Drug Design&Repositioning for Anti-microbial Resistance

Rising antimicrobial resistance is a worldwide health problem and development of new antimicrobial agents that inhibit cell growth or that inhibit specific intracellular targets, which induce resistance is critical in the fight against resistant bacteria. In this respect, our major studies focus on three branches in antimicrobial resistance using both experimental and computational approaches.

1. Investigation of metabolites from natural sources as novel antimicrobial agents.

Development of novel therapeuticals is the key to fight with the remarkable adaptability of microorganisms. Metabolites specifically from natural sources offer unlimited opportunities for new drug leads to counter multi-resistant microorganisms. Furthermore, most medicinal natural products are multi-targets, affecting more than one target simultaneously. The challenge in the search for new antimicrobial classes lies in the timely knowledge of the molecular mechanism of action of the drug and the related bacterial response. In this respect, we aim to evaluate the antimicrobial effects of plant secondary metabolites and elucidate their action mechanisms on different bacterial cells.

2. Biotransformation

Microbial systems offer limitless capabilities for achieving reactions that can hardly be afforded by conventional chemical synthesis, without multiple reaction steps in mild conditions. This process, biotransformation, can be accomplished with whole cells, their extract or isolated enzymes. Thus our aim is to transform different metabolites into safer and more active antimicrobial compounds using fungal and microbiological cultures.

3. Development new peptide based inhibitors for beta-lactamase inhibition.

One major mechanism of bacteria resistance for beta-lactam antibiotics is the production of the antibiotic inactivating beta-lactamase enzymes. Among these enzymes, TEM-1 beta-lactamase is a plasmid-encoded enzyme found in the periplasmic space of gram-negative bacteria. Commercial combinatorial therapies of beta-lactam antibiotics with beta-lactamase inhibitors have been proven to be successful in the treatment of beta-lactamase-mediated bacterial drug resistance. Unfortunately, beta-lactamases continue to evolve inhibitor-resistant mutations. Hence, novel inhibitors design is an area of intense research. In this respect, protein-based drugs have become attractive alternatives to traditional small organic molecule therapeutic compounds, with the high binding affinity and specificity they possess. In collaboration with Elif Ozkirimli (Boğaziçi University), we aim to design novel peptide-based beta-lactamase inhibitors using different approaches that not only bind and inhibit TEM-1 beta-lactamase, but that can also enter the bacterial cells to access intracellular beta-lactamase but will be neutral for mammalian cells.