posted on 2021-03-04, 07:43authored byDana Kaizerman-Kane, Maya Hadar, Roymon Joseph, Dana Logviniuk, Yossi Zafrani, Micha Fridman, Yoram Cohen
Bacterial biofilms are a major threat
to human health, causing
persistent infections that lead to millions of fatalities worldwide
every year. Biofilms also cause billions of dollars of damage annually
by interfering with industrial processes. Recently, cationic pillararenes
were found to be potent inhibitors of biofilm formation in Gram-positive
bacteria. To identify the structural features of pillararenes that
result in antibiofilm activity, we evaluated the activity of 16 cationic
pillar[5]arene derivatives including that of the first cationic water-soluble
pillar[5]arene-based rotaxane. Twelve of the derivatives were potent
inhibitors of biofilm formation by Gram-positive pathogens. Structure
activity analyses of our pillararene derivatives indicated that positively
charged head groups are critical for the observed antibiofilm activity.
Although certain changes in the lipophilicity of the substituents
on the positively charged head groups are tolerated, dramatic elevation
in the hydrophobicity of the substituents or an increase in steric
bulk on these positive charges abolishes the antibiofilm activity.
An increase in the overall positive charge from 10 to 20 did not affect
the activity significantly, but pillararenes with 5 positive charges
and 5 long alkyl chains had reduced activity. Surprisingly, the cavity
of the pillar[n]arene is not essential for the observed activity,
although the macrocyclic structure of the pillar[n]arene core, which
facilitates the clustering of the positive charges, appears important.
Interestingly, the compounds found to be efficient inhibitors of biofilm
formation were nonhemolytic at concentrations that are ∼100-fold
of their MBIC50 (the minimal concentration of a compound
at which at least 50% inhibition of biofilm formation was observed
compared to untreated cells). The structure–activity relationship
guidelines established here pave the way for a rational design of
potent cationic pillar[n]arene-based antibiofilm agents.