base). The better performance of MINP(11) over MINP(9) is
interesting. Several possible factors might have contributed to the
improvement: a stronger electron-donating ability of hydrazyl
over amino, a closer distance between the pyridyl nitrogen and
the lactone carbonyl, and higher flexibility in the pyridyl group in
MINP(11) that could be helpful to the nucleophilic attack.
2.5
2.0
1.5
1.0
0.5
0.0
We also studied the selectivity of MINP(11), our best catalyst,
for AHLs with varying chain lengths (C –C ) and oxidation state
6
10
(
3-oxo-C ) of the acyl chain. Figure 1 compares the kMINP/kNINP
8
ratio for different AHLs. The ratios were obtained by dividing
the hydrolytic yields of the MINP-catalyzed reactions with those
of the NINP-catalyzed ones (Table S1), thus eliminating the
Figure 1. Rate acceleration for the hydrolysis of different AHL
derivatives by MINP. [AHL] = 50 µM. [MINP] = 2.5 µM.
influence of inherent reactivity—note that C -AHL and 3-oxo-
6
C -AHL had a higher background reactivity due to their better
8
solubility in water. Our data clearly shows the largest rate
Table 2 summarizes the hydrolytic yields of C -AHL
8
acceleration for C -AHL among the analogues, confirming that
catalyzed by these nucleophilic catalysts. Encouragingly, the
newly synthesized MINPs in general were more active than the
Zn-based ones. Under the same reaction conditions, i.e., at 37 °C
in 10 mM HEPES buffer, MINP(9) hydrolyzed 73% of the C8-
AHL in 8 h (entry 3). Our data also shows that rigidity of the
active site was important. The highest amount of DVB
8
the micellar imprinting and post-modification yielded catalysts
with predetermined selectivity.
Selective hydrolysis of AHLs is considered a particularly
sustainable therapeutic approach to combat bacterial infections
because it does not kill the bacteria but places a limited selective
6
solubilized by surfactant 1 is 1 equivalent. When the amount of
28
pressure for the survival of bacteria. Catalytic antibodies are the
DVB in the core-cross-linking was reduced, for example, the
yield decreased monotonously from 73% all the way to 51%
only known “synthetic” catalysts that displayed modest
hydrolytic activity for AHLs under biologically relevant
(
entries 3–5). This trend was more similar to what we have
21, 29
conditions.
Our MINPs are much easier to produce than
6
observed in the binding of MINPs and was different from an
earlier catalytic study that showed the best results with
antibodies and can tolerate high temperature and organic
13a
solvents. The clear structure–activity correlation observed in
1
7
DVB/surfactant = 0.5. The high level of DVB needed implied
that collapse of the active site was particularly detrimental to the
catalysis in the current system.
MINP(9)–MINP(12) suggests that the catalytic activities could
be improved rationally through better designs of the active site.
With many possible ways to fine-tune the structures of MINPs,
further improvement should be possible, enabling new strategies
to fight bacterial resistance.
Among the nucleophilic catalysts, MINP(11) gave the best
results and MINP(12) the worst, and MINP(9) and MINP(10) had
similar activities (Table 2, entries 3 and 6–8). The dependence of
the catalytic performance on the template is a good sign,
suggesting that molecular imprinting has successfully transferred
the information from the template to the imprinted active site.
The poor performance of MINP(12) is understandable, because
imidazole is a weaker nucleophile than DMAP. Another
possibility is that the nucleophilic nitrogen and the lactone
carbonyl carbon might be either misaligned or too far for
efficient catalysis.
Acknowledgments
We thank NSF (DMR-1464927) for supporting this research.
References and notes
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Scheme 2. Post-modification of the active site of MINP(9) with a
nucleophilic catalytic group.