TY - JOUR
T1 - Hydrogel-Encapsulated Biofilm Inhibitors Abrogate the Cariogenic Activity of Streptococcus mutans
AU - Ahirwar, Parmanand
AU - Kozlovskaya, Veronika
AU - Nijampatnam, Bhavitavya
AU - Rojas, Edwin M.
AU - Pukkanasut, Piyasuda
AU - Inman, Daniel
AU - Dolmat, Maksim
AU - Law, Anna C.
AU - Schormann, Norbert
AU - Deivanayagam, Champion
AU - Harber, Gregory J.
AU - Michalek, Suzanne M.
AU - Wu, Hui
AU - Kharlampieva, Eugenia
AU - Velu, Sadanandan E.
N1 - Publisher Copyright:
© 2023 American Chemical Society. All rights reserved.
PY - 2023/6/22
Y1 - 2023/6/22
N2 - We designed and synthesized analogues of a previously identified biofilm inhibitor IIIC5 to improve solubility, retain inhibitory activities, and to facilitate encapsulation into pH-responsive hydrogel microparticles. The optimized lead compound HA5 showed improved solubility of 120.09 μg/mL, inhibited Streptococcus mutans biofilm with an IC50value of 6.42 μM, and did not affect the growth of oral commensal species up to a 15-fold higher concentration. The cocrystal structure of HA5 with GtfB catalytic domain determined at 2.35 Å resolution revealed its active site interactions. The ability of HA5 to inhibit S. mutans Gtfs and to reduce glucan production has been demonstrated. The hydrogel-encapsulated biofilm inhibitor (HEBI), generated by encapsulating HA5 in hydrogel, selectively inhibited S. mutans biofilms like HA5. Treatment of S. mutans-infected rats with HA5 or HEBI resulted in a significant reduction in buccal, sulcal, and proximal dental caries compared to untreated, infected rats.
AB - We designed and synthesized analogues of a previously identified biofilm inhibitor IIIC5 to improve solubility, retain inhibitory activities, and to facilitate encapsulation into pH-responsive hydrogel microparticles. The optimized lead compound HA5 showed improved solubility of 120.09 μg/mL, inhibited Streptococcus mutans biofilm with an IC50value of 6.42 μM, and did not affect the growth of oral commensal species up to a 15-fold higher concentration. The cocrystal structure of HA5 with GtfB catalytic domain determined at 2.35 Å resolution revealed its active site interactions. The ability of HA5 to inhibit S. mutans Gtfs and to reduce glucan production has been demonstrated. The hydrogel-encapsulated biofilm inhibitor (HEBI), generated by encapsulating HA5 in hydrogel, selectively inhibited S. mutans biofilms like HA5. Treatment of S. mutans-infected rats with HA5 or HEBI resulted in a significant reduction in buccal, sulcal, and proximal dental caries compared to untreated, infected rats.
UR - http://www.scopus.com/inward/record.url?scp=85163920336&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85163920336&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.3c00272
DO - 10.1021/acs.jmedchem.3c00272
M3 - Article
C2 - 37285134
AN - SCOPUS:85163920336
SN - 0022-2623
VL - 66
SP - 7909
EP - 7925
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 12
ER -