Bacitracin

Bacitracin

Systematic (IUPAC) name
(4R)-4-[(2S)-2-({2-[(1S)-1-amino-2-methylbutyl]- 4,5-dihydro-1,3-thiazol-5-yl}formamido)-4-methylpentanamido]-4-{[(1S)- 1-{[(3S,6R,9S,12R,15S,18R,21S)- 18-(3-aminopropyl)-12-benzyl-15-(butan-2-yl)-3-(carbamoylmethyl)- 6-(carboxymethyl)-9-(1H-imidazol-5-ylmethyl)-2,5,8,11,14,17,20- heptaoxo-1,4,7,10,13,16,19-heptaazacyclopentacosan-21-yl]carbamoyl}- 2-methylbutyl]carbamoyl}butanoic acid
Clinical data
Trade names	Baciim
AHFS/Drugs.com	monograph
Pregnancy category	AU: D US: C (Risk not ruled out)
Routes of administration	Topical, intramuscular
Legal status
Legal status	AU: S4 (Prescription only) US: OTC for topical administration; Rx-only for injection
Identifiers
CAS Number	1405-87-4
ATC code	D06AX05 (WHO) J01XX10 R02AB04 QA07AA93
PubChem	CID 439542
DrugBank	DB00626
ChemSpider	10481985
UNII	58H6RWO52I
KEGG	D00128
ChEMBL	CHEMBL1200558
Chemical data
Formula	C66H103N17O16S
Molar mass	1422.69 g/mol
SMILES O=C(O)C[C@H]3NC(=O)[C@H](Cc1cncn1)NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](NC(=O)[C@@H](CCCN)NC(=O)[C@H](CCCCNC(=O)[C@H](CC(N)=O)NC3=O)NC(=O)[C@@H](NC(=O)[C@@H](CCC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)C4N=C(SC4)\nC(N)C(C)CC)C(C)CC)C(C)CC
InChI InChI=1S/C66H103N17O16S/c1-9-35(6)52(69)66-81-48(32-100-66)63(97)76-43(26-34(4)5)59(93)74-42(22-23-50(85)86)58(92)83-53(36(7)10-2)64(98)75-40-20-15-16-25-71-55(89)46(29-49(68)84)78-62(96)47(30-51(87)88)79-61(95)45(28-39-31-70-33-72-39)77-60(94)44(27-38-18-13-12-14-19-38)80-65(99)54(37(8)11-3)82-57(91)41(21-17-24-67)73-56(40)90/h12-14,18-19,31,33-37,40-48,52-54H,9-11,15-17,20-30,32,67,69H2,1-8H3,(H2,68,84)(H,70,72)(H,71,89)(H,73,90)(H,74,93)(H,75,98)(H,76,97)(H,77,94)(H,78,96)(H,79,95)(H,80,99)(H,82,91)(H,83,92)(H,85,86)(H,87,88)/t35?,36?,37?,40-,41+,42+,43-,44+,45-,46-,47+,48?,52?,53-,54-/m0/s1 Key:CLKOFPXJLQSYAH-NVOBBBONSA-N
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Bacitracin is a mixture of related cyclic peptides produced by organisms of the licheniformis group of Bacillus subtilis var Tracy, first isolated in 1945. These peptides disrupt both gram positive and gram negative bacteria by interfering with cell wall and peptidoglycan synthesis.

Bacitracin is primarily used as a topical preparation (as it is can cause kidney damage when used internally).

While the use of any antibiotic can contribute to antibiotic resistance, localized topical applications are less frequently implicated than their systemic counterparts. However, antibiotics such as bacitracin have been shown to act as dermatological irritants and may slow healing.^[1][2]

History

The drug's unique name derives from the fact that it was isolated by John T. Goorley from a girl named Margaret Treacy (1936–1994):^[3] The surname was misspelled and the name was shortened to the more common spelling Tracy

One strain isolated from tissue debrided from a compound fracture of the tibia was particularly active. We named this growth-antagonistic strain for the patient, "Tracy I." When cell-free filtrates of broth cultures of this bacillus proved to possess strong antibiotic activity and to be non-toxic, further study seemed warranted. We have called this active principle "Bacitracin."^[4]

It was approved by FDA in 1948.

Synthesis

Bacitracin is synthesised via what is called nonribosomal peptide synthetases (NRPSs), which means that ribosomes are not involved in its synthesis.

bacABC is involved in synthesis.^[5]

Bacitracin is commercially manufactured by growing the bacteria Bacillus subtilis var Tracy I in a container of liquid growth medium. Over time, the bacteria synthesizes the antibiotic and secretes the antibiotic into the medium. The antibiotic is then extracted from the medium using chemical processes.

Composition

Bacitracin is composed of a mixture of related compounds with varying degrees of antibacterial activity. Notable fractions include bacitracin A, A1, B, B1, B2, C, D, E, F, G, and X.^[6] Bacitracin A has been found to have the most antibacterial activity. Bacitracin B1 and B2 have similar potencies and are approximately 90% as active as bacitracin A.^[7] Other bacitracin components including F and X do not appear to be extensively studied.

Spectrum of activity and susceptibility data

Bacitracin is a broad spectrum antibiotic. It targets both Gram-positive and Gram-negative bacteria, especially those that cause skin infections. The following represents susceptibility data for a few medically significant microorganisms.

• Staphylococcus aureus – ≤0.03 μg/mL – 700 μg/mL
• Staphylococcus epidermidis – 0.25 μg/mL – >16 μg/mL
• Streptococcus pyogenes – 0.5 μg/mL – >16 μg/mL

^[8]

Mechanism of action

Bacitracin interferes with the dephosphorylation of C₅₅-isoprenyl pyrophosphate, a molecule that carries the building-blocks of the peptidoglycan bacterial cell wall outside of the inner membrane.^[9]

Some have claimed that bacitracin is a protein disulfide isomerase inhibitor, but this is disputed by in vitro studies.^[10][11]

Clinical use

A tube of bacitracin ointment for eyes

Bacitracin is used in human medicine as a polypeptide antibiotic and is "approved by the U.S. Food and Drug Administration (FDA) for use in chickens and turkeys," though use in animals contributes to antibiotic resistance.^[12]

As bacitracin zinc salt, in combination with other topical antibiotics (usually polymyxin B and neomycin) as an ointment ("triple antibiotic ointment," with a common brand name Neosporin), it is used for topical treatment of a variety of localized skin and eye infections, as well as for the prevention of wound infections. A non-ointment form of ophthalmic solution is also available for eye infections.^[13]

Although allergic cross reaction with sulfa drugs has been occasionally reported, bacitracin-containing topical preparations remain a possible alternative to silver sulfadiazine (Silvadene) for burn patients with a sulfa allergy.

3D Chemical Structure of Bacitracin

Bacitracin can also be bought in pure form for those with allergies to the polymyxin B and neomycin components of the combination product.

Bacitracin is also commonly used as an aftercare antibiotic on tattoos and circumcision. It is preferred over combination products such as Neosporin because of its fewer ingredients, which lowers chances of an allergic reaction.^[14]

Patch test

In 2005–06, it was the sixth-most-prevalent allergen in patch tests (9.2%).^[15]

It was voted Allergen of the Year in 2003 by the American Contact Dermatitis Society.^[16]

In infants, bacitracin is rarely administered intramuscularly for the treatment of staphylococcal pneumonia and empyema when due to organisms shown susceptible to bacitracin. This use is extremely limited, since bacitracin is nephrotoxic and the concentration of bacitracin in the blood must be followed closely.^[17]

Bacitracin can be used to distinguish Streptococcus pyogenes from other "strep" bacteria,^[18] with S. pyogenes being sensitive to bacitracin and others resistant. In this case bacitracin is used to distinguish S. pyogenes from other β-hemolytic streptococci.

It is also commonly used to distinguish Haemophilus influenzae colonies amongst respiratory flora, since H. influenzae is intrinsically resistant to bacitracin, colonies form within the zone of inhibition.

References

1. Spann, CT; Taylor, SC; Weinberg, JM (2004). "Topical antimicrobial agents in dermatology". Disease-a-month : DM 50 (7): 407–21. doi:10.1016/j.disamonth.2004.05.011. PMID 15280871.
2. Trookman, NS; Rizer, RL; Weber, T (2011). "Treatment of minor wounds from dermatologic procedures: A comparison of three topical wound care ointments using a laser wound model". Journal of the American Academy of Dermatology 64 (3 Suppl): S8–15. doi:10.1016/j.jaad.2010.11.011. PMID 21247665.
3. https://files.nyu.edu/jmm257/public/other/bacitracin.html
4. Johnson B, Anker H, Meleney F (1945). "Bacitracin: a new antibiotic produced by a member of the B. subtilis group".Science 102 (2650): 376–377.
5. Murphy, T.; Roy, I.; Harrop, A.; Dixon, K.; Keshavarz, T. (2007). "Effect of oligosaccharide elicitors on bacitracin a production and evidence of transcriptional level control". Journal of biotechnology 131 (4): 397–403. doi:10.1016/j.jbiotec.2007.07.943. PMID 17825450.
6. "Committee for Veterinary Medicinal Products Bacitracin." Ema.europa.eu. The European Agency for the Evaluation of Medicinal Products, June 1998. Web. 18 Jan. 2013
7. Bell, Robert G. "Preparative High-Performance Liquid Chromatographic Separation and Isolation of Bacitracin Components and Their Relationship to Microbiological Activity." Journal of Chromatography 590 (1992): 163–68. Web. 21 Aug. 2012.
8. http://www.toku-e.com/Assets/MIC/Bacitracin.pdf
9. Mechanism of Action of Bacitracin: Complexation with Metal Ion and C55-Isoprenyl Pyrophosphate K. John Stone and Jack L. Strominger
10. Karala, A. R.; Ruddock, L. W. (2010). "Bacitracin is not a specific inhibitor of protein disulfide isomerase". FEBS Journal 277 (11): 2454–2462. doi:10.1111/j.1742-4658.2010.07660.x. PMID 20477872.
11. Weston, B.; Wahab, N.; Roberts, T.; Mason, R. (2001). "Bacitracin inhibits fibronectin matrix assembly by mesangial cells in high glucose". Kidney international 60 (5): 1756–1764. doi:10.1046/j.1523-1755.2001.00991.x. PMID 11703593.
12. Antibiotic use on the farm hurts people—and doesn’t help the bottom line. Discover Magazine. Accessed on September 16, 2007.
13. http://www.healthgrades.com/drug-ratings/drug/information/1246/Triple%20Antibiotic
14. Tattoo Aftercare Contradictions
15. Zug KA, Warshaw EM, Fowler JF Jr, Maibach HI, Belsito DL, Pratt MD, Sasseville D, Storrs FJ, Taylor JS, Mathias CG, Deleo VA, Rietschel RL, Marks J. Patch-test results of the North American Contact Dermatitis Group 2005–2006. Dermatitis. 2009 May–Jun;20(3):149-60.
16. History of Allergen of the Year. American Contact Dermatitis Society. Accessed on April 24, 2014.
17. FDA-approved IM injection package insert for bacitracin.
18. "Streptococcus Group A Infections: Differential Diagnoses & Workup". Retrieved Sep 23, 2009.