Editing Polymyxin

{{Short description|Group of antibiotics}}
{{Missing information|the history of Polymyxin|date=August 2019}}
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[[Image:Colistin.svg|class=skin-invert-image|thumb|[[Colistin]]]]
[[Image:Polymyxin B.svg|class=skin-invert-image|thumb|[[Polymyxin B]] (R=H is polymyxin B2, R=CH<sub>3</sub> is polymyxin B1)]]
'''Polymyxins''' are [[antibiotic]]s. Polymyxins [[Polymyxin B|B]] and E (also known as [[colistin]]) 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 peptide]]s.

They are produced in nature by [[Gram-positive bacteria]] such as ''[[Paenibacillus polymyxa]]''.

== Medical use ==
Polymyxin antibiotics are relatively [[neurotoxic]] and [[nephrotoxic]], so are usually used only as a [[drug of last resort|last resort]] if modern antibiotics are ineffective or are contraindicated. Typical uses are for infections caused by strains of [[Multiple drug resistance|multiple drug-resistant]] ''[[Pseudomonas aeruginosa]]'' or [[carbapenemase]]-producing [[Enterobacteriaceae]].<ref name=Velkov2013rev/><ref name="pmid16507149">{{cite journal | vauthors = Falagas ME, Kasiakou SK | title = Toxicity of polymyxins: a systematic review of the evidence from old and recent studies | journal = Critical Care | volume = 10 | issue = 1 | pages = R27 | date = February 2006 | pmid = 16507149 | pmc = 1550802 | doi = 10.1186/cc3995 | doi-access = free }}</ref>  Polymyxins have less effect on [[Gram-positive]] organisms, and are sometimes combined with other agents (as with [[trimethoprim/polymyxin]]) to broaden the effective spectrum.<ref name=Poirel2017rev>{{cite journal | vauthors = Poirel L, Jayol A, Nordmann P | title = Polymyxins: Antibacterial Activity, Susceptibility Testing, and Resistance Mechanisms Encoded by Plasmids or Chromosomes | journal = Clinical Microbiology Reviews | volume = 30 | issue = 2 | pages = 557–596 | date = April 2017 | pmid = 28275006 | pmc = 5355641 | doi = 10.1128/CMR.00064-16 }}</ref>

Polymyxins B are not absorbed from the gastrointestinal tract, so they are only administered orally if the goal is to disinfect the GI tract.<ref name=Poirel2017rev/>  Another [[route of administration]] is chosen for systemic treatment, e.g., parenteral (often intravenously) or by inhalation.<ref name=Velkov2013rev/><ref name=Poirel2017rev/>  They are also used externally as a cream or drops to treat [[otitis externa]]  (swimmers ear), and as a component of [[triple antibiotic ointment]] to treat and prevent skin infections.<ref name=Poirel2017rev/><ref>{{cite web| vauthors = Ogbru O |title=Neomycin sulfate (Cortisporin): Drug Side Effects and Dosing|url=http://www.medicinenet.com/neomycin-polymyxin-hydrocortisone-otic_suspension/article.htm|publisher=MedicineNet|access-date=11 June 2017|language=en}}</ref>

== Mechanism of action ==
After binding to [[lipopolysaccharide]] (LPS) in the outer membrane of Gram-negative bacteria, polymyxins disrupt both the outer and inner membranes. The hydrophobic tail is important in causing membrane damage, suggesting a [[detergent]]-like mode of action.<ref name=Velkov2013rev>{{cite journal | vauthors = Velkov T, Roberts KD, Nation RL, Thompson PE, Li J | title = Pharmacology of polymyxins: new insights into an 'old' class of antibiotics | journal = Future Microbiology | volume = 8 | issue = 6 | pages = 711–724 | date = June 2013 | pmid = 23701329 | pmc = 3852176 | doi = 10.2217/fmb.13.39 }}</ref>

Removal of the hydrophobic tail of polymyxin B yields polymyxin nonapeptide, which still binds to LPS, but no longer kills the bacterial cell. However, it still detectably increases the permeability of the bacterial cell wall to other antibiotics, indicating that it still causes some degree of membrane disorganization.<ref>{{cite book | vauthors = Tsubery H, Ofek I, Cohen S, Fridkin M | title = The Biology and Pathology of Innate Immunity Mechanisms | chapter = Structure activity relationship study of polymyxin B nonapeptide | series = Advances in Experimental Medicine and Biology | volume = 479 | pages = 219–222 | date = 2000-01-01 | pmid = 10897422 | doi = 10.1007/0-306-46831-X_18 | isbn = 978-0-306-46409-6 }}</ref>

Gram-negative bacteria can develop resistance to polymyxins through various modifications of the LPS structure that inhibit the binding of polymyxins to LPS.<ref name="pmid15951433">{{cite journal | vauthors = Tran AX, Lester ME, Stead CM, Raetz CR, Maskell DJ, McGrath SC, Cotter RJ, Trent MS | title = Resistance to the antimicrobial peptide polymyxin requires myristoylation of Escherichia coli and Salmonella typhimurium lipid A | journal = The Journal of Biological Chemistry | volume = 280 | issue = 31 | pages = 28186–28194 | date = August 2005 | pmid = 15951433 | doi = 10.1074/jbc.M505020200 | doi-access = free }}</ref>

[[Antimicrobial resistance|Antibiotic resistance]] to this drug has been increasing, especially in southern China.  Recently the gene ''[[mcr-1]]'', which confers the antibiotic resistance, has been isolated from bacterial plasmids in ''Enterobacteriaceae''.<ref>{{cite journal | vauthors = Wolf J | title = Antibiotic resistance threatens the efficacy of prophylaxis | journal = The Lancet. Infectious Diseases | volume = 15 | issue = 12 | pages = 1368–1369 | date = December 2015 | pmid = 26482598 | doi = 10.1016/S1473-3099(15)00317-5 }}</ref><ref>{{cite journal | vauthors = Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J | title = Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study | journal = The Lancet. Infectious Diseases | volume = 16 | issue = 2 | pages = 161–168 | date = February 2016 | pmid = 26603172 | doi = 10.1016/S1473-3099(15)00424-7 }}</ref>

==Chemistry==
[[File:Polymyxin structure schematic.jpg|thumb|Numbers denote sequence of amino acid loading.]]
Polymyxins are a group of cyclic non-ribosomal polypeptide (NRPs) which are biosynthesized by bacteria belonging to the genus ''[[Paenibacillus]]''. Polymyxins consist of 10 [[amino acid]] residues, six of which are L-[[α,γ-diaminobutyric acid]] (L-DAB). The DAB residues cause polymyxins to have multiple positively charged groups at physiological pH. Seven amino acid residues form the main cyclic component, while the other three extend from one of the cyclic residues as a linear chain terminating in either 6-methyloctanoic acid or 6-methylheptanoic acid at the [[N-terminus]]. During cyclization, residue 10 is bound to the bridging residue 4.<ref>{{Cite book|url=https://books.google.com/books?id=A4zptjOJfKQC&pg=PA423|title=Medicinal Natural Products: A Biosynthetic Approach| vauthors = Dewick PM |date=2002-01-03|publisher=John Wiley & Sons|isbn=9780471496410|language=en}}</ref> The amino acid residues and DAB monomers are generally in the L (levo) configuration, however certain strains such as P. polymyxa PKB1 have been observed to incorporate DAB with the D (dextro) configuration at position 3 producing variations of polymyxin B.<ref name="pmid22195566">{{cite journal | vauthors = Shaheen M, Li J, Ross AC, Vederas JC, Jensen SE | title = Paenibacillus polymyxa PKB1 produces variants of polymyxin B-type antibiotics | journal = Chemistry & Biology | volume = 18 | issue = 12 | pages = 1640–8 | date = December 2011 | pmid = 22195566 | doi = 10.1016/j.chembiol.2011.09.017 }}</ref>

Polymyxin M is also known as "mattacin".<ref name="pmid12569104">{{cite journal | vauthors = Martin NI, Hu H, Moake MM, Churey JJ, Whittal R, Worobo RW, Vederas JC | title = Isolation, structural characterization, and properties of mattacin (polymyxin M), a cyclic peptide antibiotic produced by Paenibacillus kobensis M | journal = The Journal of Biological Chemistry | volume = 278 | issue = 15 | pages = 13124–13132 | date = April 2003 | pmid = 12569104 | doi = 10.1074/jbc.M212364200 | doi-access = free }}</ref>

===Biosynthesis===
[[File:Biosynthesis of Polymyxin D.jpg|Multiple enzyme domains to form Polymyxin D natural product]]

The polymyxins are produced by [[nonribosomal peptide]] synthetase systems in [[Gram-positive bacteria]] such as ''[[Paenibacillus polymyxa]]''.  Like other NRPs, polymyxins are assembled by synthetases with multiple modules, each containing a set of enzyme domains that sequentially operate on the growing chain by adding the next residue and extending the chain through peptide-bond formation and condensation reactions. The final steps involve a thioesterase domain at the C-terminal of the last module to cyclize the molecule and liberate the chain from the enzyme.<ref name="pmid17653357">{{cite journal | vauthors = Kopp F, Marahiel MA | title = Macrocyclization strategies in polyketide and nonribosomal peptide biosynthesis | journal = Natural Product Reports | volume = 24 | issue = 4 | pages = 735–749 | date = August 2007 | pmid = 17653357 | doi = 10.1039/b613652b }}</ref>

== Research ==
Polymyxins are used to neutralize or absorb LPS contaminants in samples, for example in immunological experiments. Minimization of LPS contamination can be important because LPS can evoke strong reactions from immune cells, distorting experimental results.

By increasing permeability of the bacterial membrane system, polymyxin is also used in clinical work to increase the release of secreted toxins, such as ''Shiga'' toxin, from ''Escherichia coli''.<ref name="Yokoyama2000">{{cite journal | vauthors = Yokoyama K, Horii T, Yamashino T, Hashikawa S, Barua S, Hasegawa T, Watanabe H, Ohta M | title = Production of shiga toxin by Escherichia coli measured with reference to the membrane vesicle-associated toxins | journal = FEMS Microbiology Letters | volume = 192 | issue = 1 | pages = 139–144 | date = November 2000 | pmid = 11040442 | doi = 10.1111/j.1574-6968.2000.tb09372.x | doi-access = free }}</ref>

The global problem of advancing [[antimicrobial resistance]] has led to a renewed interest in their use.<ref>{{cite journal | vauthors = Falagas ME, Grammatikos AP, Michalopoulos A | title = Potential of old-generation antibiotics to address current need for new antibiotics | journal = Expert Review of Anti-Infective Therapy | volume = 6 | issue = 5 | pages = 593–600 | date = October 2008 | pmid = 18847400 | doi = 10.1586/14787210.6.5.593 | s2cid = 13158593 }}</ref>

=== Compound Mixtures in Polymyxin B drug ===
----In formulations for the commercial pharmaceutical Polymyxin drug, the principal Polymyxins are B1 and B2, amounting to 75% and 15% of the final mixture, respectively.<ref name=":0">{{cite journal | vauthors = Meng M, Wang L, Liu S, Jaber OM, Gao L, Chevrette L, Reuschel S | title = Simultaneous quantitation of polymyxin B1, polymyxin B2 and polymyxin B1-1 in human plasma and treated human urine using solid phase extraction and liquid chromatography-tandem mass spectrometry | journal = Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences | volume = 1012-1013 | pages = 23–36 | date = February 2016 | pmid = 26803416 | doi = 10.1016/j.jchromb.2016.01.013 }}</ref> Polymyxin B1, in turn, comprises several isomers, like isoleucine-polymyxin B1 and B1-1.<ref name=":0" /> The major impediment in the purification and isolation of one isomer is due to the minimal structural differences between Polymyxin B1 and B2, differing only in one carbon at the 6th position of the fatty acyl side chain linked to the D-Phenylalanine of the structure. Polymyxin B1 contains 6-methyl octanoic acid, while Polymyxin B2 contains 6-methyl heptanoic acid.<ref>{{cite journal | vauthors = Velkov T, Thompson PE, Nation RL, Li J | title = Structure--activity relationships of polymyxin antibiotics | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 5 | pages = 1898–1916 | date = March 2010 | pmid = 19874036 | pmc = 2907661 | doi = 10.1021/jm900999h }}</ref> Similarly, Polymyxins B3 and B4 also differ at this position, with B3 containing octanoic acid and B4 featuring heptanoic acid.<ref>{{cite journal | vauthors = Orwa JA, Govaerts C, Busson R, Roets E, Van Schepdael A, Hoogmartens J | title = Isolation and structural characterization of polymyxin B components | journal = Journal of Chromatography A | volume = 912 | issue = 2 | pages = 369–373 | date = April 2001 | pmid = 11330807 | doi = 10.1016/s0021-9673(01)00585-4 }}</ref>

== See also ==
* [[Polysporin]]
* [[Neosporin]]
* [[Lysis]]

== References ==
{{reflist|2}}

{{Cell wall disruptive antibiotics}}

[[Category:Polymyxin antibiotics]]
[[Category:Polypeptide antibiotics]]