Bacteria resist toxic substances outside mainly through drug efflux pumps, of which ABC transporter is an important type that rely on the energy of ATP hydrolysis to discharge toxic substances.

In Gram-negative bacteria such as Escherichia coli, an ABC-type drug efflux pump, Macab-TolC, has been found to transport antibiotics from inside the cell to the endometrium, the periplasm and the outer membrane in turn. Whether similar mechanism exist in Gram-positive bacteria is unclear.

Prof. ZHOU Congzhao and Prof. CHEN Yuxing from Univerisity of Science and Technology of China of Chinese Academy of Sciences revealed a novel mechanism of bacteria drug resistance by discovering a new type of efflux pump in a gram positive microbe. The study was published in Nature Communications.

Spr0694-0695 and Spr0693 were the first MacAb-like drug efflux pump in Gram-positive bacteria. The researchers analyzed the three-dimensional structure of both in Streptococcus pneumoniae using X-ray crystallography, and found that Spr0694-0695 is located on the cell membrane unlike the classical ABC transporter; whereas Spr0693 hexamer forms a nanotube-like structure that connects Spr0695 to the cell wall.

With integrated biologicalmethods, a substrate transport channel from Spr0695 to Spr0693 was identified. An alpha helix between the transmembrane and extracellular regions of Spr0695 controls the opening and closing of the channel with the energy provided by Spr0694 hydrolyzing ATP.

The study not only uncovered a new class of histone forms of gram-positive bacterial ABC transporters, but also elucidated the molecular mechanism of drug efflux and provided a structural basis for the design and modification of antibiotics. 

3D structureof Spr0693 and Spr0694-0695. (Image by YANG Hongbo)