TY - JOUR
T1 - An agonist of the MscL channel affects multiple bacterial species and increases membrane permeability and potency of common antibiotics
AU - Wray, Robin
AU - Herrera, Nadia
AU - Iscla, Irene
AU - Wang, Junmei
AU - Blount, Paul
N1 - Publisher Copyright:
© 2019 John Wiley & Sons Ltd
PY - 2019/9/1
Y1 - 2019/9/1
N2 - The bacterial MscL channel normally functions as an emergency release valve discharging cytoplasmic solutes upon osmotic stress. The channel opens and passes molecules up to 30 Å and its pore is the largest of any gated channel. Opening the MscL pore inappropriately is detrimental to the bacterial cell, suggesting MscL as a potential novel drug target. A small-molecule compound, 011A, has been shown to increase sensitivity of the Escherichia coli MscL channel, slow growth, and even decrease viability of quiescent cultures. The mscL gene is highly conserved and found in the vast majority of bacterial species, including pathogens. Here, we test the hypothesis that 011A can influence the growth and viability of other bacterial species, specifically Staphylococcus aureus and Mycobacterium smegmatis, in a MscL-dependent manner. Furthermore, we demonstrate that the 011A compound can increase potency of other antibiotics, presumably by permeabilizing the membrane and allowing easier access of the antibiotic into the cytoplasm. Thus, MscL activators have potential as novel broad-spectrum antibiotics or adjuvants that work with antibiotics to selectively allow passage across bacterial membranes.
AB - The bacterial MscL channel normally functions as an emergency release valve discharging cytoplasmic solutes upon osmotic stress. The channel opens and passes molecules up to 30 Å and its pore is the largest of any gated channel. Opening the MscL pore inappropriately is detrimental to the bacterial cell, suggesting MscL as a potential novel drug target. A small-molecule compound, 011A, has been shown to increase sensitivity of the Escherichia coli MscL channel, slow growth, and even decrease viability of quiescent cultures. The mscL gene is highly conserved and found in the vast majority of bacterial species, including pathogens. Here, we test the hypothesis that 011A can influence the growth and viability of other bacterial species, specifically Staphylococcus aureus and Mycobacterium smegmatis, in a MscL-dependent manner. Furthermore, we demonstrate that the 011A compound can increase potency of other antibiotics, presumably by permeabilizing the membrane and allowing easier access of the antibiotic into the cytoplasm. Thus, MscL activators have potential as novel broad-spectrum antibiotics or adjuvants that work with antibiotics to selectively allow passage across bacterial membranes.
UR - http://www.scopus.com/inward/record.url?scp=85067473972&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067473972&partnerID=8YFLogxK
U2 - 10.1111/mmi.14325
DO - 10.1111/mmi.14325
M3 - Article
C2 - 31177589
AN - SCOPUS:85067473972
SN - 0950-382X
VL - 112
SP - 896
EP - 905
JO - Molecular Microbiology
JF - Molecular Microbiology
IS - 3
ER -