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.

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Encapsulation and Delivery:** Bacitracin was reconstituted in 22% artificial seawater (ASW) at concentrations of 5, 10, and 50 mg/mL. This solution was then added to a lipid mixture (soya bean oil, Tween 80, and dried eggs at a 25:3:1 ratio) at a 1:4 ratio and mixed under high shear force to form single-layered lipid vesicles. These vesicles, ranging from 0.9 to 2.5 μm in size, were used as a delivery vehicle. [2]
* **Experimentally Infected Oyster Study:** Eastern oysters (*Crassostrea virginica*) free of *P. marinus* were injected with 10^7 *P. marinus* cells in 0.1 mL ASW into the digestive gland. One day post-injection, oysters were divided into groups and fed daily for 6 weeks with lipid vesicles containing either ASW (control), 5 mg bacitracin/mL, or 50 mg bacitracin/mL. Each oyster received 100 μg of the lipid vesicle paste (suspended in 4.9 mL filtered York River water) daily. [2]
* **Naturally Infected Oyster Study:** Oysters collected from the James River, Virginia, with a 100% prevalence of *P. marinus* infection, were used. The baseline infection level was determined from 25 oysters. The remaining oysters were divided into two groups of 50. For 10 weeks, one group received lipid vesicles containing ASW (control), and the other received lipid vesicles containing 10 mg bacitracin/mL. Each oyster was fed 100 μL of the lipid vesicle preparation daily. Oyster deaths were recorded daily. [2]

Absorption
Bacitracin is poorly absorbed systemically in topical, ophthalmic, and oral formulations. Intramuscular bacitracin is rapidly and completely absorbed.
Excretion
Bacitracin is primarily excreted via the kidneys; 87% of the intramuscular dose is excreted in the urine after 6 hours.
Volume of Distribution
There is currently no data on the volume of distribution of bacitracin in the human body.
Clearance
Research on the clearance rate of bacitracin in the human body is insufficient. A 1947 study involving 9 subjects showed a renal clearance rate of 105-283 mL/min, with a mean renal clearance rate of 159 mL/min.
After oral administration, bacitracin is primarily excreted in the feces. After intramuscular injection, 10-40% of the dose is slowly excreted via glomerular filtration and appears in the urine within 24 hours. The fate of a significant portion of bacitracin is unknown; it is presumed that it may remain in the body or be destroyed.
/Breast Milk/ It is unclear whether bacitracin is distributed in breast milk.
Bacitracin is widely distributed throughout the body and can be detected in ascites and pleural effusion after intramuscular injection. The drug has a very low protein binding rate. Only trace amounts of bacitracin can cross the blood-brain barrier into the cerebrospinal fluid unless there is meningitis.
Bacitracin is not absorbed by the gastrointestinal tract, pleura, or synovium. After systemic injection, the drug is rapidly and completely absorbed. In adult patients with normal renal function, systemic injection of 200-300 units/kg of bacitracin every 6 hours maintains serum concentrations at 0.2-2 μg/mL. After a single systemic injection of 10,000-20,000 units, serum concentrations peak within 1-2 hours and remain detectable in serum for 6-8 hours post-injection. There is currently no data on serum bacitracin concentrations in infants.

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Metabolism/Metabolites
Data on the metabolism of bacitracin in humans is unclear. Since bacitracin is a protein, it is expected to be metabolized into smaller polypeptides and amino acids. However, the structure of bacitracin may protect it from degradation by proteases. Bacitracin is primarily metabolized into amino acids and small peptides via the metabolite deamidated bacitracin, which lacks microbial activity. The main metabolites in feces are bacitracin A, B1, B2, F, deamidated bacitracin, and catabolite peptides. Only hydrolysis products (dipeptides and tripeptides) are present in urine and bile. Biological Half-Life: Currently, there is no data on the half-life of bacitracin in humans. The half-life of bacitracin in serum is 1.5 hours…

Toxicity Overview
Identification and Uses: Bacitracin is a grayish-white powder formulated for human and veterinary use. It is an antimicrobial veterinary drug used in wound powders and ointments, dermatological preparations, ointments for the eyes and ears, and as a feed additive for pigs and poultry to promote growth. In humans, intramuscular bacitracin has been used to treat pneumonia and empyema in infants caused by Staphylococcus aureus susceptible to the drug. Bacitracin can also be used topically, alone or in combination with other anti-infective drugs, for the prevention or treatment of superficial skin infections caused by susceptible bacteria. Bacitracin has been used orally to treat Clostridium difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis). Bacitracin can also be used alone or in combination with other anti-infective drugs for short-term topical treatment of superficial ocular infections caused by susceptible bacteria. Human Exposure and Toxicity: Topical application of bacitracin has low toxicity; however, some patients have experienced rashes and anaphylactic reactions. Symptoms of anaphylactic reactions include generalized itching, swelling of the lips and face, sweating, and chest tightness; severe cases may result in hypotension, loss of consciousness, respiratory arrest, and cardiac arrest. Another report states that a patient experienced anaphylactic shock after flushing and packing an infected pacemaker pocket with bacitracin solution. Intramuscular bacitracin is nephrotoxic, potentially leading to renal failure due to tubular and glomerular necrosis. Initial symptoms may include proteinuria, hematuria, casts in the urine, and elevated blood drug concentrations, eventually progressing to oliguria, azotemia, and renal failure. Infants are much less sensitive to this toxicity than older children and adults, and significant nephrotoxicity is usually not observed in infants. Nephrotoxicity may also occur after local application to the abdominal surgical site or perfusion into infected cavities. In vitro studies have shown that zinc bacitracin does not cause chromosomal aberrations in human peripheral blood lymphocytes. Animal studies: In two studies, rats were administered feed-grade and/or pure zinc bacitracin by gavage at doses of 0, 36, 72, 144, 250, 500, and 1000 mg/kg body weight/day for 28 days (dose range exploration studies); or 0, 11, 34, 150, 250, and 500 mg/kg body weight/day for 13 weeks. The most relevant effects in these studies were post-administration salivation, loose stools, decreased food utilization, and (13-week study only) mild gastric pathological changes. In the 13-week study, post-administration salivation (brown face) was observed in all dose groups, and hyperexcitability was observed in female rats in all treatment groups. In a 1-year study, feed-grade zinc bacitracin was added to the diet of rats at doses equivalent to 0, 1, 10, and 50 mg/kg body weight/day. Rats that were not sacrificed were fed a control diet, and their fertility and reproductive status were assessed. No toxic effects were observed at the highest tested dose. No signs of nephrotoxicity were observed, despite the known history of nephrotoxicity following systemic administration of bacitracin. No increased tumor incidence or adverse effects on reproductive capacity were observed compared to the control group. In a teratogenicity study, rats were administered feed-grade and/or pure zinc bacitracin via gavage on days 7 to 17 of gestation at doses of 0, 11, 34, 150, 250, and 500 mg/kg body weight. Zinc bacitracin had no adverse effects on embryo-fetal development and did not cause irreversible structural malformations at the highest tested dose. Drooling, loose stools, increased water intake, and slight weight loss were observed in female rats after administration. In vitro Salmonella mutation assays, mouse lymphoma cell mutation assays, and in vivo rat bone marrow cell chromosomal aberration assays and rat spleen cell unplanned DNA synthesis assays were all negative. Ecotoxicity studies: Nitrification was accelerated in soil exposed to 100 mg/kg zinc bacitracin, compared to control soil.

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Effects during pregnancy and lactation
◉ Overview of medication use during lactation
Bacitracin is considered to pose a low risk to breastfed infants due to its low absorption rate for topical and oral applications. [1] Only water-soluble creams or gels should be applied to the breasts, as ointments may expose infants to high concentrations of mineral oil through licking. [2] Therefore, other creams are recommended for application to the breasts.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Adverse reactions
Skin sensitizers - Substances that can cause allergic reactions of the skin. Non-human toxicity values
Guinea pig LD50: 2 g/kg
Mouse intravenous LD50: 360 mg/kg
Mouse subcutaneous LD50: 1300 mg/kg
Mouse intraperitoneal LD50: 300 mg/kg
Rat intraperitoneal LD50: 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-thiazolyl-4-carbonyl]amino]-4-methylpentanoyl]amino]-5-[[(2R,3S)-1-[[(3R,6R,9R,12R,15R,18R,21R)-3-(2-amino-2-oxoethyl)-18-(3-aminopropionyl) It has been reported that lichens A compound exists in Bacillus with the following composition: (yl)-12-benzyl-15-[(2R)-but-2-yl]-6-(carboxymethyl)-9-(1H-imidazol-5-ylmethyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptaazacyclopentan-21-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-5-oxopenic acid. Related data have been published.
See also: Bacitracin A (note moved here).

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Bacitracin is a compound composed of at least nine bacitracins. 60-80% of commercially available formulations are bacitracin A. The bacilli that produce bacitracin were first isolated in 1945 from a knee abrasion in a child named Margaret Tracy. Bacitracin was approved by the U.S. Food and Drug Administration (FDA) on July 29, 1948. The physiological action of bacitracin is through reducing cell wall synthesis and repair. Bacitracin is a cyclic polypeptide antibiotic complex, with bacitracin A as its main component. It is produced by spore-forming bacteria with antibacterial activity, such as Bacillus subtilis, a lichenifying bacterium. Bacitracin binds to C55-isoprene pyrophosphate, a bisphospholipid transport molecule responsible for transporting the basic units that make up bacterial cell wall peptidoglycan. This conjugate interferes with the enzymatic dephosphorylation of C55-isoprene pyrophosphate, thereby preventing peptidoglycan synthesis and inhibiting bacterial cell growth. Indications: Bacitracin is indicated for topical use in the treatment of acute and chronic local skin infections. It is sometimes used intramuscularly for the treatment of streptococcal pneumonia and empyema in infants and young children. Bacitracin can also be formulated into ointments with neomycin and polymyxin B for over-the-counter use. A bacitracin ointment containing neomycin, polymyxin B, and hydrocortisone is indicated for the treatment of secondary infectious skin conditions that have responded to corticosteroids.

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Therapeutic Uses
Antibacterial Agent; Topical Anti-infective Agent
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that tracks human clinical studies funded by public and private sources worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov provides a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being investigated); the study title, description, and design; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as MedlinePlus (providing patient health information) and PubMed (providing citations and abstracts of academic articles in the medical field) from the National Library of Medicine (NLM). Bacitracin is indexed in this database. Bacitracin is used in combination with other anti-infective drugs and corticosteroids to treat ocular diseases that respond to corticosteroids, particularly in cases requiring corticosteroid use and where there is a bacterial infection or risk of infection. /US Product Label Contains/ Bacitracin is used orally for the treatment of Clostridium difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis). The US Food and Drug Administration (FDA) has designated bacitracin as an orphan drug for the treatment of this disease. /Not included on US product label/

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Drug Warning/Black Box Warning/Warning: Nephrotoxicity: Parenteral (intramuscular) bacitracin treatment may lead to renal failure due to tubular and glomerular necrosis. Its use should be limited to infants with staphylococcal pneumonia and empyema caused by pathogens sensitive to bacitracin. It should only be used if adequate laboratory facilities are available and the patient can be continuously monitored. Renal function should be carefully assessed daily before and during treatment. The recommended daily dose should not be exceeded, and adequate fluid intake and urine output should be maintained to avoid nephrotoxicity. If nephrotoxicity occurs, the drug should be discontinued immediately. Concomitant use with other nephrotoxic drugs should be avoided, especially streptomycin, kanamycin, polymyxin B, polymyxin E (colistin), and neomycin.
Intramuscular bacitracin is nephrotoxic and can lead to renal failure due to tubular and glomerular necrosis. Initially, proteinuria, hematuria, casts in the urine, and elevated blood drug concentrations may occur, followed by gradual oliguria, azotemia, and renal failure. Infants are much less sensitive to this toxicity than older children and adults, and serious nephrotoxicity is generally not observed in infants. Bacitracin is contraindicated in patients with kidney disease or impaired renal function, patients with a history of allergic or toxic reactions to this drug, or patients who experience oliguria or progressive azotemia during bacitracin treatment despite maintaining normal fluid intake. Pharmacodynamics: Bacitracin is a polypeptide mixture that inhibits bacterial cell wall formation and oxidatively cleaves DNA. Its duration of action is short because it must be administered locally every 3 to 4 hours. Intramuscular bacitracin is nephrotoxic and may lead to kidney failure. Mechanism of Action: Bacitracin binds to divalent metal ions such as Mn(II), Co(II), Ni(II), Cu(II), or Zn(II). These complexes bind to C₅₅-isoprene pyrophosphate, preventing the hydrolysis of lipid polyterpene pyrophosphate and ultimately inhibiting cell wall synthesis. Bacitracin metal complexes can also bind to and oxidatively cleave DNA. Bacitracin interferes with bacterial cell wall synthesis by blocking the function of lipid carrier molecules responsible for transporting cell wall subunits across the cell membrane. It is effective against many Gram-positive bacteria, including Staphylococcus, Streptococcus (especially Group A Streptococcus), Corynebacterium, and Clostridium. It is also effective against Actinomycetes, Treponema pallidum, and some Gram-negative bacteria, such as Neisseria and Haemophilus influenzae, but most Gram-negative bacteria are resistant to it. The mechanism of action of bacitracin depends on the drug concentration at the site of infection and the sensitivity of the infecting microorganism, and may manifest as bactericidal or bacteriostatic effects. Bacitracin inhibits bacterial cell wall synthesis by preventing the incorporation of amino acids and nucleotides into the cell wall. The drug may interfere with the final dephosphorylation step in the phospholipid carrier cycle, thereby preventing the transfer of peptidoglycan to the growing cell wall. Bacitracin also disrupts the bacterial plasma membrane and is effective against protoplasts. Bacitracin is a polypeptide antibiotic effective against Gram-positive bacteria. Its mechanism of action is to interfere with cell wall synthesis by inhibiting the dephosphorylation of lipid carriers. We found that bacitracin can induce nucleic acid degradation, especially RNA. Several model RNA and DNA oligonucleotides were used in our study of the nuclease activity of bacitracin. These oligonucleotides were labeled with the 5' end of a 32P radioisotope, and their cleavage sites and cleavage efficiencies were determined after treatment with bacitracin. Bacitracin induced RNA degradation at guanosine residues, particularly preferentially degrading single-stranded RNA regions. Bacitracin also degraded DNA to some extent, but a concentration 10 times higher was required to achieve a similar degradation effect as RNA. DNA degradation sites were very rare and preferentially occurred near cytidine residues. The reaction did not involve free radicals and likely proceeded via a hydrolysis mechanism. Phosphate groups at the cleavage sites were present at the 3' end of the RNA product and the 5' end of the DNA fragment. Notably, the presence of EDTA did not affect RNA degradation but completely inhibited DNA degradation. Divalent metal ions such as Mg²⁺, Mn²⁺, or Zn²⁺ are absolutely essential for DNA degradation. The ability of bacitracin to degrade nucleic acids through hydrolysis is a surprising discovery, and whether this property can enhance the mechanism of action in antibiotic therapy warrants attention. Bacitracin has been used in combination with polymyxin B in topical formulations for the treatment of bacterial infections. Colistin belongs to the polymyxin class of antibiotics and is effective against most Gram-negative bacilli. This study investigated whether colistin affects the sensitivity of Staphylococcus aureus to bacitracin. Staphylococcus aureus isolates were first incubated with colistin, and the results showed increased sensitivity of Staphylococcus aureus to bacitracin. Subsequently, the effects of the combined use of colistin and bacitracin on Staphylococcus aureus were confirmed by checkerboard assay and time-kinesthetic kinetics. Triton X-100-induced autolysis was significantly enhanced in Staphylococcus aureus after exposure to colistin. Colistin exposure also led to a reduction in positive charge on the cell surface and caused significant leakage of Na⁺, Mg²⁺, K⁺, Ca²⁺, Mn²⁺, Cu²⁺, and Zn²⁺. In addition, cell surface disruption and morphological irregularities were observed when bacteria were exposed to colistin and bacitracin. Bacitracin showed stronger antimicrobial activity against Staphylococcus aureus in the presence of colistin. This may be due to colistin disrupting the bacterial cell membrane. This study suggests that the combined use of colistin and bacitracin has the potential to treat clinical Staphylococcus aureus infections. [1]

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Bacitracin significantly reduced the in vitro growth rate of two marine Parkinson's isolates. After co-culturing with bacitracin at a concentration of 1 mg/mL, the doubling time of the LMTX-1 isolate increased from 27 ± 2.1 hours to 34 ± 2.9 hours (P < 0.001), and the doubling time of the Perkinsus-1 isolate increased from 15 ± 1.9 hours to 22.2 ± 2.4 hours (P < 0.001). At a bacitracin concentration of 10 mg/mL, the survival rate of both isolates was significantly reduced (P < 0.0001). In two clinical trials, researchers tested the sensitivity of Pseudomonas marinus to bacitracin in vivo. In the first trial, researchers injected 10⁷ Perkinsus-1 cells into individual eastern oysters (Crassostrea virginica) and then fed them daily with liposome-encapsulated bacitracin at concentrations of 5 or 50 mg/mL for 6 weeks. Compared to control oysters treated only with seawater encapsulation (3.2 × 10⁵ ± 4.7 × 10⁵ dormant spores/g, P < 0.05), oysters treated with 5 mg/mL bacitracin (3.3 × 10⁴ ± 2.5 × 10⁴ dormant spores/g) or 50 mg/mL bacitracin (5.3 × 10⁴ ± 6.4 × 10⁴ dormant spores/g) showed significantly lower parasite loads. In the second experiment, naturally infected oysters (mean 10.9 × 10⁶ ± 30.7 × 10⁶ dormant spores/g) were treated with 10 mg/mL of bacitracin for 10 weeks. The infection level of the treated oysters (2.5 × 10⁶ ± 3 × 10⁶ dormant spores/g) was significantly lower than that of the control oysters (67.4 × 10⁶ ± 144 × 10⁶ dormant spores/g, P < 0.05). Although the infection intensity of the bacitracin-treated oysters was significantly reduced, the survival rate was only 10%. This may be because the damage to vital organs of the infected oysters was too severe and extensive to be reversed. The in vitro and in vivo results of this study suggest that bacitracin may be useful for the chemotherapy of Pseudomonas marinus. [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.)