▎ WuXi AppTec content team editor
A collaborative team led by the laboratory of Professor Li Jian of Monash University in Australia recently published a paper online in the journal Nature Communications, which for the first time reported the development of a new generation of peptide antibiotic F365 (QPX9003). This is the first new peptide drug with a high therapeutic index for multidrug-resistant gram-negative bacteria since polymyxin was first applied to clinical treatment more than 60 years ago, with great potential and application prospects. The drug is currently licensed to Qpex Biopharma Pharmaceuticals in the United States, and its Phase I clinical trials in the United States are nearing completion.
Since this century, bacterial resistance has become a huge threat to human health around the world. The sharp increase in multidrug-resistant bacterial infections has made antibiotic drugs face severe challenges, especially the deadly multi-drug-resistant Gram-negative bacteria infection, which has seriously threatened human health and become an important medical problem facing the world. Currently, polymyxin is the last line of defense for the treatment of multidrug-resistant gram-negative infections.
Polymyxin was first discovered in the 1940s and is a lipopeptide produced by Bacillus polymyxoidis. Polymyxin B and colistin were first used in clinical treatment in the late 1950s. However, polymyxins are deficient in terms of safety (nephrotoxicity and acute toxicity), pharmacokinetics (low drug exposure in the lungs, easy to bind to pulmonary surfactants), and efficacy (inefficiencies in the treatment of lung infections), which severely limit clinical use. Therefore, there is an urgent need to develop safe and efficient new antibiotics.
Professor Li Jian's team at Monash University used chemical biology to systematically change multiple non-conservative positions in the molecular structure of polymyxin, and for the first time achieved the separation of therapeutic efficacy and toxicity, and successfully developed a new generation of peptide antibiotic F365 (QPX9003). Animal experiments have demonstrated that F365 can safely and effectively treat infections caused by multidrug-resistant gram-negative bacteria, especially lung infections. The research team cleverly applied the multi-reconstruction effect model (structure-bactericidal activity-nephrotoxicity-acute toxicity-drug generation), rationally designed drug molecules, and used systematic pharmacology to analyze the mechanisms of antibiotic sterilization and toxicity, which provided new ideas for the development of new highly efficient and safe antibiotics.
▲Chemical structure and lipopeptide design strategy of polymyxin. (a) Polymyxin structure; (b) Polymyxin B and bacterial lipopolysaccharide molecular interaction model; (c) strategy for designing novel polypeptide antibiotics based on multiconfiguration model (structure-bactericidal activity-nephrotoxicity-acute toxicity-pharmacokinesis); (d) F365 and bacterial lipopolysaccharide molecular interaction model. (Image source: References[1])
Through the systematic analysis of the polymyxin structure-activity model, Professor Li Jian's team found that N-terminal fatty acid groups, 3-position diaminobutyric acid (Dab) residues and 6- and 7-position amino acid residues are variable in natural polymyxins. By integrating chemical biology research, rational drug design, all-chemical synthesis and lead compound optimization to obtain lipopeptide F365, the research team found that the appropriate reduction of hydrophobicity of 6 and 7-position residues, shortening the side chain of 3-position amino acid residues, and replacing N-end caprylyl with 2,4-dichlorobenzoyl groups can significantly reduce nephrotoxicity and acute toxicity, weaken the binding ability with pulmonary surfactants and improve bactericidal activity.
▲Nephrotoxicity, acute toxicity and in vitro activity of polymyxins and lead compounds in mice. (a) Renal histopathological results in mice treated with the drug; (b) changes in MIC values in the presence of pulmonary surfactant; (c) maximum tolerance measurement; (d) relative safety index; (e-g) minimum bacteriostatic concentrations of polymyxin B, F287, and F365. (Image source: References[1])
Experiments have shown that for Pseudomonas aeruginosa and Acinetobacter baumannii, the activity of F365 is 2-fold and 8-fold higher than that of polymyxin B, respectively. In vitro passages have shown lower resistance to F365 than Polymyxin B. Studies using mouse pneumonia models showed a significant increase in the therapeutic index of F365. The protein binding rate of F365 in mouse, rat and human plasma was significantly lower than that of polymyxin B and colistin. In mice and rats, F365 has higher systemic clearance, shorter half-lives, and higher plasma free drug peaks than polymyxin B. In rats, the urine recovery of F365 was more than 4 times that of polymyxin B, indicating that the renal reabsorption of F365 was greatly reduced. Because F365 is safer, the effective drug exposure in mouse alveolar epithelial lining (ELF) at high doses is much higher than polymyxin B and colistin, and it is almost unbound with lung surfactants, so it has a fairly good effect on lung infections caused by multidrug-resistant gram-negative bacteria in mouse models, even including moderately polymyxin-resistant strains.
Transcriptomic analysis showed that acinetobacter baumann gene expression was significantly affected after polymyxin and F365 treatments. In particular, genes associated with fatty acid biosynthesis were the most upregulated, suggesting that F365 may have a stronger perturbation of bacterial cell membranes. By comparing the effects of polymyxin and F365 on the human renal tubular epithelial HK-2 cell transcriptome, it was found that F365 had the least interference with the HK-2 transcriptome, which was consistent with the low cytotoxicity of F365.
Matrix-enhanced surface-assisted laser desorption/ionization mass spectrometry imaging (ME-SALDI-MS) showed that the distribution, accumulation, and metabolism of F365 were very different from polymyxin B and colistin in mouse kidney tissue. In summary, low renal reabsorption and accumulation result in a significant reduction in the nephrotoxicity of F365. Toxicological experiments with 14-day repeated administration of GLP in cynomolgus monkeys also demonstrated that no nephrotoxicity was observed at a test dose of 20 mg/kg/day, and no acute toxicity symptoms were observed even at the highest test dose of 50 mg/kg/day.
▲Matrix-enhanced surfaces of polymyxin and F365 in mouse kidney distribution, accumulation and metabolism assist laser desorption/ionization mass spectrometry imaging. (Image source: References[1])
The research results were jointly completed by Professor Li Jian's team and Qpex Biopharma, usa, and Dr. Kade Roberts, Zhu Yan and Dr. Mohammad Azad are the co-first authors of this paper. The 13-year study was supported by a grant from the National Institutes of Health (NIH), the National Institute of Allergy and Infectious Diseases (NIAID) and the National Health and Medical Research Council of Australia (NHMRC).
Corresponding Author Information: Professor Li Jian is a Fellow of the American Academy of Microbiology and the director of the Antibiotic Systems Pharmacology Laboratory at the Institute of Biomedical Discovery at Monash University, and has long been engaged in anti-infective system pharmacology research and new drug development.
Resources:
More recommendations
Click "Watching" and go again