Polypeptide antibiotic

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Polypeptide antibiotic
Drug class
Bacitracin structure.svg
Bacitracin, a polypeptide antibiotic derived from Bacillus subtilis.
Class identifiers
UseVarious
ATC code D06A
Biological target Cell Wall, Peptidoglycan
Chemical class Polypeptides
Clinical data
Drugs.com Drug Classes
Legal status
In Wikidata

Polypeptide antibiotics are a chemically diverse class of anti-infective and antitumor antibiotics containing non-protein polypeptide chains. Examples of this class include actinomycin, bacitracin, colistin, and polymyxin B. Actinomycin-D has found use in cancer chemotherapy. Most other polypeptide antibiotics are too toxic for systemic administration, but can safely be administered topically to the skin as an antiseptic for shallow cuts and abrasions. [1]

Contents

Actinomycin-D is believed to produce its cytotoxic effects by binding DNA and inhibiting RNA synthesis. [2] Other polypeptide antibiotics are thought to act by permeabilizing the bacterial cell membrane, but the details are largely unknown. [3]

Animal studies have shown actinomycin-D is corrosive to skin, irritating to the eyes and mucous membranes of the respiratory tract, and highly toxic by the oral route. It has also been shown to be carcinogenic, mutagenic, embryotoxic and teratogenic. [2] Adverse effects of other polypeptide antibiotics include kidney and nerve damage when given by injection.

Polypeptide antibiotics are produced by all living organisms; largely by bacteria and generally function as natural host defence, presenting new medicinal opportunities. [4] These antibiotics act via permeabilising the bacterial cell membrane, or neutralising is toxicity to cause cell death in bacteria. [5] Its predominant clinical use is as a topical medication, however successful laboratory trials are limited. A common polypeptide antibiotic is bacitracin, derived from the bacteria; Bacillus subtilis . [6] As a therapeutic drug, it has minimal harmful effects and low toxicity, however side effects in patients may include minor skin irritation and anaphylaxis in severe cases. [7]

The development of new polypeptide antibiotics are used as an alternative drug therapy for patients with resistance to more commonly used medications. [8] However further research is required to support the safety of use, and the biological response of the human body to polypeptide antibiotics. [9]

History

In 1947, polymyxins, the first antibiotic polypeptides were discovered, produced by the bacterium Paenibacillus polymyxa. [10] 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). [9] As a result of new safety procedures, during the 1960s classes of polymyxins including colistin, became less popular due to the discovery of their toxic natures. The re-emergence of colistin use began in the late 1980s, via intravenous injection (IV) methods or inhalation to manage bacterial infections for which no other options are available, such as those caused by P. aeruginosa . [9]

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. [4] This inhibition causes the permeability of the cell envelope to increase, cell contents leakage, and eventually cell death. [11] [4] 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. [11] [12]

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. [6] It does this by inhibiting the removal of phosphate from lipid compounds, thus deactivating its function to transport peptidoglycan; the main component of bacterial cell membranes, to the microbial cell wall. [13]

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. [14] 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. [15] 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. [16] 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. [17] Patients who continued to have new development of lesions further required alternative drug therapy, in a study undertaken by Ruby and Nelson, 1973. [13] [17] [18] 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. [5] [8] The application of polymyxin to treat serious cases of infections caused by Pseudomonas aeruginosa strains is rare. It is used when the patient has developed resistance to less toxic and more commonly used antibiotics, in this case are aminoglycosides and antipseudomonal penicillins. [8] 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. [19]

Polymyxin E, also referred to as colistin, is one of the few polypeptide antibiotics able to be systematically absorbed via oral consumption. [20] 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. [19]

Bleomycin

Bleomycin is a polypeptide antibiotic derived from a bacterium, Streptomyces verticillus. Its mechanism of action involves bleomycin binding to guanine bases in deoxyribonucleic acid (DNA) with the oxidation of ferrous iron to ferric iron. [21] 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. [21]

Bleomycin's medical application is as an anti-tumour drug mainly in germinative tumours and Hodgkin's lymphoma, however its use is limited by pulmonary toxicity. [22] [23] In a study of combining bleomycin and other medicinal agents in bladder cancer cells, results showed bleomycin induced DNA damage to all the cell lines tested. [24] Thus, bleomycin as a combination therapy may be an option to treat tumours. [24] Efficacy rates of bleomycin in conjunction with cisplatin and etoposide in testicular cancer is approximately 90% successful. [25] Bleomycin also does not induce myelosuppression with decreased bone marrow activity, or immunosuppression; suppressing the immune responses in patients unlike alternative cytotoxic drugs. [26] However, further trials are required as pulmonary toxicity occurs in approximately 10% of patients, with around 1% cases of death due to pulmonary fibrosis. [24]

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. [27] 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. [28] This method of resistance occurrence may account for the inability for polypeptide antibiotics to act on gram-negative bacterium i.e. bacteria with thin peptidoglycan layers, where cases of changes of growth medium produced changes in the outer membrane. [28]

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. [13] [29] 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. [27]

Bacteria when grown and replicated in concentrations under toxic levels do not develop secondary resistance; in which patients initially respond to the antibiotic, but subsequently develop resistance. [27] This may factor in the ability for polypeptide antibiotics to survive in nature, and allow for the development of new antibiotics to regulate resistance of drugs and other classes of antibiotics. [27]

With the increase in cases of drug resistance to conventional medications, the development of new alternative drugs such as polypeptide antibiotics is required. The ability for polypeptide to overcome resistance in most cases, stems from their mechanism of action to inhibit cell wall synthesis, and thus prevent the multiplication of bacterial cells before resistance is able to develop. [30]

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. [7] Clinical trials and studies with polypeptide antibiotic use during pregnancy are limited, and have produced no definite conclusions of risk to the foetus. [5] However, use of bacitracin as a topical or ophthalmic medication is considered relatively safe during breastfeeding, due to the skin's low absorption rate of chemicals. [7]

Bacitracin has minimal adverse effects and relatively low toxicity. [7] Side effects such as minor skin irritation, fever and nausea are present in some instances. [7] However, cases of anaphylaxis; a severe allergic reaction which can potentially lead to death, have been reported after multiple uses of topical bacitracin on lesions in patients. [31] Bacitracin use as an irrigation solution and topical bacitracin use after rhinoplasty procedures have also produced rare cases of anaphylaxis. [7]

Use of polymyxins may cause nephrotoxicity and neuropathy; damage to the kidney via systemic use of drugs or toxins, and nerve damage that can cause pain, numbness and weakness respectively. [7] Colistin is considered to have high toxicity, mainly having renal and neurological effects, including but not limited to decreased urine secretion, increased urea nitrogen concentrations in the blood and acute tubular necrosis. [7] This is the result of Colistin removal via renal excretion, thus renal function should be monitored. Neurological effects are more common to develop in children, causing weakness, lethargy, confusion and respiratory paralysis. [7]

Bleomycin use causes side effects ranging from nausea, vomiting, anorexia and fevers, to fatal pulmonary toxicity in 1–2% of cases resulting in death. [24] [32] 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. [23] Immediately after administration, bleomycin can also cause fever chills and hypotension or low blood pressure. However, the main limiting factor or bleomycin use is pulmonary toxicity. Reactive oxygen species produced via the redox reactions that occur due to its mechanism of action involving binding to guanine bases in DNA, which results in reduced membrane stability. [23] 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. [23]

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. [7] Most investigations conclude they act via lysing cell membranes, however whether they act independently or coupled with other factors is undetermined. [5] [33]

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. [9]

Optimal dosages for Polymyxins have been studied, however produced definitive conclusions caused by design limitations of the study and an insufficient amount of clinical trials carried out. [34] 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. [34]

Areas for research on bleomycin include documenting the toxicity that occurs in roughly 10% of cases. [35] 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. [35] Investigations on identification of patients with pulmonary toxicity caused by bleomycin are also incomplete, as other common syndromes observed in cancer patients produce visually similar X-rays. [36] [37]

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. [30]

The ability for antibiotic polypeptides to overcome the challenge of bacteria developing resistance in most cases, is derived from their inhibition of cell wall synthesis and thus bacterial cell replication. [30] However, whilst this acts against bacteria during multiplication, microbes generally exist outside of replication. Thus producing a new challenge, and providing an area for potential future research on polypeptide antibiotic mechanism of actions and how to manipulate them. [38]

Related Research Articles

<span class="mw-page-title-main">Antibiotic</span> Antimicrobial substance active against bacteria

An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of such infections. They may either kill or inhibit the growth of bacteria. A limited number of antibiotics also possess antiprotozoal activity. Antibiotics are not effective against viruses such as the ones which cause the common cold or influenza. Drugs which inhibit growth of viruses are termed antiviral drugs or antivirals. Antibiotics are also not effective against fungi. Drugs which inhibit growth of fungi are called antifungal drugs.

<span class="mw-page-title-main">Vancomycin</span> Antibiotic medication

Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections. It is administered intravenously to treat complicated skin infections, bloodstream infections, endocarditis, bone and joint infections, and meningitis caused by methicillin-resistant Staphylococcus aureus. Blood levels may be measured to determine the correct dose. Vancomycin is also taken orally to treat Clostridioides difficile infections. When taken orally, it is poorly absorbed.

<i>Klebsiella pneumoniae</i> Species of bacterium

Klebsiella pneumoniae is a Gram-negative, non-motile, encapsulated, lactose-fermenting, facultative anaerobic, rod-shaped bacterium. It appears as a mucoid lactose fermenter on MacConkey agar.

<span class="mw-page-title-main">Aminoglycoside</span> Antibacterial drug

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer more generally to any organic molecule that contains amino sugar substructures. Aminoglycoside antibiotics display bactericidal activity against Gram-negative aerobes and some anaerobic bacilli where resistance has not yet arisen but generally not against Gram-positive and anaerobic Gram-negative bacteria.

<span class="mw-page-title-main">Polymyxin</span> Group of antibiotics

Polymyxins are antibiotics. Polymyxins B and E are used in the treatment of Gram-negative bacterial infections. They work mostly by breaking up the bacterial cell membrane. They are part of a broader class of molecules called nonribosomal peptides.

<span class="mw-page-title-main">Aztreonam</span> Chemical compound

Aztreonam, sold under the brand name Azactam among others, is an antibiotic used primarily to treat infections caused by gram-negative bacteria such as Pseudomonas aeruginosa. This may include bone infections, endometritis, intra abdominal infections, pneumonia, urinary tract infections, and sepsis. It is given by intravenous or intramuscular injection or by inhalation.

<span class="mw-page-title-main">Nitrofurantoin</span> Antibacterial drug

Nitrofurantoin, sold under the brand name Macrobid among others, is an antibacterial medication of the nitrofuran class used to treat urinary tract infections (UTIs), although it is not as effective for kidney infections. It is taken by mouth.

<span class="mw-page-title-main">Colistin</span> Antibiotic

Colistin, also known as polymyxin E, is an antibiotic medication used as a last-resort treatment for multidrug-resistant Gram-negative infections including pneumonia. These may involve bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter. It comes in two forms: colistimethate sodium can be injected into a vein, injected into a muscle, or inhaled, and colistin sulfate is mainly applied to the skin or taken by mouth. Colistimethate sodium is a prodrug; it is produced by the reaction of colistin with formaldehyde and sodium bisulfite, which leads to the addition of a sulfomethyl group to the primary amines of colistin. Colistimethate sodium is less toxic than colistin when administered parenterally. In aqueous solutions, it undergoes hydrolysis to form a complex mixture of partially sulfomethylated derivatives, as well as colistin. Resistance to colistin began to appear as of 2015.

<span class="mw-page-title-main">Bacitracin</span> Polypeptide antibiotic

Bacitracin is a polypeptide antibiotic. It is a mixture of related cyclic peptides produced by Bacillus licheniformis bacteria, that was first isolated from the variety "Tracy I" in 1945. These peptides disrupt Gram-positive bacteria by interfering with cell wall and peptidoglycan synthesis.

<span class="mw-page-title-main">Neomycin/polymyxin B/bacitracin</span> Antibiotic medication

Neomycin/polymyxin B/bacitracin, also known as triple antibiotic ointment, is an antibiotic medication used to reduce the risk of infections following minor skin injuries. It contains the three antibiotics neomycin, polymyxin B, and bacitracin. It is for topical use.

<i>Pseudomonas aeruginosa</i> Species of bacterium

Pseudomonas aeruginosa is a common encapsulated, Gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, P. aeruginosa is a multidrug resistant pathogen recognized for its ubiquity, its intrinsically advanced antibiotic resistance mechanisms, and its association with serious illnesses – hospital-acquired infections such as ventilator-associated pneumonia and various sepsis syndromes. P. aeruginosa is able to selectively inhibit various antibiotics from penetrating its outer membrane - and has high resistance to several antibiotics. According to the World Health Organization P. aeruginosa poses one of the greatest threats to humans in terms of antibiotic resistance.

<i>Burkholderia cepacia</i> complex Species of bacterium

Burkholderia cepacia complex (BCC) is a species complex consisting of Burkholderia cepacia and at least 20 different biochemically similar species of Gram-negative bacteria. They are catalase-producing and lactose-nonfermenting. Members of BCC are opportunistic human pathogens that most often cause pneumonia in immunocompromised individuals with underlying lung disease. Patients with sickle-cell haemoglobinopathies are also at risk. The species complex also attacks young onion and tobacco plants, and displays a remarkable ability to digest oil.

<span class="mw-page-title-main">Amikacin</span> Antibiotic medication

Amikacin is an antibiotic medication used for a number of bacterial infections. This includes joint infections, intra-abdominal infections, meningitis, pneumonia, sepsis, and urinary tract infections. It is also used for the treatment of multidrug-resistant tuberculosis. It is used by injection into a vein using an IV or into a muscle.

<span class="mw-page-title-main">Polymyxin B</span> Antibiotic medication

Polymyxin B, sold under the brand name Poly-Rx among others, is an antibiotic used to treat meningitis, pneumonia, sepsis, and urinary tract infections. While it is useful for many Gram negative infections, it is not useful for Gram positive infections. It can be given by injection into a vein, muscle, or cerebrospinal fluid or inhaled. The injectable form is generally only used if other options are not available. It is also available as the combinations bacitracin/polymyxin B and neomycin/polymyxin B/bacitracin for use on the skin.

<i>Acinetobacter baumannii</i> Species of bacterium

Acinetobacter baumannii is a typically short, almost round, rod-shaped (coccobacillus) Gram-negative bacterium. It is named after the bacteriologist Paul Baumann. It can be an opportunistic pathogen in humans, affecting people with compromised immune systems, and is becoming increasingly important as a hospital-derived (nosocomial) infection. While other species of the genus Acinetobacter are often found in soil samples, it is almost exclusively isolated from hospital environments. Although occasionally it has been found in environmental soil and water samples, its natural habitat is still not known.

<span class="mw-page-title-main">Tyrothricin</span> Chemical compound

Tyrothricin is an antibiotic mixture which was isolated from Brevibacillus brevis by Rene Dubos in the late 1930s. It was later shown by Dubos and Rollin Hotchkiss to be a mixture of two different antibiotics: gramicidin and tyrocidine.

Multidrug resistant Gram-negative bacteria are a type of Gram-negative bacteria with resistance to multiple antibiotics. They can cause bacteria infections that pose a serious and rapidly emerging threat for hospitalized patients and especially patients in intensive care units. Infections caused by MDR strains are correlated with increased morbidity, mortality, and prolonged hospitalization. Thus, not only do these bacteria pose a threat to global public health, but also create a significant burden to healthcare systems.

Antibiotic synergy is one of three responses possible when two or more antibiotics are used simultaneously to treat an infection. In the synergistic response, the applied antibiotics work together to produce an effect more potent than if each antibiotic were applied singly. Compare to the additive effect, where the potency of an antibiotic combination is roughly equal to the combined potencies of each antibiotic singly, and antagonistic effect, where the potency of the combination is less than the combined potencies of each antibiotic.

<span class="mw-page-title-main">MCR-1</span>

The mobilized colistin resistance (mcr) gene confers plasmid-mediated resistance to colistin, one of a number of last-resort antibiotics for treating Gram-negative infections. mcr-1, the original variant, is capable of horizontal transfer between different strains of a bacterial species. After discovery in November 2015 in E. coli from a pig in China it has been found in Escherichia coli, Salmonella enterica, Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae. As of 2017, it has been detected in more than 30 countries on 5 continents in less than a year.

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