Research and development of a new generation of polypeptide antibiotics for super bacterial infection

A collaborative team led by Professor Li Jian's laboratory at Monash University, Australia, recently published a paper online in the journal Nature Communications, reporting for the first time the development of a new generation of polypeptide antibiotic F365 (QPX9003)

Since this century, bacterial resistance has become a huge threat to human health worldwide

Polymyxins, first discovered in the 1940s, are lipopeptides produced by Paenibacillus polymyxa

The team of Professor Li Jian of Monash University used chemical biological methods to systematically change multiple non-conserved positions in the molecular structure of polymyxin, realizing the separation of therapeutic efficacy and toxicity for the first time, and successfully developed a new generation of polypeptide antibiotics F365 ( QPX9003)

▲Chemical structure and lipopeptide design strategy of polymyxin

Through systematic analysis of the structure-activity model of polymyxin, Professor Li Jian's team found that the N-terminal fatty acyl group, the 3-diaminobutyric acid (Dab) residue and the 6- and 7-amino acid residues are the most common in natural polymyxins.

▲ Nephrotoxicity, acute toxicity, and in vitro activity of polymyxins and lead compounds in mice

Experiments show that for Pseudomonas aeruginosa and Acinetobacter baumannii, the activity of F365 is 2 times and 8 times higher than that of polymyxin B, respectively

Transcriptomic analysis showed that Acinetobacter baumannii gene expression was significantly affected after polymyxin and F365 treatment

▲Transcriptome changes in Acinetobacter baumannii AB5075 and HK-2 cells after treatment with polymyxin B, colistin, F287, F319 and F365

Matrix-enhanced surface-assisted laser desorption/ionization mass spectrometry imaging (ME-SALDI-MS) results revealed very different distribution, accumulation, and metabolism of F365 compared with polymyxin B and colistin in mouse kidney tissue

▲Matrix-enhanced surface-assisted laser desorption/ionization mass spectrometry imaging of the distribution, accumulation and metabolism of polymyxin and F365 in mouse kidney

References:

[1] Roberts, KD, Zhu, Y.