The role of the native environment on membrane bioenergetics: A physiological perspective

The rise of multi-drug resistant bacterial infections is a worldwide growing concern. Despite being one of the greatest medical advances of the 20th century, classical antibiotics are no longer effective against such organisms. Unfortunately, patients infected with drug-resistant bacteria are more likely to experience worse clinical outcomes, as well as have higher mortality rates. The bacterial respirasome is one of the most promising target spaces in the search for novel antibiotics, since many pathogenic organisms display unique respiratory adaptations: e.g., a change in the pathogens’ metabolism upon infection of the host. More importantly, these adaptations are often essential for the cell viability of the pathogen, what makes them excellent candidates for targeted inhibition.
These drug targets frequently are membrane-bound respiratory proteins. For this reason, they have a significantly different biochemical and biophysical behavior than that of cytoplasmic or other water-soluble proteins, and so they are notoriously difficult to study. Most remarkably, membrane proteins are amphipathic, interacting with the aqueous environment, but also surrounded by a highly hydrophobic environment. Lipid composition is extremely complex: lipids of different polarities, hydrophobic electron carriers, etc. Altogether, a multicomponent system that ought to be considered if we aim to design efficient drugs that will interact with these enzymes (i.e., inhibit them) in their native environments.