ATP-dependent lipid A-core flippase (MsbA) (MsbA)

MsbA is an essential ATP-binding cassette (ABC) transporter located in the inner membrane of Gram-negative bacteria. It functions as a lipid flippase, utilizing the energy from ATP hydrolysis to translocate lipid A-core—the hydrophobic anchor of lipopolysaccharide (LPS)—from the inner leaflet to the outer leaflet of the cytoplasmic membrane. This translocation is a critical and rate-limiting step in the biogenesis of the bacterial outer membrane, which serves as a protective barrier against environmental insults and many existing antibiotics. Due to its essentiality for bacterial survival and the lack of a direct human homolog, MsbA is a high-priority target for the development of novel antibacterial agents. Small molecule inhibitors, including quinoline and tetrahydrobenzothiophene derivatives, have been identified that effectively block MsbA function. These inhibitors typically work by trapping the transporter in a specific conformational state, preventing the completion of the catalytic cycle. This leads to the toxic accumulation of LPS precursors in the inner membrane, resulting in membrane defects and eventual bacterial cell death, making it a potent target for treating multidrug-resistant Gram-negative infections.

Other names

Lipid A export ATP-binding/permease protein MsbALipid A flippaseABC transporter MsbALipopolysaccharide transporter MsbA

Inhibition of lipid A transport by allosterically trapping the transporter in an inward-facing or outward-facing conformation, thereby blocking ATP hydrolysis and the translocation of lipopolysaccharide precursors to the outer membrane.