Antimicrobial Peptides Knock on Antibiotic Replacement Door

Since the 1920 s and 1930 s, the discovery and application of antibiotics have saved countless lives. If humans benefited from it before, now the world has to work on the consequences of antibiotic abuse-the emergence and spread of drug-resistant bacteria.

Bacteria that are resistant to almost all antibiotics are generally referred to as superbugs. With the emergence of drug-resistant bacteria line-up more powerful and even super bacteria. Countries around the world have gradually realized that the abuse of antibiotics and the emergence of drug-resistant bacteria are becoming a serious crisis facing the world. Especially since this year, the issue has attracted unprecedented attention. In September this year, the G20 communiqué in Hangzhou promised to "promote the prudent use of antibiotics"; in the same month, 193 member states attending the United Nations General Assembly signed a declaration pledging to strengthen the control of antibiotics.

In addition to strengthening supervision in policy, technically speaking, finding alternatives is also a way to achieve the goal of reducing antibiotic use. At present, the development of antibiotic substitutes is becoming a priority issue in the field of biomedicine. Among them, antimicrobial peptides have become the "star of hope" for antibiotic substitutes because of their broad-spectrum and efficient bactericidal activity against bacteria and are not easy to produce drug resistance ".

Antimicrobial peptide is a kind of small molecule polypeptide with biological activity, which is an important part of the biological innate immune system. It has a wide range of sources, and has a broad spectrum of antibacterial effects.

In 1980, Swedish scientists induced a polypeptide with antibacterial activity in silkworm pupa for the first time. Then in 2005, scientists from a growth in the Nordic pine forest surface of the saprophytic ascomycetes for the first time isolated a defensin-mycelium, which by blocking the synthesis of bacterial cell wall to prevent the reproduction of bacteria, Gram-positive bacteria (such as Staphylococcus, Streptococcus, pneumococcus, etc.) has a strong defense.

NZ2114, a derivative of myceliomycin, is a better derivative peptide than the parent peptide obtained by high-throughput mutation, and its antibacterial activity against Staphylococcus aureus is significantly improved, more than 30 times higher than the parent peptide. To further enhance the antibacterial activity of NZ2114 against Staphylococcus aureus (hereinafter referred to as Staphylococcus aureus), especially against methicillin-resistant Staphylococcus aureus (hereinafter referred to as MRSA). The Wang Jianhua team of the Feed Research Institute of the Chinese Academy of Agricultural Sciences further modified NZ2114 to obtain the mutant MP1102.

Wang Jianhua team is a long-term commitment to antimicrobial peptides and antibiotic alternatives research team. The team conducted a series of studies on the molecular structure, gene expression, bactericidal properties and bactericidal mechanism of anti-gram-positive antibacterial peptides, anti-gram-negative antibacterial peptides, Lfcin and its derived peptides.

The experiments of Wang Jianhua's team proved that the antibacterial activity of MRSA of MP1102 was 15 times that of NZ2114. For example, if MP1102 was treated with S. aureus infected mice at concentrations of 5 mg/kg, 10 mg/kg, and 20 mg/kg, 90% of S. aureus was killed within 12 hours.

At the same time, MP1102 also has antibacterial activity against Clostridium perfringens, which causes gas gangrene, food poisoning and other diseases. "Mechanistic studies have shown that MP1102 has a dual bactericidal mechanism of damaging cell membranes and interfering with intracellular DNA against Clostridium perfringens." Wang Jianhua said that MP1102 has better antibacterial activity against Clostridium perfringens than mycelimycin and NZ2114 and other antibiotics such as bacitracin zinc, aureomycin and virginiamycin.

Since then, the team has introduced net positively charged and hydrophobic amino acids into the mycelimycin sequence to design the antimicrobial peptide MP1106, which has nearly 40 times higher activity against Staphylococcus aureus than the parent peptide. In order to improve the bactericidal targeting of mycelium, the research team connected the Staphylococcus aureus pheromone to mycelium to construct the targeted antimicrobial peptide of Staphylococcus aureus. The results showed that the targeted antimicrobial peptide had specific bactericidal effect on the target bacteria, and did not show antibacterial activity against other probiotics such as Bacillus, Streptococcus lactis, Enterococcus faecalis and so on.

Not only that, Wang Jianhua's team has also successively established efficient production systems of myceliamycin, NZ2114, MP1102 and MP1106 to realize efficient secretory expression of this series of products, with yields of 748 mg/L, 2390 mg/L, 695 mg/L and 2134 mg/L respectively, which is the highest expression yield of the same type of antibacterial peptide.

In addition to the series of work on fungal defensin research, Wang Jianhua's team also carried out continuous research in the fields of sea earthworm peptide and its derivative peptide, Lfcin and its derivative peptide molecular structure, recombinant expression, bactericidal properties and bactericidal mechanism. For example, Wang Jianhua's team designed derivative peptides N2 and N6 on the basis of the derivative peptide NZ17074 of sea earthworm peptide 3. Compared with the parent peptide, the antibacterial activity of N2 and N6 against gram-negative bacteria pathogens was significantly improved, and at the same time had strong environmental stability. At the same time, the team also successfully obtained recombinant antimicrobial peptides with activity.

The work of the team has attracted great attention from international counterparts. In the past three years, Wang Jianhua's team has published 18 SCI papers, obtained 7 authorized invention patents, and the papers have been cited 157 times. Peers believe that the developed antimicrobial peptides have the advantages of high sterilization efficiency, good stability, resistance, low immunogenicity, low preparation cost and high yield.

This year, 24 European and American scholars co-signed a review in the academic journal The Lancet Infectious Diseases, listing the fungal defensin antimicrobial peptides developed by the team as the first ideal alternative to traditional antibiotics. At the same time, the representative scholar of German antibacterial microorganism research Tonga Schneider (Tanja Schneider) believes that the high-efficiency production platform of fungal defensin antimicrobial peptides against gram-positive cocci developed by the team has the advantages of low cost, easy operation and high yield, and has great development prospects.

As an emerging biotechnology industry, the antimicrobial peptide industry has long been difficult to separate and purify, and high cost of chemical synthesis due to the wide range of sources and types of antimicrobial peptides, small molecular mass and low natural content. It is urgent to establish genetically modified high-efficiency and low-cost production. Way. The work of Wang Jianhua's team has made breakthroughs in a series of bottleneck technologies such as antimicrobial peptide product design and low-cost production.

Wang Jianhua revealed to reporters that some varieties of the MP series have completed the pilot test, have the level of industrialization, start some evaluation experiments, and have independent intellectual property rights. It is believed that in the near future, China will be at the forefront of the world in the field of antimicrobial peptide production.