The ever increasing bacterial resistance to the antibiotic drugs of the present and
consequently the risk of public safety is prompting the researchers to search for an
alternative approach to the antibiotic design. . This resistance has led to the increased
interest to design targeted covalent inhibitors, which have in the past been regarded as
dangerous due to their reactive structure and nonspecific
mode of action, thus deeming
them a bad research starting point. This belief was changed when several of the well
established drugs were proven to act as targeted covalent inhibitors. The most known of
them being acetylsalicylic acid and penicillin, which are avalable since 1899 and 1928,
respectivelly.
Peptidoglycan that forms the bacterial cell wall is a rigid structure, formed by interlinked
polymer chains consisting of an alternating monomers of Nacetylmuramic
acid and Nacetylglucosamine.
Due to it's absence in mammalian cells, this structure offers an
excellent target for development of new antibacterial drugs.
In this work, we synthesised 14 substances that were found to be potential MurA
inhibitors using virtual anchoring on MurA's active site. The substances were synthesized
using Nalkylation
of a chloracetylchloride warhead using scaffolds that vary in structure.
The aim was to acheive more noncovalent
interactions between the molecule and the
enzyme's active site, which would result in a lower IC50 value. This value was determined
using a colorimetric method that forms a colored complex with the inorganic phosphate
that is present when the enzyme is active. Using these values we will be able to determine
if and how effectively each compound is able to affect the enzyme's performance.
The synthesised compounds 15
show an inhibiting effect on the isolated E.coli MurA
enzyme, with IC50 in the concentration range from 44,4 to 452,4 μmol/L, while compound
6 exhibits complete absence of inhibitory activity.
|
