The Bacterial Mecanosensitive Channel MscL as a Novel Antibiotic Target

Abstract

Antibiotic resistance is one of the biggest threats to global health, food security and development according to the World Health Organization. Since the most common bacterial pathogens are becoming resistant to the existing antibiotics, new research is urgently needed to develop new tools to respond to this crisis. The bacterial Mechanosensitive Channel of Large conductance, MscL, was the first cloned mechanosensitive channel and is to date the largest gated pore known. MscL serves the physiological role of an emergency release valve that gates under a sudden hypoosmotic shock, opening its 30 Å pore in response to tension in the membrane as the bacterial cell swells. Early in the study of MscL, it was clear that mutations resulting in more sensitive channels that gated at lower tensions were detrimental to bacterial growth and even caused bacterial death. This observation led to the idea of using MscL as a target for identifying novel antibacterial drugs. We performed an HTS screen of 200,000 compounds that led to the finding of compounds that reduce bacterial growth in a MscL dependent manner. While the vast majority of these are novel compounds, the known antibiotic streptomycin also came through the screen. Further research of this finding showed that streptomycin both activates and uses the open MscL pore as one pathway to enter the bacterial cells. We have now advanced our studies of the novel compounds, and have characterized the first ligands that specifically modify MscL gating. We propose that such compounds targeting MscL may not only be useful as antibiotics, but also as adjuvants that specifically permeabilize bacterial cells allowing antibiotic entrance to the cytoplasm, thus increasing potency and specificity of antibiotics to bacterial cells and decreasing potential side effects.