Structural basis for dual-mode inhibition of the ABC transporter MsbA

Mucking up the membrane

28 September 2018

Bacterial pathogens that shield their cellular insides with a double membrane have been notoriously difficult to kill using antibiotic agents. A team from Genentech, a subsidiary of Roche, has now discovered a drug that blocks the sugar-coated fat molecules that form the highly impermeable membrane from reaching their final destination on the outside of nasty ‘Gram-negative’ superbugs, such as Escherichia coli and Klebsiella pneumonia.

The researchers searched through a large chemical library for compounds capable of blocking MsbA, a bacterial enzyme involved in shuttling these membrane molecules, known as lipopolysaccharides, out of the cytoplasm. They found one such compound, which they optimized to have better properties. Structural analysis of this optimized drug in complex with MsbA revealed an unprecedented mechanism of action — a dual-mode inhibition of the target enzyme that could provide the playbook for designing other antibiotics.

This finding, reported in Nature, offers a promising new strategy for treating these types of infectious microbes, and could help inspire other efforts to discover drugs that work against similar vulnerabilities in bacterial defenses.

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References

1. Nature 557, 196–201 (2018) doi: 10.1038/s41586-018-0083-5