Release date:2019/11/1 17:43:15

Polypeptide Antibiotic

​The polypeptide antibiotic is obtained by extracting from a culture solution of polymyxa or aeruginosa. With the development of biotechnology, the clinical application of peptides as drugs has become more and more extensive, and the corresponding formulation studies have received increasing attention. Compared with traditional small molecule organic drugs, peptides have poor stability characteristics. This paper introduces the research status of peptide drug preparations from three aspects: stability, sustained release system and non-injection route. Polypeptide antibiotics have polypeptide structural features including polymyxins (polymyxin B, polymyxin E), bacitracin (bacillus, gramicidin) and vancomycin.

Action Characteristic of Polypeptide Antibiotic

Among the peptide antibiotics, different antibiotics have different antibacterial effects. They can respectively resist infections of Gram-positive bacteria, Gram-negative bacteria, Pseudomonas aeruginosa, fungi, viruses, spirochetes, protozoa. Also, they have a better therapeutic effect to sepsis, respiratory infections, Urinary tract infections, bovine mastitis and other diseases. They can inhibit bacteria in small doses and can be sterilized in large doses.

Action Mechanism  of 
Polypeptide Antibiotic

Such antibiotics first affect the outer membrane of sensitive bacteria. The amino group of the cyclic polypeptide portion of the drug forms an electrostatic interaction with the divalent cation binding site of the bacterial outer membrane lipopolysaccharide, destroying the integrity of the outer membrane. Therefore, the fatty acid portion of the drug can penetrate the outer membrane, thereby increasing the permeability of the cytoplasmic membrane, leading to the escape of small molecules such as phosphoric acid and nucleoside in the cytoplasm, causing cell dysfunction to die directly. Because of the thick cell wall outside the Gram-positive bacteria, which prevents the drug from entering the bacteria, such antibiotics have no effect on them.

The mechanism of action of peptide antibiotics is also different. Polymyxins can alter the function of bacterial cytoplasmic membranes, while bacitracin acts on cell walls and cytoplasm. The biggest advantage of peptide antibiotics is that bacteria are not easy to produce drug resistance, but the disadvantage is that it is more toxic. In addition to damage to bacterial cell membranes, peptide antibiotics also act on animal cell membranes, mainly to the kidneys and nervous system.
Pharmacological Properties  of 
Polypeptide Antibiotic

The stability of the peptide, the cause of the instability of the peptide: (1) Deamidation reaction; (2) Oxidation; (3) Hydrolysis; (4) Formation of erroneous disulfide bonds;  (5) Racemization; (6) β-elimination; (7) Denaturation, adsorption, aggregation or precipitation.

Ways to improve the stability of peptides:

(1) Site-directed mutagenesis: The stability of a polypeptide can be improved by genetically replacing a residue which causes instability of the polypeptide or introducing a residue that increases the stability of the polypeptide.

(2) Chemical modification: There are many chemical modification methods for polypeptides, and the most studied ones are
PEGylation. PEG is a water-soluble polymer compound that is degradable and non-toxic in the body. When PEG is combined with a polypeptide, it can improve thermal stability, resist degradation of protease, reduce antigenicity, and prolong half-life in vivo. Choosing the appropriate modification method and controlling the degree of modification can improve the activity of the original organism.

(3) Additives: The stability of the polypeptide can be improved by adding additives such as sugars, polyols, gelatin, amino acids, and certain salts. Sugars and polyols force more water molecules around the protein at low concentrations, thus increasing the stability of the polypeptide. During lyophilization, the above materials may also replace water to form hydrogen bonds with the polypeptide to stabilize the native conformation of the polypeptide, and may also increase the glass transition temperature of the lyophilized product. In addition, surfactants such as SDS, Tween, and Pluronic prevent adsorption, aggregation, and precipitation of the polypeptide surface.

(4) Lyophilization: A series of chemical reactions such as deamidation, β-elimination, and hydrolysis of the polypeptide requires water to participate, and water can also serve as a mobile phase for other reactants. In addition, a decrease in water content can increase the denaturation temperature of the polypeptide. Thus, lyophilization increases the stability of the polypeptide.

Future Development  of 
Polypeptide Antibiotic

In recent years, although some progress has been made in the study of the non-injection route of polypeptides, there are still many difficulties. The mucosal delivery of almost all peptide drugs requires a penetration enhancer, which is cumbersome and has problems in how to reduce its stimulating effect and whether long-term use affects epithelial integrity. The use of microparticles instead of penetration enhancers may be a promising oral administration method. At present, although some achievements have been made in overcoming the osmotic barrier and the enzyme barrier, there has been no breakthrough. In addition, the problem of liver clearance of peptides should be taken seriously, and the relationship between liver clearance mechanism, structure and clearance will help to realize the dream of oral administration of peptides.
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