Novel MscL agonists that allow multiple antibiotics cytoplasmic access activate the channel through a common binding site

English version

Autoři: Robin Wray ^aff001; Junmei Wang ^aff002; Irene Iscla ^aff001; Paul Blount ^aff001
Působiště autorů: Department of Physiology, UT Southwestern Medical Center, Dallas, Texas, United States of America ^aff001; Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, University of Pittsburgh School of Pharmacy, Pittsburg, Pennsylvania, United States of America ^aff002
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0228153

Souhrn

The antibiotic resistance crisis is becoming dire, yet in the past several years few potential antibiotics or adjuvants with novel modes of action have been identified. The bacterial mechanosensitive channel of large conductance, MscL, found in the majority of bacterial species, including pathogens, normally functions as an emergency release valve, sensing membrane tension upon low-osmotic stress and discharging cytoplasmic solutes before cell lysis. Opening the huge ~30Å diameter pore of MscL inappropriately is detrimental to the cell, allowing solutes from and even passage of drugs into to cytoplasm. Thus, MscL is a potential novel drug target. However, there are no known natural agonists, and small compounds that modulate MscL activity are just now being identified. Here we describe a small compound, K05, that specifically modulates MscL activity and we compare results with those obtained for the recently characterized MscL agonist 011A. While the structure of K05 only vaguely resembles 011A, many of the findings, including the binding pocket, are similar. On the other hand, both in vivo and molecular dynamic simulations indicate that the two compounds modulate MscL activity in significantly different ways.

Klíčová slova:

Antibiotic resistance – Antibiotics – Biochemical simulations – Cysteine – Free energy – Glutamate – Molecular dynamics – Staphylococcus aureus

Zdroje

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Novel MscL agonists that allow multiple antibiotics cytoplasmic access activate the channel through a common binding site

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