Bacterial cell wall synthesis; undecaprenyl pyrophosphate

In combination with colistin, bacitracin (64 μg/mL, 24 h) demonstrated antibacterial action against Staphylococcus aureus BA01611 [1]. Cell borders become hazy as bacitracin (64 μg/mL, 1 or 2 h) breaks down the cell surface and creates clusters of grape-like cells [1].

In models of HCC, bacitracin (0–100 mg/kg, surgical injection, once day for 12 days) has demonstrated antitumor activity [3].

The Time-Kill Assay[1]
The time-killing curve assays were performed in triplicate to study the effect of the combination of bacitracin and colistin on S. aureus BA01611 growth as previously described by Mun et al. (2013) with minor modifications (Mun et al., 2013). A single bacterial colony was added to 2 mL of the MHB and grown overnight at 37°C with shaking at 180 rpm. The overnight culture was diluted with pre-warmed MHB to obtain a starting inoculum of approximately 5 × 105 CFU/mL. The S. aureus BA01611 strain was exposed to colistin at the concentrations of 0 or 1/2 MIC (64 μg/mL) in the presence or absence of 1/2 MIC (64 μg/mL, except 8 μg/mL for S. aureus BA01511) bacitracin. Samples were taken at 0, 2, 4, 6, 8, 16, and 24 h, serially diluted, spread on drug-free plates, and incubated at 37°C for 24 h before counting the colonies. Each experiment was repeated three times.

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Scanning Electron Microscope (SEM)[1]
SEM were performed as described previously (You et al., 2013). S. aureus BA01611 cells were treated with 1/2 MIC (64 μg/mL) colistin and/or 1/2 MIC (64 μg/mL, except 8 μg/mL for S. aureus BA01511) bacitracin for 1 h and 2 h. Untreated controls were also prepared. The bacterial cells were collected via centrifugation at 10,000 × g and then the pellet formed was washed with PBS for three times. Fixation was done by suspending the bacterial cells into 0.25% of glutaraldehyde solution (in PBS, pH 7.0) and then incubated at room temperature for 1 h before collecting the fixed bacterial pellet. Dehydration of the bacterial cells was done by washing the pellets with ethanol at different concentrations up to 100%. After the critical-point drying, the bacterial cells were observed with a field-emission scanning electron microscopy (FE-SEM; FEI Inspect F50).

Susceptibility Screen[1]
The susceptibility screen assay was performed as described previously (Haaber et al., 2015). S. aureus strains were grown overnight and the cultures were adjusted to subsamples of 5 × 105 CFU/mL in the warm MH broth. Colistin sodium sulfate was added as an inducer at the concentrations of 1/2 MIC (64 μg/mL) for each strain. After 90 min at 37°C with shaking at 180 rpm, 10 μL aliquots of the cultures were spotted on MH agar plates containing bacitracin at a concentration of 1/2 MIC (64 μg/mL). The plates were incubated overnight at 37°C before checking the bacterial growth. Each experiment was repeated three times.

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Determination of the in vitro Effects of Combinations of bacitracin and Colistin[1]
The antimicrobial combination assays were conducted with bacitracin plus colistin by using the broth microdilution checkerboard technique (Mataraci and Dosler, 2012). The test was performed using 96-well microtiter plates containing colistin and bacitracin in twofold serial concentrations. Bacterial suspensions were prepared to yield a final inocula of ∼5 × 105 CFU/mL. Plates were read after overnight incubation at 37°C. Fractional Inhibitory Concentration (FIC) Index was calculated according to the formulas: FICbacitracin = MICbacitracin+colistin/MICbacitracin, FICcolistin = MICbacitracin+colistin/ MICcolistin, FIC Index = FICbacitracin+ FICcolistin. FIC Index values were interpreted according to Mun et al. (2013): synergy (FIC Index ≤ 0.5); partial synergy (FIC Index > 0.5 to ≤ 0.75); additivity (FIC Index > 0.75 to ≤ 1); no interaction (indifference) (FIC Index > 1 to ≤ 4) and antagonism (FIC Index > 4.0) (Mun et al., 2013). Each experiment was repeated three times.

Animal/Disease Models: HCC model (implanted with MH134 cells) [3]
Doses: 0, 10, 50 and 100 mg/kg
Route of Administration: intramuscularinjection, one time/day for 12 days
Experimental Results: Tumor volume decreases. Reduce the percentage of PDI-stained vessel density.

Absorption
Topical, ophthalmic, and oral formulations of bacitracin are poorly absorbed systemically. Intramuscular bacitracin is readily and completely absorbed.

Route of Elimination
Bacitracin is mainly excreted renally with 87% of and intramuscular dose being recovered in the urine after 6 hours.

Volume of Distribution
Data regarding the volume of distribution of bacitracin in humans is not readily available.

Clearance
Data regarding the clearance of bacitracin in humans has not been well studied. A study of 9 subjects in 1947 shows a renal clearance of 105-283mL/min with an average renal clearance of 159mL/min.

Bacitracin is excreted in feces following oral administration. After IM administration, 10-40% of the dose is excreted slowly by glomerular filtration and appears in the urine within 24 hours. A considerable amount of bacitracin has not been accounted for and is thought to be either retained or destroyed in the body.

/MILK/ It is not known whether bacitracin is distributed into milk.

Bacitracin is widely distributed in all body organs and is present in ascitic and pleural fluids following IM injection. The drug is only slightly protein bound. Only trace amounts of bacitracin cross the blood-brain barrier into the CSF, unless the meninges are inflamed.

Bacitracin is not absorbed from the GI tract, pleura, or synovia. The drug is rapidly and completely absorbed following global injection. A bacitracin dosage of 200-300 units/kg administered globally every 6 hr gives sustained serum concentrations of 0.2-2 ug/mL in adult patients with normal renal function. After a single global dose of 10,000-20,000 units, the maximum serum concentration occurs after 1-2 hr, and detectable amounts of bacitracin are present in the serum 6-8 hr after injection in adult patients with normal renal function. There are no data on serum concentrations of bacitracin in infants.

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Metabolism / Metabolites
Data regarding the metabolism of bacitracin in humans is not readily available. Because bacitracin is a protein it is expected to be metabolized into smaller polypeptides and amino acids. However, the structure of bacitracin may afford it some protection from the action of proteases.

Bacitracin is metabolized to amino acids and smaller peptides via the main metabolite desamidobacitracin, which is microbiologically inactive. Main metabolites in feces are bacitracin A, B1, B2, F, desamidobacitracin and catabolic peptides. In urine and bile only hydrolytic cleavage products (di- and tripeptides) are present.

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Biological Half-Life
Data regarding the half life of bacitracin in humans is not readily available.
The half-life of bacitracin in serum was 1.5 hr ... .

Toxicity Summary
IDENTIFICATION AND USE: Bacitracin is greyish white powder formulated into both a human and animal medicinal agent. It is an antibacterial veterinary medicine agent used in wound powders and ointments, dermatologic preparations, eye and ear ointments, as well as feed additives in swine and poultry rations for growth promotion. In humans, IM bacitracin has been used in infants for the treatment of pneumonia and empyema caused by staphylococci susceptible to the drug. Bacitracin is also used topically alone or in combination with other anti-infectives for the prevention or treatment of superficial skin infections caused by susceptible organisms. Bacitracin has been used orally for the treatment of Clostridium difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis). It is also used alone or in combination with other anti-infective agents in the short-term topical treatment of superficial infections of the eye caused by susceptible bacteria. HUMAN EXPOSURE AND TOXICITY: Bacitracin has a low order of toxicity when applied topically; however, rashes and allergic anaphylactoid reactions have occurred in some patients. Anaphylactoid reactions have ranged from generalized itching, swelling of the lips and face, sweating, and tightness of the chest, to hypotension, unconsciousness, apnea, and cardiac arrest. Anaphylaxis has also been reported in a patient after irrigation and packing of an infected pacemaker pocket with a bacitracin solution. IM bacitracin is nephrotoxic and may cause renal failure due to renal tubular and glomerular necrosis. Albuminuria, hematuria, cylindruria, and rising blood concentrations of the drug may occur initially, followed eventually by oliguria, azotemia, and renal failure. Infants are much less prone to this toxicity than are older children and adults, and substantial renal toxicity usually does not occur in infants. Nephrotoxicity may also occur after local application over the site of abdominal operations or after instillation into infected cavities. Zinc bacitracin was negative in in vitro tests for chromosomal aberrations in human peripheral lymphocytes. ANIMAL STUDIES: In two studies, rats received feed-grade and/or pure zinc bacitracin by gavage at doss of 0, 36, 72, 144, 250, 500, and 1000 mg/kg bw/day for 28 days (range-finding study), or 0, 11, 34,150, 250, and 500 mg/kg bw/day for 13 weeks. In these studies the most relevant effects were post-dosing salivation, loose feces, decreased food utilization and (13-week study only) minor pathological changes in the stomach. In the 13-week study post-dosing salivation (brown facial staining) was observed at all dose levels, as well as over-excitation in females from all treated groups. In a 1-year study, rats received feed-grade zinc bacitracin in their diet at doses equivalent to 0, 1, 10, and 50 mg/kg bw/day. The rats that were not sacrificed received control feed and their fertility and reproduction was examined. No toxic effects were observed up to the highest dose tested. There were no signs of nephrotoxicity, which is known to occur after systemic administration of bacitracin. Compared to controls, there was no increase in neoplasms, and the ability to reproduce was not adversely affected. In a teratogenicity study, rats received feed-grade and/or pure zinc bacitracin by gavage at dose levels of 0, 11, 34, 150, 250 and 500 mg/kg bw on days 7 to 17 of pregnancy. Zinc bacitracin had no adverse effects on embryo-fetal development, and did not produce irreversible structural malformation up to the highest dose tested. In dams, post-dosing salivation, soft feces, increased water intake, and slightly decreased body weight gain were noted. Zinc bacitracin was negative in in vitro tests for gene mutations in Salmonella typhimurium, gene mutations, in mouse lymphoma cells and in in vivo tests for chromosomal aberrations in rate bone marrow cells, unscheduled DNA synthesis in rat spleen cells. ECOTOXICITY STUDIES: Referenced to control soil, nitrification was accelerated in soil exposed to 100 mg/kg zinc bacitracin.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because it is poorly absorbed after topical application and oral ingestion, bacitracin is considered a low risk to the nursing infant.[1] Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking.[2] Therefore, an alternate cream product is preferred for application to the breast.

◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Adverse Effects
Skin Sensitizer - An agent that can induce an allergic reaction in the skin.

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Non-Human Toxicity Values
LD50 Guinea pig 2 g/kg

LD50 Mouse iv 360 mg/kg

LD50 Mouse sc 1300 mg/kg

LD50 Mouse ip 300 mg/kg

LD50 Rat ip 190 mg/kg

[1]. Colistin Induces S. aureus Susceptibility to Bacitracin. Front Microbiol. 2018 Nov 20;9:2805.

[2]. Bacitracin Inhibits the Oyster Pathogen Perkinsus marinus in Vitro and in Vivo. Journal of Aquatic Animal Health. Volume 11, 1999 - Issue 2.

[3]. Enhancement of hexokinase II inhibitor-induced apoptosis in hepatocellular carcinoma cells via augmenting ER stress and anti-angiogenesis by protein disulfide isomerase inhibition. J Bioenerg Biomembr. 2012 Feb;44(1):101-15.

(4S)-4-[[(2S)-2-[[(4R)-2-[(1R,2R)-1-amino-2-methylbutyl]-4,5-dihydro-1,3-thiazole-4-carbonyl]amino]-4-methylpentanoyl]amino]-5-[[(2R,3S)-1-[[(3R,6R,9R,12R,15R,18R,21R)-3-(2-amino-2-oxoethyl)-18-(3-aminopropyl)-12-benzyl-15-[(2R)-butan-2-yl]-6-(carboxymethyl)-9-(1H-imidazol-5-ylmethyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclopentacos-21-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-5-oxopentanoic acid has been reported in Bacillus licheniformis with data available.
See also: Bacitracin A (annotation moved to).

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Bacitracin is a combination of at least 9 bacitracins. 60-80% of commercially prepared bacitracin is bacitracin A. The bacillus that produces bacitracin was first isolated from a knee scrape in 1945 from the knee wound of a child named Margaret Tracy. Bacitracin was granted FDA approval on 29 July 1948.

The physiologic effect of bacitracin is by means of Decreased Cell Wall Synthesis & Repair.

Bacitracin is a complex of cyclic polypeptide antibiotics, mainly bacitracin A, produced by spore-forming organisms belonging to the licheniformin group of the Bacillus subtilis with antibacterial activity. Bacitracin binds to C55-isoprenyl pyrophosphate, a biphosphate lipid transport molecule that carries the building blocks of the peptidoglycan bacterial cell wall. The binding interferes with the enzymatic dephosphorylation of the C55-isoprenyl pyrophosphate and prevents peptidoglycan synthesis, thereby inhibiting bacterial cell growth.

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Drug Indication
Bacitracin is indicated in topical formulations for acute and chronic localized skin infections. Occasionally, it is also used intramuscularly for infantile streptococcal pneumonia and empyema. Bacitracin is also formulated as an ointment with neomycin and polymyxin B for over the counter use. A bacitracin ointment formulated with neomycin and polymyxin B along with hydrocortisone is indicated for the treatment of corticosteroid responsive dermatoses with secondary infection.

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Therapeutic Uses
Anti-Bacterial Agents; Anti-Infective Agents, Local

/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Bacitracin is included in the database.

Bacitracin is used in combination with other anti-infective agents and corticosteroids for the treatment of corticosteroid-responsive ocular conditions when a corticosteroid is indicated and a bacterial infection or risk of infection exists. /Included in US product labe/

Bacitracin has been used orally for the treatment of Clostridium difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis). Bacitracin is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition. /NOT included in US product label/

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Drug Warnings /BOXED WARNING/ WARNING Nephrotoxicity: Bacitracin in parenteral (intramuscular) therapy may cause renal failure due to tubular and glomerular necrosis. Its use should be restricted to infants with staphylococcal pneumonia and empyema when due to organisms shown to be susceptible to bacitracin. It should be used only where adequate laboratory facilities are available and when constant supervision of the patient is possible. Renal function should be carefully determined prior to and daily during therapy. The recommended daily dose should not be exceeded and fluid intake and urinary output should be maintained at proper levels to avoid kidney toxicity. If renal toxicity occurs the drug should be discontinued. The concurrent use of other nephrotoxic drugs, particularly streptomycin, kanamycin, polymyxin B, polymyxin E (colistin), and neomycin should be avoided.

IM bacitracin is nephrotoxic and may cause renal failure due to renal tubular and glomerular necrosis. Albuminuria, hematuria, cylindruria, and rising blood concentrations of the drug may occur initially, followed eventually by oliguria, azotemia, and renal failure. Infants are much less prone to this toxicity than are older children and adults, and substantial renal toxicity usually does not occur in infants.

Bacitracin is contraindicated in patients with renal disese or impairment, in patients with a history of previous hypersensitivity or toxic reactions to the drug, or in patients who, during bacitracin therapy, experience oliguria while maintaining normal fluid intake, or who experience progressive azotemia.

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Pharmacodynamics
Bacitracin is a mixture of polypeptides that prevent the formation of the bacterial cell wall and oxidatively cleave DNA. It has a short duration of action as it must be given every 3 to 4 hours topically. Bacitracin is nephrotoxic when given intramuscularly and may lead to renal failure.

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Mechanism of Action
Bacitracin binds to a divalent metal ion such as Mn(II), Co(II), Ni(II), Cu(II), or Zn(II). These complexes bind C₅₅-isoprenyl pyrophosphate, preventing the hydrolysis of a lipid dolichol pyrophosphate, which finally inhibits cell wall synthesis. Bacitracin metal complexes also bind and oxidatively cleave DNA.

Bacitracin interferes with bacterial cell wall synthesis by blocking the function of the lipid carrier molecule that transfers cell wall subunits across the cell membrane. It is active against many gram positive bacteria including staphylococci, streptococci (particularly group A streptococci), corynebacteria, and clostridia. It is also active against Actinomyces, Treponema pallidum and some gram negative species such as Neisseria and Haemophilus influenzae, although most Gram-negative organisms are resistant. .

Bacitracin may be bactericidal or bacteriostatic in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. Bacitracin inhibits bacterial cell wall synthesis by preventing the incorporation of amino acids and nucleotides into the cell wall. The drug probably interferes with the final dephosphorylation step in the phospholipid carrier cycle and in this manner bacitracin prevents the transfer of the mucopeptide to the growing cell wall. Bacitracin also damages the bacterial plasma membrane and is active against protoplasts.

Bacitracin is a polypeptide antibiotic active against Gram-positive bacterial strains. Its mechanism of action postulates disturbing the cell wall synthesis by inhibiting dephosphorylation of the lipid carrier. We have discovered that bacitracin induces degradation of nucleic acids, being particularly active against RNA. In the examination of the nucleolytic activity of bacitracin several model RNA and DNA oligomers were used. The oligomers were labeled at their 5' ends with (32)P radioisotope and following treatment with bacitracin the cleavage sites and efficiency were determined. Bacitracin induces degradation of RNA at guanosine residues, preferentially in single-stranded RNA regions. Bacitracin is also able to degrade DNA to some extent but comparable effects to those observed with RNA require its 10-fold higher concentration. The sites of degradation in DNA are very infrequent and preferentially occur near cytidine residues. Free radicals are not involved in the reaction, and which probably proceeds via a hydrolytic mechanism. The phosphate groups at the cleavage sites are present at the 3' ends of RNA products and at the 5' ends of DNA fragments. Importantly, the presence of EDTA does not influence RNA degradation but completely inhibits the degradation of DNA. For DNA degradation divalent metal ions like Mg(2+), Mn(2+) or Zn(2+) are absolutely necessary. The ability of bacitracin to degrade nucleic acids via a hydrolytic mechanism was a surprising observation, and it is of interest whether these properties can contribute to its mechanisms of action during antibiotic treatment.

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Bacitracin has been used in topical preparations with polymyxin B for bacterial infections. Colistin belongs to the polymyxin group of antibiotics and is effective against most Gram-negative bacilli. This study investigated whether colistin could affect the susceptibility of S. aureus to bacitracin. S. aureus isolates were first incubated with colistin and the susceptibility of S. aureus to bacitracin was increased. The effect of the combination of colistin and bacitracin on S. aureus was then confirmed by the checkerboard assay and the time-kill kinetics. The Triton X-100-induced autolysis was significantly increased after S. aureus was exposed to colistin. Exposure to colistin also led to a less positive charge on the cell surface and a significant leakage of Na+, Mg2, K+, Ca2+, Mn2+, Cu2+, and Zn2+. Finally, disruptions on the cell surface and an irregular morphology were observed when the bacteria were exposed to colistin and bacitracin. Bacitracin had a stronger antibacterial activity against S. aureus in the presence of colistin. This could be due to the fact that colistin damaged the bacterial membrane. This study suggests that combination of colistin with bacitracin has a potential for treating clinical S. aureus infections.[1]

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The in vitro growth rates of two isolates of Perkinsus marinus were significantly reduced by bacitracin. Upon coincubation with 1 mg bacitracin/mL, the doubling times rose from 27 ± 2.1 h to 34 ± 2.9 h for the LMTX-1 isolate (P < 0.001) and from 15 ± 1.9 h to 22.2 ± 2.4 h for the Perkinsus-1 isolate (P < 0.001). At 10 mg bacitracin/mL, viability of both isolates was much reduced (P < 0.0001). The sensitivity of P. marinus to bacitracin was examined in vivo in two clinical trials. In the first, individual eastern oysters Crassostrea virginica were injected with 107 Perkinsus-1 cells, then fed bacitracin at a concentration of 5 or 50 mg/mL encapsulated in lipid vesicles daily for 6 weeks. Parasite body burden was significantly reduced in oysters administered 5 mg bacitracin/mL (3.3 × 104 ± 2.5 × 104 hypnospores/g wet tissue) or 50 mg/mL (5.3 × 104 ± 6.4 × 104 hypnospores/g) as compared with control oysters (3.2 × 105 ± 4.7 × 105 hypnospores/g, P < 0.05) that received encapsulated seawater only. In the second experiment, naturally infected oysters (average, 10.9 × 106 ± 30.7 × 106 hypnospores/g) received encapsulated bacitracin at 10 mg/mL for 10 weeks. Treated oysters had significantly lower levels of infection (2.5 × 106 ± 3 × 106 hypnospores/g) than did control oysters (67.4 × 106 ± 144 × 106 hypnospores/g, P < 0.05). Despite the sharp decrease in infection intensity in the bacitracin-treated oysters, survival rate improved by only 10%. It is possible that damage to the vital organs of infected oysters was too advanced and widespread to be reversed. The in vitro and in vivo findings of this study suggest that bacitracin has promise for use in P. marinus chemotherapy.[2]

C66H103N17O16S

1422.6933

1421.748

C, 55.72; H, 7.30; N, 16.74; O, 17.99; S, 2.25

1405-87-4

1405-87-4; 1405-89-6 (Zinc)

60196264

White to light yellow solid powder

1.4±0.1 g/cm3

1755.5±65.0 °C at 760 mmHg

221-225°C

1015.5±34.3 °C

0.0±0.3 mmHg at 25°C

1.655

-2.21

17

21

31

100

2850

15

S1C([H])([H])[C@@]([H])(C(N([H])[C@]([H])(C(N([H])[C@@]([H])(C([H])([H])C([H])([H])C(=O)O[H])C(N([H])[C@@]([H])(C(N([H])[C@@]2([H])C(N([H])[C@@]([H])(C(N([H])[C@@]([H])(C(N([H])[C@@]([H])(C(N([H])[C@@]([H])(C(N([H])[C@]([H])(C([H])([H])C(=O)O[H])C(N([H])[C@]([H])(C([H])([H])C(N([H])[H])=O)C(N([H])C([H])([H])C([H])([H])C([H])([H])C2([H])[H])=O)=O)=O)C([H])([H])C2=C([H])N=C([H])N2[H])=O)C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])=O)[C@]([H])(C([H])([H])[H])C([H])([H])C([H])([H])[H])=O)C([H])([H])C([H])([H])C([H])([H])N([H])[H])=O)=O)[C@@]([H])(C([H])([H])[H])C([H])([H])C([H])([H])[H])=O)=O)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])=O)N=C1[C@@]([H])([C@]([H])(C([H])([H])[H])C([H])([H])C([H])([H])[H])N([H])[H]

CLKOFPXJLQSYAH-YBVXDRQKSA-N

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-/m1/s1

(4S)-4-[[(2S)-2-[[(4R)-2-[(1R,2R)-1-amino-2-methylbutyl]-4,5-dihydro-1,3-thiazole-4-carbonyl]amino]-4-methylpentanoyl]amino]-5-[[(2R,3S)-1-[[(3R,6R,9R,12R,15R,18R,21R)-3-(2-amino-2-oxoethyl)-18-(3-aminopropyl)-12-benzyl-15-[(2R)-butan-2-yl]-6-(carboxymethyl)-9-(1H-imidazol-5-ylmethyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclopentacos-21-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-5-oxopentanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~100 mg/mL (~70.29 mM)

Solubility in Formulation 1: 100 mg/mL (70.29 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)