Polypeptide antibiotic

In 1947, polymyxins, the first antibiotic polypeptides were discovered, produced by the bacterium Paenibacillus polymyxa. The first clinical use of polymyxins was in 1959, with its compound polymyxin E; more commonly known as colistin. Colistin was not put through drug safety procedures that are now implemented by drug-regulation organisations, such as the Food and Drug Administration (FDA). Polypeptide antibiotics target bacterial cell membranes, more specifically prevents the transport of peptidoglycan precursors synthesised in the cytoplasm, to components that have a major function in the growth of bacteria cell walls. The ability for polypeptide antibiotics to inhibit bacterial cell wall growth and thus bacterial replication, is a main factor in the approach to develop new antibacterial drugs. ==Medical use==

Bacitracin Bacitracin is a polypeptide antibiotic derived from a bacterium, Bacillus subtilis, and acts against bacteria through the inhibition of cell wall synthesis. Bacitracin has been used in clinical practice mainly as a topical medication due to its toxicity being too high for parental use, however evidence successful treatment in clinical trials is limited. Surgeons are able to use Bacitracin in skin grafting procedures, due to its non-toxic quality. Pseudomembranous colitis; the inflammation of the large intestine was successfully treated with Bacitracin as an oral treatment, in the case of the two patients having relapses of the infection and allergic reactions, respectively, to the common antibiotic treatment with vancomycin. In 1980, the use of oral bacitracin successfully treated four cases of colitis and diarrhea associated with antibiotic use, caused by the bacteria Clostridioides difficile. However, two of the patients relapsed, whilst the other two cases experienced early stages of relapse. One relapsed patient was subsequently treated successfully with vancomycin. Bacitracin was also trialled in bullous impetigo, an acute blistering infection, however produced ineffective results with no significant difference in success rate in comparison to the placebo trials. Patients who continued to have new development of lesions further required alternative drug therapy, in a study undertaken by Ruby and Nelson, 1973. As a result, further studies of Bacitracin treatment in Impetigo, and to compare vancomycin and bacitracin are required. Polymyxins Polymyxins are a class of polypeptide antibiotics that act on bacteria via disrupting the transport mechanism of the cell wall. Polymyxins are also distributed as an inhaled medication to treat minor respiratory tract infections due to Pseudomonas, such as cystic fibrosis. More commonly, polymyxin is distributed as a topical medication for patients with superficial infections, such as infected varicose ulcers. Polymyxin E, also referred to as colistin, is one of the few polypeptide antibiotics able to be systematically absorbed via oral consumption. It is used to treat leukaemia patients who have low levels of white blood cells. With use, non-toxic side effects of casts and azotaemia in the urine are observed in most patients. The oxidation donates an electron that the oxygen accepts to form a reactive species of oxygen. The reactive oxygen entities attack DNA bases which store information, and thus inhibits DNA synthesis. Bleomycin also acts via interfering with cell wall synthesis in the target bacteria, however the exact mechanism of action is undetermined. Thus, bleomycin as a combination therapy may be an option to treat tumours. Bleomycin also does not induce myelosuppression with decreased bone marrow activity, or immunosuppression; suppressing the immune responses in patients unlike alternative cytotoxic drugs. However, further trials are required as pulmonary toxicity occurs in approximately 10% of patients, with around 1% cases of death due to pulmonary fibrosis. ==Resistance==

Polypeptide antibiotics are able to exhibit resistance, with various resistance patterns occurring amongst closely related species of bacteria, and in some cases, present on different strains of the same species. The development of resistance is result of the bacteria mutating in response to the use of these medicines, for example resistance via blocking the site of action so it cannot act against the function of the bacteria. Polypeptide antibiotic resistance eliminates the drug's effectiveness, thus allowing the bacteria to survive, replicate and continue harming to the patient. However, resistance rarely occurs in polypeptide antibiotics such as Bacitracin, although there have been cases seen in Staphylococcus aureus. This is an issue in patients with common infections that were previously able to be treated with antibiotics. As a result, the infection is difficult or unable to be cured, and in serious cases may lead to severe disabilities or death. ==Adverse effects==

Polypeptide antibiotic use may result in minor side effects, and in rare cases, cause severe and possibly chronic adverse effects, predominantly when administered via intramuscular injection. Bacitracin use as an irrigation solution and topical bacitracin use after rhinoplasty procedures have also produced rare cases of anaphylaxis. More commonly, skin reactions occur including erythema or redness of the skin, hyperpigmentation with darker patches of skin, and the presence or formation of vesicles. These oxidants can cause lung inflammation and damage alveolar epithelial cells, resulting in the release of cytokines and growth factors that stimulate the rapid myofibroblast growth; cells between a fibroblast and a smooth muscle cell, as well as the secretion of a pathologic extracellular matrix where cells migrate, proliferate and differentiate, thus leading to fibrosis. ==Future research==

Despite multiple research articles on polypeptide antibiotics, the understanding of their exact mechanism of action and the extent of their toxicity and effects remain unknown. Evidence for low toxicity and harmful effects is limited, requiring further research to address the safe use to polypeptides antibiotics. Colistin was developed before drug-safety procedure requirements were instigated by organisations such as the Food and Drug Administration (FDA). Thus clinical trials and studies of the movement of the drug through the body and the body's biological response to antibiotic polypeptide were not established to the current set standards. Although, polymyxin use as a combination therapy with other therapeutic agents is an option for further study, and considered relatively safe as an alternative drug therapy to antibiotics. Pulmonary toxicity is affected by age and dosage, and is more commonly developed in patients over 70 years and in cases with higher dosages. However, this set age isn't definite and toxicity is unpredictable; occasionally occurring in young patients with low accumulative doses, thus future studies aim to maximise efficacy and minimise toxic effects. Future research targets the increased emergence of resistance to antibacterial drugs, via the development polypeptide antibiotics as alternative drug therapies. This development involves expanding polypeptide antibiotic diversity and optimising function, whilst reducing toxic affects. == References ==