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

INTRODUCTION
No single class of drugs has improved public health and the quality of life more dramatically
than antibiotics. Before the introduction of sulfonamides in the 1930s, β-lactam antibiotics in the
1940s and tetracyclins, aminoglycosides and macrolides in the 1950s, one in three deaths
worldwide was attributed to a bacterial infection. [1] Antibiotics clearly represent medicinal
chemistry’s ultimate benefit to mankind. Although the success of antibiotics has lead to a
temporary victory over bacterial infection there should be little reason for complacency. Many
bacterial strains have accomplished a fight back through the development of resistance against
many antibiotics only introduced less than 50 years ago. Both mutations and more importantly
the efficient and rapid exchange of genetic information between bacteria have resulted in multidrug
resistant strains that spread through hospitals at an alarming rate. Currently antibiotic
management with stringent policies of “reserve antibiotics” have prevented a humanitarian
disaster, but it is clearly evident that there is an urgent need for novel antibiotics, ideally
comprising completely different chemical structures and possibly new mechanisms of action as
compared to the classical compounds. The development of novel antibiotics should be viewed as
a race against time due to the adaptability of bacterial strains. A statement of the World Health
Organisation (WHO) predicts that by 2020, 30 % of all bacterial infections cannot be successfully
treated because of resistance. [2] While the major pharmaceutical companies have committed
themselves to the development of novel antibiotics their strategy relies on traditional medicinal
chemistry involving the screening of large numbers of compounds either of natural or synthetic
origin and depends on serendipity and the quality and structural diversity of the compound
libraries available. A new and radical approach towards the development of novel antibiotics is
highly desirable. This approach should take the adaptability of bacteria into account and should
be rapid and flexible and therefore able to react in a short period of time towards the threat posed
by drug resistance.
The principle of evolutionary chemistry, using dynamic combinatorial libraries (DCLs) would be
such an option, proposed and developed by Sanders and Lehn. [3-10] It relies on the basic principle
that a number of building blocks bind via non-covalent interactions to a given guest molecule.
Reversible bond formation between the individual building blocks assembles a stable receptor
(macrocyclic or open chained) around the chosen target. The Le-Chatelier principle will drive the
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