Antibacterial drugs generally refer to drugs with bactericidal or antibacterial activity, including different kinds of synthetic drugs such as antibiotics, sulfonamides, imidazoles, nitroimidazoles, quinolones, etc. Antibacterial drugs can inhibit and kill pathogens at a certain concentration. Certain products obtained by culturing microorganisms such as bacteria, actinomycetes, and fungi, or same or similar substances produced by chemical semi-synthetic methods, can also be fully chemically synthesized.
Figure 1. A summary of the traditional problems involved in antimicrobial treatment of infectious biofilms.
- Brief Introduction of Antibacterial drugs and Liposomes
Antibacterial drugs are mainly divided into eight categories, including β-lactams such as penicillins, cephalosporins, carbapenems, β-lactams containing enzyme inhibitors and monocyclic amides, etc.; aminoglycosides; tetracyclines; fluoroquinolones; folate pathway inhibitors; chloramphenicol; glycopeptide packages; macrolides.
Some antibiotics, due to their own toxicity, as well as the effect of drug biological distribution and pharmacokinetics, have limited clinical application. Although some antibiotics may have good antibacterial activity, they cannot be used as first-line drugs due to serious adverse reactions unless other drugs are proved to be ineffective.
Therefore, according to the pharmacokinetics and curative effect of the required drugs, they can be made into drug-loaded liposomes, which can effectively avoid the above problems. Liposomes, as antibiotic carriers, can improve the pharmacokinetics and biological distribution of drugs, reduce drug toxicity, enhance targeted selectivity to lesions, increase the drug’s antibacterial activity against intracellular and extracellular pathogens, and reduce the occurrence of drug resistance.
- Distribution Characteristics of Liposomes in Vivo
As a carrier of antibiotics, liposomes can slowly and continuously release drugs in the body and maintain effective concentration for a long time. Compared with free antibiotics, there is no need to repeatedly use drugs in a short period of time. Being encapsulated by liposomes, the drug can not only improve its pharmacokinetics and biological distribution, but also avoid hydrolysis by various enzymes.
After conventional intravenous injection of liposomes, they are captured and recognized by the body’s immune system as foreign antigens, thus activate the non-specific defense mechanism of macrophages in the body, and are swallowed by macrophages, making the liposomes accumulate in the organs with abandunt macrophages, such as liver, spleen, lung, kidney, etc., which can shorten the time that the drug stays in the blood circulation. The proportion of liposomes engulfed by the mononuclear phagocyte system depends on their properties, such as the size, whether charged and the amount of charge, and the fluidity. Small liposomes with a diameter of <100nm can be completely eliminated in the blood circulation from several hours to several weeks, while multivesicular liposomes may be completely eliminated in only a few minutes.
Stealth liposomes with stable spatial structure can continuously and slowly release drugs and target the infection part to enhance the antibacterial effect of antibiotics. Liposomal antibiotics improve the way of drug metabolism and extend the time that the drug stays in the blood circulation and tissues. When liposomes are administered intravenously, they can selectively concentrate on the reticuloendothelial system, and 70%~89% are concentrated on the liver and spleen. Therefore, liposome antibiotics can be used to treat infectious diseases of organs and tissues filled with reticuloendothelial.
Studies have found that liposome technology can be used to establish a bone marrow drug delivery system to selectively deliver drugs in the blood to bone marrow tissues, and to increase the effective drug concentration in the bone marrow. It is expected to be used for the treatment of acute and chronic bone marrow inflammation. Biofilm is the main component of many microorganisms, including many pathogens. The main component is a negatively charged polysaccharide protein complex, so positively charged particles are prone to aggregate on their surface. Positively charged liposomes have good intrinsic affinity with biological membranes and can target biological membranes. Therefore, compared with free antibiotics, cationic antibiotic liposomes have stronger antibacterial activity.
- Novel Liposomesfor Antibacterial Drugs
- Liposome for treatment of tuberculosis
Pulmonary tuberculosis (PTB) is an infectious disease of the lung caused by Mycobacterium tuberculosis, which seriously threatens human health. The source of infection of Mycobacterium tuberculosis is mainly excreted pulmonary tuberculosis patients, which spread through the respiratory tract. The infection of tubercule bacillus in healthy people does not necessarily cause the disease. It only occurs when the body’s immunity is weakened. Statistics from the World Health Organization (WHO) show that 8 to 10 million cases of tuberculosis occur every year in the world, and about 3 million people die from tuberculosis every year. It is the single infectious disease that causes the largest number of deaths.
Tuberculosis accompanied with bacterial infection are generally serious and difficult to treat. Antimicrobial liposomes prolong the retention time of the drug in the body, achieve a sustained release effect, and at the same time, they help to reduce toxicity, and increase the drug concentration at the infected site. The anti-tuberculosis drugs isoniazid and rifampicin are prepared into liposomes. Compared with the unprepared drugs, they show a significantly enhanced antibacterial effect, reduced liver toxicity, and there is a certain slow-release effect.
- Liposome for treatment of intracellular bacterial infection
There are many drugs for the treatment of intracellular bacterial infections, such as ampicillin (for Listeria monocytogenes), gentamicin (for Brucella, Salmonella typhimurium, and bacterium Listeria monocytogenes), ciprofloxacin (for Salmonella typhimurium and Francisella tularensis).
Polyethylene glycol modified liposomes can not only protect liposomes from phagocytosis by the mononuclear macrophage system, but also prolong the blood circulation time of liposomes and reduce drug toxicity. Polyethylene glycol modifed liposomes encapsulated with higher concentration of Ciprofloxacin have significantly lower drug toxicity than free drugs. Liposomes are used as carriers to treat intracellular infections caused by Listeria, and the results show that they have good curative effects. In the treatment of stubborn intracellular infectious diseases, after preparing antibacterial drugs into liposomes, their antibacterial activity is significantly higher than that of free drugs.
- Liposomes for treatment of extracellular bacterial infection
There are many drugs for treating extracellular bacterial infections, such as amikacin (for Pseudomonas aeruginosa, Staphylococcus aureus), gentamicin (for Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia), Ciprofloxacin (for Pseudomonas aeruginosa, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae), and Ofloxacin (for Enterococcus faecalis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa).
At present, the resistance of some bacteria to many antibiotics can spread widely due to plasmid transmission. Quinolones are not affected by plasmid-transmitted drug resistance and have no cross-resistance with many antibacterial drugs. Quinolones are antibacterial drugs that mainly act on gram-negative bacteria, and their effect on gram-positive bacteria is weak. The liposome drug delivery system can be used for antibacterial of extracellular bacteria of aminoglycosine and quinolones. Aminoglycoside and fluoroquinolone liposomes are used to treat rat models of lung infection caused by Klebsiella pneumoniae and Pseudomonas aeruginosa. It was found that the effect of using antibiotic liposomes once a day is equivalent to using free drugs 2 times a day and the drug’s clearance time in the blood is prolonged with its concentration also increasing. Some stealth liposomes with stable spatial structure can continuously and slowly release drugs and target the infection site to enhance the antibacterial effect of antibiotics.