Polypeptide antibiotic: Difference between revisions

From Wikipedia, the free encyclopedia
Browse history interactively
← Previous editNext edit →
Content deleted Content added
VisualWikitext
Rescuing 1 sources and tagging 0 as dead. #IABot (v1.6.5)
Recent changes
Line 1: Line 1:
{{Infobox drug class
| Image = Bacitracin structure.svg
| Alt =
| Caption = [[Bacitracin]], a polypeptide antibiotic derived from Bacillus subtilis.
| Synonyms =
<!-- Class identifiers -->
| Use = Various
| ATC_prefix = D06A
| Biological_target = [[Cell Wall]], [[Peptidoglycan]]
| Chemical_class = [[Polypeptides]]
<!-- Clinical data -->
| Drugs.com = {{Drugs.com|drug-class|antibiotics}}
}}

{{Use dmy dates|date=May 2012}}
{{Use dmy dates|date=May 2012}}
'''Polypeptide antibiotics''' are a chemically diverse [[antibiotic classes|class]] of [[antibiotics|anti-infective]] and [[Chemotherapy#Cytotoxic antibiotics|antitumor antibiotic]]s 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.<ref>[http://www.olemiss.edu/courses/phcy201/cdh2.htm The University of Mississippi - Antibiotics] {{webarchive|url=https://web.archive.org/web/20080609060831/http://www.olemiss.edu/courses/phcy201/cdh2.htm |date=9 June 2008 }}</ref>
'''Polypeptide antibiotics''' are a chemically diverse [[antibiotic classes|class]] of [[antibiotics|anti-infective]] and [[Chemotherapy#Cytotoxic antibiotics|antitumor antibiotic]]s 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.<ref>[http://www.olemiss.edu/courses/phcy201/cdh2.htm The University of Mississippi - Antibiotics] {{webarchive|url=https://web.archive.org/web/20080609060831/http://www.olemiss.edu/courses/phcy201/cdh2.htm |date=9 June 2008 }}</ref>
Line 5: Line 19:


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 [[carcinogen]]ic, mutagenic, embryotoxic and teratogenic.<ref name=actoD/> Adverse effects of other polypeptide antibiotics include kidney and nerve damage when given by injection.
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 [[carcinogen]]ic, mutagenic, embryotoxic and teratogenic.<ref name=actoD/> 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.<ref>{{Cite journal|last=Hancock|first=Robert E. W.|last2=Chapple|first2=Daniel S.|date=June 1999|title=Peptide Antibiotics|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC89271/|journal=Antimicrobial Agents and Chemotherapy|volume=43|issue=6|pages=1317–1323|issn=0066-4804|pmid=10348745|access-date=11 April 2020|via=}}</ref> These [[Antibiotic|antibiotics]] act via permeabilising the bacterial cell membrane, or neutralising is toxicity to cause cell death in bacteria.<ref name=":4">{{Cite web|title=Polypeptide Antibiotics: Bacitracin, Colistin, Polymyxin B - Infectious Diseases|url=https://www.msdmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/polypeptide-antibiotics-bacitracin,-colistin,-polymyxin-b|last=Werth|first=Brian J.|date=May 2020|website=MSD Manual Professional Edition|language=en|url-status=live|archive-url=|archive-date=|access-date=2020-04-11}}</ref> 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|''Bacillus subtilis'']].<ref>{{Cite web|title=Polypeptide Antibacterials|url=http://www.cyto.purdue.edu/cdroms/cyto2/17/chmrx/polypep.htm|last=Coppoc|first=Gordon L.|date=April 1996|website=www.cyto.purdue.edu|url-status=live|archive-url=|archive-date=|access-date=2020-03-30}}</ref> 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.<ref name=":7" />

The development of new polypeptide antibiotics are used as an alternative drug therapy for patients with resistance to more commonly used medications.<ref name=":9" /> However further research is required to support the safety of use, and the biological response of the human body to polypeptide antibiotics.<ref name=":8" />

==History==
{{See also|Protein structure}}In 1947, [[Polymyxin|Polymyxins]], the first antibiotic polypeptides were discovered, produced by the bacterium ''[[Paenibacillus polymyxa]].''<ref>{{Cite journal|last=Wrong|first=N. M.|last2=Smith|first2=R. C.|last3=Hudson|first3=A. L.|last4=Hair|first4=H. C.|date=June 1951|title=The treatment of pyogenic skin infections with bacitracin ointment|url=https://www.ncbi.nlm.nih.gov/pubmed/14835814|journal=Treatment Services Bulletin. Canada. Department of Veterans' Affairs|volume=6|issue=6|pages=257–261|pmid=14835814|via=}}</ref> 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).<ref name=":8" /> 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 ''[[Pseudomonas aeruginosa|P. aeruginosa]]''.<ref name=":8">{{Cite journal|last=Nation|first=Roger L|last2=Li|first2=Jian|date=December 2009|title=Colistin in the 21st Century|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869076/|journal=Current opinion in infectious diseases|volume=22|issue=6|pages=535–543|doi=10.1097/QCO.0b013e328332e672|issn=0951-7375|pmc=2869076|pmid=19797945|via=}}</ref>

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.<ref name=":11" /> This inhibition causes the permeability of the [[cell envelope]] to increase, cell contents leakage, and eventually [[cell death]].<ref name=":12">{{Cite journal|last=Falagas|first=Matthew E.|last2=Kasiakou|first2=Sofia K.|last3=Saravolatz|first3=Louis D.|date=2005-05-01|title=Colistin: The Revival of Polymyxins for the Management of Multidrug-Resistant Gram-Negative Bacterial Infections|url=https://academic.oup.com/cid/article/40/9/1333/371785|journal=Clinical Infectious Diseases|language=en|volume=40|issue=9|pages=1333–1341|doi=10.1086/429323|issn=1058-4838}}</ref><ref name=":11">{{Cite journal|last=Hancock|first=Robert E. W.|last2=Chapple|first2=Daniel S.|date=June 1999|title=Peptide Antibiotics|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC89271/|journal=Antimicrobial Agents and Chemotherapy|volume=43|issue=6|pages=1317–1323|issn=0066-4804|pmid=10348745|via=}}</ref> 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.<ref name=":12" /><ref>{{Cite journal|last=Patrzykat|first=Aleksander|last2=Friedrich|first2=Carol L.|last3=Zhang|first3=Lijuan|last4=Mendoza|first4=Valentina|last5=Hancock|first5=Robert E. W.|date=March 2002|title=Sublethal Concentrations of Pleurocidin-Derived Antimicrobial Peptides Inhibit Macromolecular Synthesis in Escherichia coli|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC127508/|journal=Antimicrobial Agents and Chemotherapy|volume=46|issue=3|pages=605–614|doi=10.1128/AAC.46.03.605-614.2002|issn=0066-4804|pmid=11850238|via=}}</ref>

==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.<ref>{{Cite web|title=Polypeptide Antibacterials|url=http://www.cyto.purdue.edu/cdroms/cyto2/17/chmrx/polypep.htm|last=Coppoc|first=Gordon L.|date=April 1996|website=www.cyto.purdue.edu|url-status=live|archive-url=|archive-date=|access-date=2020-03-30}}</ref> 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. <ref name=":10">{{cite journal |last1=O'Donnell |first1=Judith A. |last2=Gelone |first2=Steven P. |last3=Safdar |first3=Amar |title=Topical Antibacterials |journal=Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases |date=2015 |volume=1 |pages=452-462}}</ref>

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<ref>{{cite journal |last1=Gallagher |first1=James J. |last2=Branksi |first2=Ludwik K. |last3=Williams-Bouyer |first3=Natalie |last4=Villarreal |first4=Cynthia |last5=Herndon |first5=David N. |title=Treatment of infection in burns |journal=Total Burn Care |date=2012 |pages=137-156}}</ref>. [[Pseudomembranous colitis]]; the inflammation of the large intestine was successfully treated with Bacitracin as an oral treatment, in the case of the two patients suffering relapses of the infection and allergic reactions, respectively, to the common antibiotic treatment with [[vancomycin]].<ref>{{Cite journal|last=Tedesco|first=F. J.|date=September 1980|title=Bacitracin therapy in antibiotic-associated pseudomembranous colitis|url=https://www.ncbi.nlm.nih.gov/pubmed/6903494|journal=Digestive Diseases and Sciences|volume=25|issue=10|pages=783–784|doi=10.1007/BF01345299|issn=0163-2116|pmid=6903494|via=}}</ref> Bacitracin was 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.<ref name=":5" /> Patients who continued to have new development of lesions further required alternative drug therapy, in a study undertaken by Ruby and Nelson, 1973.<ref name=":0">{{cite journal |last1=O'Donnell |first1=Judith A. |last2=Gelone |first2=Steven P. |last3=Safdar |first3=Amar |title=Topical Antibacterials |journal=Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases |date=2015 |volume=1 |pages=452-462}}</ref><ref name=":5">{{cite journal|last1=Junkins-Hopkins|first1=Jacqueline M.|date=April 2010|editor-last=Busam|editor-first=Klaus J.|title=Blistering Skin Diseases|url=|journal=Dermatopathology|volume=|pages=210-249|via=}}</ref><ref>{{Cite journal|last=Koning|first=Sander|last2=van der Sande|first2=Renske|last3=Verhagen|first3=Arianne P|last4=van Suijlekom‐Smit|first4=Lisette WA|last5=Morris|first5=Andrew D|last6=Butler|first6=Christopher C|last7=Berger|first7=Marjolein|last8=van der Wouden|first8=Johannes C|date=2012-01-18|title=Interventions for impetigo|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025440/|journal=The Cochrane Database of Systematic Reviews|volume=2012|issue=1|doi=10.1002/14651858.CD003261.pub3|issn=1469-493X|pmc=7025440|pmid=22258953}}</ref> As a result, further studies of Bacitracin treatment in Impetigo, and to compare vancomycin and bacitracin are required.

=== Polymyxins ===
[[Polymyxin|Polymyxins]] are a of class polypeptide antibiotics that act on bacteria via disrupting the transport mechanism of the cell wall.<ref name=":4" /><ref name=":9" /> The application of polymyxin to treat serious cases of infections caused by [[Pseudomonas aeruginosa|''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.<ref name=":9">{{Cite journal|last=Tam|first=Vincent H.|last2=Schilling|first2=Amy N.|last3=Vo|first3=Giao|last4=Kabbara|first4=Samer|last5=Kwa|first5=Andrea L.|last6=Wiederhold|first6=Nathan P.|last7=Lewis|first7=Russell E.|date=September 2005|title=Pharmacodynamics of Polymyxin B against Pseudomonas aeruginosa|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1195418/|journal=Antimicrobial Agents and Chemotherapy|volume=49|issue=9|pages=3624–3630|doi=10.1128/AAC.49.9.3624-3630.2005|issn=0066-4804|pmc=1195418|pmid=16127031|via=}}</ref> 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.<ref>{{Cite book|last=Shanson|first=D.C|title=Microbiology in Clinical Practice|publisher=Butterworth-Heinemann|year=1989|isbn=978-0-7236-1403-6|location=|pages=51-118}}</ref>

Polymyxin E, a compound of polymyxin also referred to as [[Colistin]], is one of the few polypeptide antibiotics able to systematically absorb via oral consumption.<ref>{{Cite web|url=https://www.msdmanuals.com/en-au/professional/infectious-diseases/bacteria-and-antibacterial-drugs/polypeptide-antibiotics-bacitracin,-colistin,-polymyxin-b|title=Polypeptide Antibiotics: Bacitracin, Colistin, Polymyxin B - Infectious Diseases|website=MSD Manual Professional Edition|language=en-AU|access-date=2020-04-12}}</ref> It is used in treatment of Leukaemia patients who suffer low levels of white blood cells. With use, non-toxic side effects of casts and azotaemia in the urine are observed in most patients.<ref name=":2">{{Cite journal|last=Shanson|first=D.C|date=1989|title=Antimicrobial chemotherapy—general principles|url=|journal=Microbiology in Clinical Practice|volume=|pages=51-118|via=}}</ref>

==Resistance==
{{See also|Drug 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.<ref name=":1">{{Cite journal|last=Axelsen|first=Paul H.|date=2008-03-01|title=A Chaotic Pore Model of Polypeptide Antibiotic Action|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2242772/|journal=Biophysical Journal|volume=94|issue=5|pages=1549–1550|doi=10.1529/biophysj.107.124792|issn=0006-3495|pmc=2242772|pmid=18065456}}</ref> 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.<ref name=":6" /> 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.<ref name=":6">{{Cite journal|last=Lysenko|first=E. S.|last2=Gould|first2=J.|last3=Bals|first3=R.|last4=Wilson|first4=J. M.|last5=Weiser|first5=J. N.|date=March 2000|title=Bacterial phosphorylcholine decreases susceptibility to the antimicrobial peptide LL-37/hCAP18 expressed in the upper respiratory tract|url=https://www.ncbi.nlm.nih.gov/pubmed/10678986|journal=Infection and Immunity|volume=68|issue=3|pages=1664–1671|doi=10.1128/iai.68.3.1664-1671.2000|issn=0019-9567|pmid=10678986}}</ref>

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''.<ref name=":10" /><ref>{{Cite journal|last=Chambers|first=Henry F.|last2=DeLeo|first2=Frank R.|date=September 2009|title=Waves of Resistance: Staphylococcus aureus in the Antibiotic Era|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871281/|journal=Nature reviews. Microbiology|volume=7|issue=9|pages=629–641|doi=10.1038/nrmicro2200|issn=1740-1526|pmc=2871281|pmid=19680247|via=}}</ref> This is an issue in patients suffering from 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.<ref name=":1" />

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.<ref name=":1" /> 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.<ref name=":1" />
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.<ref name=":13">{{Cite journal|last=Clardy|first=Jon|last2=Fischbach|first2=Michael A.|last3=Walsh|first3=Christopher T.|date=December 2006|title=New antibiotics from bacterial natural products|url=https://www.nature.com/articles/nbt1266|journal=Nature Biotechnology|language=en|volume=24|issue=12|pages=1541–1550|doi=10.1038/nbt1266|issn=1546-1696|via=}}</ref>

==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]].<ref name=":3" /> Clinical trials and studies with polypeptide antibiotic use during pregnancy are limited, and have produced no definite conclusions of risk to the foetus.<ref name=":14" /> However use of Bacitracin as a [[Topical medication|topical]] or [[Ophthalmic drug administration|ophthalmic]] medication is considered relatively safe during breastfeeding, due to the skins low absorption rate of chemicals.<ref name=":3">{{Citation|last=Nguyen|first=Rosalee|title=Bacitracin Topical|date=2020|url=http://www.ncbi.nlm.nih.gov/books/NBK536993/|work=StatPearls|publisher=StatPearls Publishing|pmid=30725678|access-date=2020-04-19|last2=Sun|first2=Yan}}</ref>

Bacitracin has minimal adverse effects and relatively low toxicity.<ref name=":7" /> Side effects such as minor skin irritation, fever and nausea are present in some instances.<ref name=":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.<ref>{{Cite web|url=https://www.allergy.org.au/patients/about-allergy/anaphylaxis|title=Anaphylaxis|last=Administrator|website=Australasian Society of Clinical Immunology and Allergy (ASCIA)|language=en-gb|access-date=2020-03-30}}</ref> The use of bacitracin as an irrigation solution as well as topically after rhinoplasty procedures have also produced rare cases of anaphylaxis.<ref name=":7">{{Citation|last=Nguyen|first=Rosalee|title=Bacitracin Topical|date=2020|url=http://www.ncbi.nlm.nih.gov/books/NBK536993/|work=StatPearls|publisher=StatPearls Publishing|pmid=30725678|access-date=2020-04-15|last2=Sun|first2=Yan}}</ref>

<br />
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.<ref name=":3" /> 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.<ref name=":3" /> 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.<ref name=":3" />

==Future research==

Despite multiple research articles on polypeptide antibiotics, the understanding of their mechanism of action and the extent of their toxicity and effects remain unknown.<ref name=":3" /> Most investigations conclude they act via lysing cell membranes, however whether they act independently or coupled with other factors is undetermined.<ref name=":4" /><ref>{{Cite journal|last=Kohanski|first=Michael A|last2=Dwyer|first2=Daniel J|last3=Collins|first3=James J|date=June 2010|title=How antibiotics kill bacteria: from targets to networks|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896384/|journal=Nature reviews. Microbiology|volume=8|issue=6|pages=423–435|doi=10.1038/nrmicro2333|issn=1740-1526|pmc=2896384|pmid=20440275|via=}}</ref><ref name=":14">{{Cite web|title=Polypeptide Antibiotics: Bacitracin, Colistin, Polymyxin B - Infectious Diseases|url=https://www.msdmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/polypeptide-antibiotics-bacitracin,-colistin,-polymyxin-b|last=Werth|first=Brian J.|date=May 2020|website=MSD Manual Professional Edition|language=en|url-status=live|archive-url=|archive-date=|access-date=2020-05-07}}</ref>

Evidence for low toxicity and harmful affects is limited, requiring further research to address the safe use to polypeptides antibiotics. Colistin was developed before drug-safety procedure requirements were instigated, 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.<ref name=":8" />

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.<ref>{{Cite journal|last=Clardy|first=Jon|last2=Fischbach|first2=Michael A.|last3=Walsh|first3=Christopher T.|date=December 2006|title=New antibiotics from bacterial natural products|url=https://www.nature.com/articles/nbt1266|journal=Nature Biotechnology|language=en|volume=24|issue=12|pages=1541–1550|doi=10.1038/nbt1266|issn=1546-1696|via=}}</ref>

The ability for antibiotic polypeptides to overcome resistance in most cases, is derived from their inhibition of cell wall synthesis and thus bacterial cell replication.<ref name=":13" /> 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.<ref>{{Cite journal|last=Coates|first=Anthony|last2=Hu|first2=Yanmin|last3=Bax|first3=Richard|last4=Page|first4=Clive|date=November 2002|title=The future challenges facing the development of new antimicrobial drugs|url=https://www.nature.com/articles/nrd940|journal=Nature Reviews Drug Discovery|language=en|volume=1|issue=11|pages=895–910|doi=10.1038/nrd940|issn=1474-1784|via=}}</ref>


==References==
==References==
{{reflist|colwidth=30em}}
{{reflist|colwidth=30em}}
<br /><references />


{{Cell wall disruptive antibiotics}}
{{Antibiotics and chemotherapeutics for dermatological use}}
{{Throat preparations}}


[[Category:Polypeptide antibiotics| ]]
[[Category:Polypeptide antibiotics| ]]

Revision as of 09:54, 25 May 2020

Polypeptide antibiotic
Drug class
Bacitracin, a polypeptide antibiotic derived from Bacillus subtilis.
Class identifiers
UseVarious
ATC codeD06A
Biological targetCell Wall, Peptidoglycan
Chemical classPolypeptides
Clinical data
Drugs.comDrug 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]

Actinomycin-D is believed to produce its cytotoxic effects by binding DNA and inhibiting RNA synthesis.[2] The mechanism of action of other polypeptide antibiotics is thought to be directed to bacterial membranes, 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

See also: Protein structure

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.[11] This inhibition causes the permeability of the cell envelope to increase, cell contents leakage, and eventually cell death.[12][11] 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.[12][13]

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.[14] 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. [15]

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[16]. Pseudomembranous colitis; the inflammation of the large intestine was successfully treated with Bacitracin as an oral treatment, in the case of the two patients suffering relapses of the infection and allergic reactions, respectively, to the common antibiotic treatment with vancomycin.[17] Bacitracin was 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.[18] Patients who continued to have new development of lesions further required alternative drug therapy, in a study undertaken by Ruby and Nelson, 1973.[19][18][20] As a result, further studies of Bacitracin treatment in Impetigo, and to compare vancomycin and bacitracin are required.

Polymyxins

Polymyxins are a of class 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.[21]

Polymyxin E, a compound of polymyxin also referred to as Colistin, is one of the few polypeptide antibiotics able to systematically absorb via oral consumption.[22] It is used in treatment of Leukaemia patients who suffer low levels of white blood cells. With use, non-toxic side effects of casts and azotaemia in the urine are observed in most patients.[23]

Resistance

See also: Drug 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.[24] 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.[25] 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.[25]

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.[15][26] This is an issue in patients suffering from 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.[24]

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.[24] 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.[24]

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.[27]

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.[28] Clinical trials and studies with polypeptide antibiotic use during pregnancy are limited, and have produced no definite conclusions of risk to the foetus.[29] However use of Bacitracin as a topical or ophthalmic medication is considered relatively safe during breastfeeding, due to the skins low absorption rate of chemicals.[28]

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.[30] The use of bacitracin as an irrigation solution as well as topically 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.[28] 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.[28] 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.[28]

Future research

Despite multiple research articles on polypeptide antibiotics, the understanding of their mechanism of action and the extent of their toxicity and effects remain unknown.[28] Most investigations conclude they act via lysing cell membranes, however whether they act independently or coupled with other factors is undetermined.[5][31][29]

Evidence for low toxicity and harmful affects is limited, requiring further research to address the safe use to polypeptides antibiotics. Colistin was developed before drug-safety procedure requirements were instigated, 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]

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.[32]

The ability for antibiotic polypeptides to overcome resistance in most cases, is derived from their inhibition of cell wall synthesis and thus bacterial cell replication.[27] 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.[33]

References

  1. ^ The University of Mississippi - Antibiotics Archived 9 June 2008 at the Wayback Machine
  2. ^ a b Cosmegen (dactinomycin for injection) Prescribing Information.Revised: 05/2010, Lundbeck Inc.
  3. ^ Axelsen, PH (1 March 2008). "A chaotic pore model of polypeptide antibiotic action". Biophysical Journal. 94 (5): 1549–50. doi:10.1529/biophysj.107.124792. PMC 2242772. PMID 18065456.
  4. ^ Hancock, Robert E. W.; Chapple, Daniel S. (June 1999). "Peptide Antibiotics". Antimicrobial Agents and Chemotherapy. 43 (6): 1317–1323. ISSN 0066-4804. PMID 10348745. Retrieved 11 April 2020.
  5. ^ a b c Werth, Brian J. (May 2020). "Polypeptide Antibiotics: Bacitracin, Colistin, Polymyxin B - Infectious Diseases". MSD Manual Professional Edition. Retrieved 11 April 2020.{{cite web}}: CS1 maint: url-status (link)
  6. ^ Coppoc, Gordon L. (April 1996). "Polypeptide Antibacterials". www.cyto.purdue.edu. Retrieved 30 March 2020.{{cite web}}: CS1 maint: url-status (link)
  7. ^ a b c d Nguyen, Rosalee; Sun, Yan (2020), "Bacitracin Topical", StatPearls, StatPearls Publishing, PMID 30725678, retrieved 15 April 2020
  8. ^ a b c Tam, Vincent H.; Schilling, Amy N.; Vo, Giao; Kabbara, Samer; Kwa, Andrea L.; Wiederhold, Nathan P.; Lewis, Russell E. (September 2005). "Pharmacodynamics of Polymyxin B against Pseudomonas aeruginosa". Antimicrobial Agents and Chemotherapy. 49 (9): 3624–3630. doi:10.1128/AAC.49.9.3624-3630.2005. ISSN 0066-4804. PMC 1195418. PMID 16127031.
  9. ^ a b c d Nation, Roger L; Li, Jian (December 2009). "Colistin in the 21st Century". Current opinion in infectious diseases. 22 (6): 535–543. doi:10.1097/QCO.0b013e328332e672. ISSN 0951-7375. PMC 2869076. PMID 19797945.
  10. ^ Wrong, N. M.; Smith, R. C.; Hudson, A. L.; Hair, H. C. (June 1951). "The treatment of pyogenic skin infections with bacitracin ointment". Treatment Services Bulletin. Canada. Department of Veterans' Affairs. 6 (6): 257–261. PMID 14835814.
  11. ^ a b Hancock, Robert E. W.; Chapple, Daniel S. (June 1999). "Peptide Antibiotics". Antimicrobial Agents and Chemotherapy. 43 (6): 1317–1323. ISSN 0066-4804. PMID 10348745.
  12. ^ a b Falagas, Matthew E.; Kasiakou, Sofia K.; Saravolatz, Louis D. (1 May 2005). "Colistin: The Revival of Polymyxins for the Management of Multidrug-Resistant Gram-Negative Bacterial Infections". Clinical Infectious Diseases. 40 (9): 1333–1341. doi:10.1086/429323. ISSN 1058-4838.
  13. ^ Patrzykat, Aleksander; Friedrich, Carol L.; Zhang, Lijuan; Mendoza, Valentina; Hancock, Robert E. W. (March 2002). "Sublethal Concentrations of Pleurocidin-Derived Antimicrobial Peptides Inhibit Macromolecular Synthesis in Escherichia coli". Antimicrobial Agents and Chemotherapy. 46 (3): 605–614. doi:10.1128/AAC.46.03.605-614.2002. ISSN 0066-4804. PMID 11850238.
  14. ^ Coppoc, Gordon L. (April 1996). "Polypeptide Antibacterials". www.cyto.purdue.edu. Retrieved 30 March 2020.{{cite web}}: CS1 maint: url-status (link)
  15. ^ a b O'Donnell, Judith A.; Gelone, Steven P.; Safdar, Amar (2015). "Topical Antibacterials". Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 1: 452–462.
  16. ^ Gallagher, James J.; Branksi, Ludwik K.; Williams-Bouyer, Natalie; Villarreal, Cynthia; Herndon, David N. (2012). "Treatment of infection in burns". Total Burn Care: 137–156.
  17. ^ Tedesco, F. J. (September 1980). "Bacitracin therapy in antibiotic-associated pseudomembranous colitis". Digestive Diseases and Sciences. 25 (10): 783–784. doi:10.1007/BF01345299. ISSN 0163-2116. PMID 6903494.
  18. ^ a b Junkins-Hopkins, Jacqueline M. (April 2010). Busam, Klaus J. (ed.). "Blistering Skin Diseases". Dermatopathology: 210–249.
  19. ^ O'Donnell, Judith A.; Gelone, Steven P.; Safdar, Amar (2015). "Topical Antibacterials". Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 1: 452–462.
  20. ^ Koning, Sander; van der Sande, Renske; Verhagen, Arianne P; van Suijlekom‐Smit, Lisette WA; Morris, Andrew D; Butler, Christopher C; Berger, Marjolein; van der Wouden, Johannes C (18 January 2012). "Interventions for impetigo". The Cochrane Database of Systematic Reviews. 2012 (1). doi:10.1002/14651858.CD003261.pub3. ISSN 1469-493X. PMC 7025440. PMID 22258953.
  21. ^ Shanson, D.C (1989). Microbiology in Clinical Practice. Butterworth-Heinemann. pp. 51–118. ISBN 978-0-7236-1403-6.
  22. ^ "Polypeptide Antibiotics: Bacitracin, Colistin, Polymyxin B - Infectious Diseases". MSD Manual Professional Edition. Retrieved 12 April 2020.
  23. ^ Shanson, D.C (1989). "Antimicrobial chemotherapy—general principles". Microbiology in Clinical Practice: 51–118.
  24. ^ a b c d Axelsen, Paul H. (1 March 2008). "A Chaotic Pore Model of Polypeptide Antibiotic Action". Biophysical Journal. 94 (5): 1549–1550. doi:10.1529/biophysj.107.124792. ISSN 0006-3495. PMC 2242772. PMID 18065456.
  25. ^ a b Lysenko, E. S.; Gould, J.; Bals, R.; Wilson, J. M.; Weiser, J. N. (March 2000). "Bacterial phosphorylcholine decreases susceptibility to the antimicrobial peptide LL-37/hCAP18 expressed in the upper respiratory tract". Infection and Immunity. 68 (3): 1664–1671. doi:10.1128/iai.68.3.1664-1671.2000. ISSN 0019-9567. PMID 10678986.
  26. ^ Chambers, Henry F.; DeLeo, Frank R. (September 2009). "Waves of Resistance: Staphylococcus aureus in the Antibiotic Era". Nature reviews. Microbiology. 7 (9): 629–641. doi:10.1038/nrmicro2200. ISSN 1740-1526. PMC 2871281. PMID 19680247.
  27. ^ a b Clardy, Jon; Fischbach, Michael A.; Walsh, Christopher T. (December 2006). "New antibiotics from bacterial natural products". Nature Biotechnology. 24 (12): 1541–1550. doi:10.1038/nbt1266. ISSN 1546-1696.
  28. ^ a b c d e f Nguyen, Rosalee; Sun, Yan (2020), "Bacitracin Topical", StatPearls, StatPearls Publishing, PMID 30725678, retrieved 19 April 2020
  29. ^ a b Werth, Brian J. (May 2020). "Polypeptide Antibiotics: Bacitracin, Colistin, Polymyxin B - Infectious Diseases". MSD Manual Professional Edition. Retrieved 7 May 2020.{{cite web}}: CS1 maint: url-status (link)
  30. ^ Administrator. "Anaphylaxis". Australasian Society of Clinical Immunology and Allergy (ASCIA). Retrieved 30 March 2020.
  31. ^ Kohanski, Michael A; Dwyer, Daniel J; Collins, James J (June 2010). "How antibiotics kill bacteria: from targets to networks". Nature reviews. Microbiology. 8 (6): 423–435. doi:10.1038/nrmicro2333. ISSN 1740-1526. PMC 2896384. PMID 20440275.
  32. ^ Clardy, Jon; Fischbach, Michael A.; Walsh, Christopher T. (December 2006). "New antibiotics from bacterial natural products". Nature Biotechnology. 24 (12): 1541–1550. doi:10.1038/nbt1266. ISSN 1546-1696.
  33. ^ Coates, Anthony; Hu, Yanmin; Bax, Richard; Page, Clive (November 2002). "The future challenges facing the development of new antimicrobial drugs". Nature Reviews Drug Discovery. 1 (11): 895–910. doi:10.1038/nrd940. ISSN 1474-1784.


Stub icon

This molecular biology article is a stub. You can help Wikipedia by expanding it.

Retrieved from "https://en.wikipedia.org/w/index.php?title=Polypeptide_antibiotic&oldid=958713061"