains of S. aureus results from a multitude of factors that include the widespread and sometimes inappropriate use of antimicrobials, the extensive use of various agents as growth promoters in animal feed, and, with the increase in regional and international travel, the relative ease with which antimicrobial-resistant strains cross geographic barriers. Our research focuses on the molecular analyses of antibiotic resistance mechanisms and the biological cost of resistance from the perspective of S. aureus. Understanding the molecular mechanisms of resistance is one of the prerequisites for the identification of novel drug targets and finally for the development of effective new chemotherapeutic agents.

Multidrug-resistant bacteria
Colonization/infection with multidrug-resistant bacteria (MDRB) such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae, and carbapenemase producing Gram-negative pathogens is an increasing problem worldwide. Our research focuses on molecular mechanisms of resistance and epidemiology of MDRB.

Neisseria gonorrhoeae
Antimicrobial drug resistance in Neisseria gonorrhoeae has become an increasing public health problem. Hence, surveillance of resistance development is of crucial importance to implement adequate treatment guidelines. Our research focuses on the epidemiology of antibiotic resistance among gonococcal isolates in Germany.

The alarming increase of antibiotic-resistant bacterial pathogens points to the need for new antiinfective therapies. Consequently, antibiotic resistance has been called one of the world’s most pressing public health problems. A worrisome trend is the spread of metallo-β-lactamases among Gram-negative pathogens that can confer resistance to almost all β-lactams including carbapenems and consequently present a major challenge for treatment of individual patients.
Our research focuses on the development and evaluation of new antimicrobials active against MDRB. In particular our research aims at developing a new anti-infective agent by identifying metallo-β-lactamase inhibitors which will restore the bactericidal activity of common β-lactam antibiotics against multidrug-resistant Gram-negative pathogens.

Microbial Pathogenicity

Staphylococcus aureus

Staphylococcus aureus is known as a significant human pathogen causing a wide spectrum of diseases ranging from superficial cutaneous infections to life-threatening systemic maladies. Despite improved public health conditions and the availability of potent antimicrobial agents S. aureus has remained a major cause of morbidity and mortality.

During chronic S. aureus infections, variants of this pathogen can emerge that are able to persist in patients for months or years in a dormant metabolic state. These bacteria are designated ‘‘small colony variants’’ (SCVs) due to their special growth characteristics. Our research focuses on the prevalence and clinical significance of SCVs, the molecular analysis of the SCV phenotype, as well as the adaptation mechanisms protecting this versatile pathogen against antibiotic therapy and host defences.

Selected Publications:

  • Wichelhaus T.A., Böddinghaus B., Schäfer V., Brade V.: Molecular characterization of rpoB mutations conferring cross-resistance to rifamycins on methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. (1999) 43:2813-2816.
  • Wichelhaus T.A., Schafer V., Brade V., Boddinghaus B.: Differential effect of rpoB mutations on antibacterial activities of rifampicin and KRM-1648 against Staphylococcus aureus. J. Antimicrob. Chemother. (2001) 47:153-156.
  • Wichelhaus T.A., Boddinghaus B., Besier S., Schafer V., Brade V., Ludwig A.: Biological cost of rifampin resistance from the perspective of Staphylococcus aureus. Antimicrob. Agents Chemother. (2002) 46:3381-3385.
  • Besier S., Hunfeld K.P., Giesser I., Schäfer V., Brade V., Wichelhaus T.A.: Selection of ketolide resistance in Staphylococcus aureus. Int. J. Antimicrob. Agents (2003) 22: 87-88.
  • Besier S., Ludwig A., Brade V., Wichelhaus T.A.: Molecular analysis of fusidic acid resistance in Staphylococcus aureus. Mol. Microbiol. (2003) 47: 463-469.
  • Besier S., Ludwig A., Brade V., Wichelhaus T.A.: Compensatory adaptation to the loss of biological fitness associated with the acquisition of fusidic acid resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. (2005) 49: 1426-1431.
  • Besier S., Smaczny C., von Mallinckrodt C., Krahl A., Ackermann H., Brade V., Wichelhaus T.A.: Clinical significance of Staphylococcus aureus small colony variants in cystic fibrosis lung disease. J. Clin. Microbiol. (2007) 45: 168-172.
  • Besier S., Ludwig A., Ohlsen K., Brade V., Wichelhaus T.A.: Molecular analysis of the thymidine-auxotrophic small colony variant phenotype of Staphylococcus aureus. Int. J. Med. Microbiol. (2007) 297: 217-225.
  • Zander J., Besier S., Saum S.H., Dehghani F., Loitsch S., Brade V., Wichelhaus T.A.: Influence of dTMP on the phenotypic appearance and intracellular persistence of Staphylococcus aureus. Infect. Immun. (2008) 76: 1333-1339.
  • Besier S., Ludwig A., Zander J., Brade V., Wichelhaus T.A.: Linezolid resistance in Staphylococcus aureus: gene dosage effect, stability, fitness costs, and cross-resistances. Antimicrob. Agents Chemother. (2008) 52: 1570-1572.
  • Besier S., Zander J., Kahl B.C., Kraiczy P., Brade V., Wichelhaus T.A.: The thymidine-dependent small colony variant phenotype is associated with hypermutability and antibiotic resistance in clinical Staphylococcus aureus isolates. Antimicrob. Agents Chemother. (2008) 52: 2183-2189.
  • Besier S., Zander J., Siegel E., Saum S.H., Hunfeld K.P., Ehrhart A., Brade V., Wichelhaus T.A.: Thymidine-dependent Staphylococcus aureus small-colony-variants: relevant human pathogens not only in cystic fibrosis lung disease. J. Clin. Microbiol. (2008) 46:3829-3832.
  • Zander J., Besier S., Ackermann H., Wichelhaus T.A.: Synergistic antimicrobial activity of folic acid antagonists and nucleoside analogs. Antimicrob. Agents Chemother. (2010) 54:1226-1231.
  • Zander J., Hartenfeller M., Hähnke V., Proschak E., Besier S., Wichelhaus T.A., Schneider G.: Multistep virtual screening for rapid and efficient identification of non-nucleoside bacterial thymidine kinase inhibitors. Chem. Eur. J. (2010) 16:9630-9637.
  • Zander J., Besier S., Faetke S., Saum S.H., Müller V., Wichelhaus T.A.: Antimicrobial activities of trimethoprim/sulfamethoxazole, 5-iodo-2'-deoxyuridine and rifampicin against Staphylococcus aureus. Int. J. Antimicrob. Agents. (2010) 36:562-565.
  • Göttig S., Pfeifer Y., Wichelhaus T.A., Zacharowski K., Bingold T., Averhoff B., Brandt C., Kempf V.A.: Global spread of New Delhi metallo-β-lactamase 1. Lancet Infect Dis (2010) 10:828-9.
  • Kaase M., Nordmann P., Wichelhaus T.A., Gatermann S.G., Bonnin R.A., Poirel L.: NDM-2 carbapenemase in Acinetobacter baumannii from Egypt. J. Antimicrob. Chemother. (2011) 66:1260-2.
  • Pfeifer Y., Wilharm G., Zander E., Wichelhaus T.A., Göttig S., Hunfeld KP., Seifert H., Witte W., Higgins P.G.: Molecular characterization of blaNDM-1 in an Acinetobacter baumannii strain isolated in Germany in 2007. J. Antimicrob. Chemother. (2011) 66: 1998–2001.
  • Mattner F., Bange F.C., Meyer E., Seifert H., Wichelhaus T.A., Chaberny I.F.: Preventing the spread of multidrug-resistant gram-negative pathogens: recommendations of an expert panel of the german society for hygiene and microbiology. Dtsch. Arztebl. Int. (2012) 109:39-45.
  • De Rosa M-, Zanfardino A., Notomista E., Wichelhaus T.A., Saturnino C., Varcamonti M., .Soriente A.: Novel promising linezolid analogues: rational design, synthesis and biological. evaluation. Eur J Med Chem. (2013) 69:779-85.
  • Horn N.N., Kresken M., Körber-Irrgang B., Göttig S., Wichelhaus C., Wichelhaus T.A.: Antimicrobial susceptibility and molecular epidemiology of Neisseria gonorrhoeae in Germany. Int J Med Microbiol. (2014) 304:586-91.
  • Gruber T.M., Göttig S., Mark L., Christ S., Kempf V.A., Wichelhaus T.A., Hamprecht A. Pathogenicity of pan-drug-resistant Serratia marcescens harbouring blaNDM-1. J Antimicrob Chemother. (2014) Epub ahead of print]

Selected Books and Book Chapters:

  • Wichelhaus T.A.: Antibiotika – Moderne Therapiekonzepte. ISBN: 3-89599-737-4 (2004) UNI-MED-Verlag.
  • Wichelhaus T.A.: Molecular typing, antibiotic resistance and biological fitness of Staphylococcus aureus, a potent human pathogen. ISBN: 3-8322-3418-7 (2004) Shaker-Verlag.
  • Kresken M., Hafner D., Schmitz F.J., Wichelhaus T.A.: PEG-Resistenzstudie 2007. ISBN: 978-3-00-024936-5 (2009) Antiinfectives Intelligence-Verlag.
  • Wichelhaus T.A.: Neisseria gonorrhoeae. In: GERMAP 2012 – Antibiotika-Resistenz und -Verbrauch. ISBN 978-3-00-045503-22 (2014) Antiinfectives Intelligence-Verlag.