Feeling the tension: the bacterial mechanosensitive channel of large conductance as a model system and drug target

The drug-resistance crisis has become dire and new antibiotic targets and strategies are required. Mechanosensitive channel of large conductance (MscL) is a conserved bacterial mechanosensitive channel that plays the role of ‘osmotic-emergency-release-valve. It has the largest-gated pore known allowing osmoprotectants out, and other compounds into the cell. Inappropriate gating of the channel can lead to slow growth, decreased viability, and an increase in potency for many antibiotics. The ‘membrane permeability’ observed for some antibiotics, including streptomycin, is mediated by directly binding to and activating MscL. Novel compounds that are MscL agonists have also recently been isolated. Although the compounds are diverse, the binding sites of all characterized MscL-specific agonists are within the same general region of the MscL complex, leading to an in silico screening for compounds that bind this region. In sum, these studies demonstrate that MscL is a viable drug target that may lead to a new generation of antibiotics and adjuvants.