TY - JOUR
T1 - In Silico Screen Identifies a New Family of Agonists for the Bacterial Mechanosensitive Channel MscL
AU - Wray, Robin
AU - Blount, Paul
AU - Wang, Junmei
AU - Iscla, Irene
N1 - Funding Information:
Funding: This research was funded by Grants I-1420 of the Welch Foundation, GM121780 from the National Institutes of Health (NIH), and 1955260 from the National Science Foundation (NSF).
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/4
Y1 - 2022/4
N2 - MscL is a highly conserved mechanosensitive channel found in the majority of bacterial species, including pathogens. It functions as a biological emergency release valve, jettisoning solutes from the cytoplasm upon acute hypoosmotic stress. It opens the largest known gated pore and has been heralded as an antibacterial target. Although there are no known endogenous ligands, small compounds have recently been shown to specifically bind to and open the channel, leading to decreased cell growth and viability. Their binding site is at the cytoplasmic/membrane and subunit interfaces of the protein, which has been recently been proposed to play an essential role in channel gating. Here, we have targeted this pocket using in silico screening, resulting in the discovery of a new family of compounds, distinct from other known MscL-specific agonists. Our findings extended the study of this functional region, the progression of MscL as a viable drug target, and demonstrated the power of in silico screening for identifying and improving the design of MscL agonists.
AB - MscL is a highly conserved mechanosensitive channel found in the majority of bacterial species, including pathogens. It functions as a biological emergency release valve, jettisoning solutes from the cytoplasm upon acute hypoosmotic stress. It opens the largest known gated pore and has been heralded as an antibacterial target. Although there are no known endogenous ligands, small compounds have recently been shown to specifically bind to and open the channel, leading to decreased cell growth and viability. Their binding site is at the cytoplasmic/membrane and subunit interfaces of the protein, which has been recently been proposed to play an essential role in channel gating. Here, we have targeted this pocket using in silico screening, resulting in the discovery of a new family of compounds, distinct from other known MscL-specific agonists. Our findings extended the study of this functional region, the progression of MscL as a viable drug target, and demonstrated the power of in silico screening for identifying and improving the design of MscL agonists.
KW - antibiotic resistance
KW - bacterial channels
KW - bacterial drug target
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U2 - 10.3390/antibiotics11040433
DO - 10.3390/antibiotics11040433
M3 - Article
C2 - 35453186
AN - SCOPUS:85127646699
SN - 2079-6382
VL - 11
JO - Antibiotics
JF - Antibiotics
IS - 4
M1 - 433
ER -