The Development of Novel Antibiotics Using ... - Jacobs University

Introduction
complete remodel of the cell wall via replacing the part D-Ala-D-Ala by D-Ala-D-Lac. They
acquire resistance to Penicillin as previously mentioned by releasing β-lactamases, which
hydrolyze the β-lactam ring. Bacteria get nutrients through pores of proteins. These pores are the
same portals for entry of antibiotics into the cell. Bacteria synthesize proteins, which form
smaller pores, thus permitting nutrients to enter the cell and excluding antibiotics with larger
size. Bacteria resist Streptomycin by making modification of the chemical structure of the
antibiotic though addition of some groups into its structural framework, thus preventing it from
doing its proper task. Protein pumps are one of the most efficient mechanisms by which bacteria
resist antibiotics. Staphylococcus aureus resists Ciprofloxacin and Tetracycline antibiotics by
pumping the antibiotic out of cells faster than it comes in. The rapid development of antibiotic
resistance has led to a continual need to discover novel drugs using innovative approaches.
Dynamic combinatorial chemistry (DCC) can provide such approach.
1.2 Dynamic Combinatorial Chemistry
Over the past two decades, DCC has attracted considerable and growing interest in supramolecular
chemistry. 1-7 Unlike conventional synthesis, DCC involves generation of an equilibrating
mixture of interchanging species in solution forming in reversible reactions. The mixture of
library members, which forms in a DCC, constitutes a dynamic combinatorial library (DCL). In
DCC, library members are formed under thermodynamic control. The composition of the DCL is
subject to change by addition of an external guest acting as a trigger, which acts by shifting the
equilibrium towards the preferential formation of the most stable host/guest complexes, in other
words ideally from the DCL mixture of compounds one host molecule is formed selectively that
is able to recognize the guest. In DCC therefore, amplified targets can form in high yields with
sufficient purity in covalent reversible reactions (Figure 1.1).
DCC allows generation of a diverse collection of structurally unique compounds, which cannot
be obtained by other classical synthetic approaches. Direct screening of the DCL can be achieved
by electrospray ionization time-of-flight mass spectrometry (ESI-TOF/MS). Electrospray mass
spectrometry (ESI-MS) showed considerable promise in the analysis of DCLs as a soft ionization
technique due its ability to provide precise mass values, high resolution and little or almost no
fragmentations. High performance liquid chromatography (HPLC) is another sophisticated
tool, which can be used to monitor the exchange and amplification processes in DCLs. The
2 | P a g e