Fighting multidrug-resistant bacteria

Samenvatting

The unabated emergence of antibiotic resistance and the unattractive economy around antibiotic discovery have resulted in a state of crisis in treatment of infections. Resistance to beta-lactam antibiotics is most disconcerting, since they represent arguably the most important class of broad-spectrum antibacterials. The main resistance mechanism in Gram-negative bacteria is based on the hydrolytic inactivation of beta-lactams by beta-lactamases. A class of these enzymes, i.e. carbapenemases, causes resistance to carbapenems, a subgroup of beta-lactam antibiotics, which are considered as the antibiotics of the "last resort". Moreover, expression of carbapenemases in multidrug resistant (MDR) bacteria is threatening the treatment of patients not only with carbapenems, but also with all other classes of beta-lactam antibiotics. I propose to develop two novel types of inhibitors for class B carbapenemases (metallo-beta-lactamases), which operate by a novel mechanism. I will use organic synthesis, X-ray crystallography and in vitro biochemistry as tools. These inhibitors are expected (1) to overcome antibacterial resistance caused by carbapenemases, (2) restore the susceptibility of MDR bacteria to beta-lactams and, (3) minimize side reactions with unrelated mammalian enzymes. In this work, I will use my knowledge and skills in drug discovery from the lab of Prof. S. Mobashery at the University of Notre Dame (US) and from my Ph.D. studies in Groningen (NL), which include drug design and synthesis, in vitro studies, and demonstration of drug's efficacy in living bacteria. The proposed research will be performed at the University of Groningen in the group of Prof. A.J. Minnaard and in collaboration with Prof. D.J. Slotboom and Dr. A.K.H Hirsch. With the concerted focus on "Tackling the Antimicrobial Challenge", the Faculty of Sciences at the University of Groningen provides an exceptional environment for the proposed work.

Kenmerken

Projectnummer

722.015.001

Hoofdaanvrager

Dr. A.A. Bastian

Verbonden aan

Rijksuniversiteit Groningen, Faculty of Science and Engineering (FSE), Stratingh Instituut voor Chemie

Uitvoerders

Dr. A.A. Bastian

Looptijd

01/01/2016 tot 30/09/2016