ATP binding cassette (ABC) transporters are found in all species. ATP-binding cassette (ABC) transporters constitute a ubiquitous superfamily of integral membrane proteins that are responsible for the ATP-powered translocation of many substrates across membranes. ABC transporters are formed by two transmembrane domains and two highly conserved nucleotide binding domains (NBDs) that bind and hydrolyze ATP. In particular, ABC transporters have a characteristic architecture that consists minimally of four domains: two ABC domains (or nucleotide-binding domains) with highly conserved sequence motifs and two transmembrane domains (TMDs). ATP-binding cassette (ABC) transporters move substrates across membranes, including nutrients, toxins, peptides and small inorganic ions.
MsbA flips the building block of the outer membrane, lipid A, across the inner membrane. Especially, MsbA is a homodimeric bacterial lipid flippase homolog of P-glycoprotei. Fortunately, MsbA is an essential ATP-binding cassette (ABC) transporter from Gram-negative bacteria. Moreover, MsbA transports amphipathic substrates including precursors of lipopolysaccharides from the inner leaflet to the outer leaflet of the cytoplasmic membrane. Purified MsbA displays basal ATPase activity. Phospholipids and a variety of lipid A species can modulate the ATPase activity. Furthermore, MsbA flips the building block of the outer membrane, lipid A, across the inner membrane. As a result, MsbA is an antibacterial target that offers a potential new strategy to overcome existing antibiotic-resistance mechanisms.
G907 acts as a selective inhibitor of an inward-facing state of MsbA with an IC50 of 18 nM. Particularly, G907 traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket.
All in all, G907 is a selective small-molecule antagonist with bactericidal activity, revealing an unprecedented mechanism of ABC transporter inhibition.