Tetracycline; protein synthesis of bacteria
With MIC90s of 1.0, 0.25, 0.5, 0.25, and 2.0 μg/mL, respectively, omadacycline shows activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), beta-hemolytic streptococci, penicillin-resistant Streptococcus pneumonia (PRSP), and Haemophilus influenzae (H. influenzae)[2]. Through ribosomal protection and active tetracycline efflux, omadacycline effectively combats strains that express resistance to tetracycline and other antibiotics[2].

With MIC90s of 1.0, 0.25, 0.5, 0.25, and 2.0 μg/mL, respectively, omadacycline shows activity against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), beta-hemolytic streptococci, penicillin-resistant Streptococcus pneumonia (PRSP), and Haemophilus influenzae (H. influenzae)[2]. Through ribosomal protection and active tetracycline efflux, omadacycline effectively combats strains that express resistance to tetracycline and other antibiotics[2].

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Omadacycline demonstrates potent in vitro antibacterial activity against a broad spectrum of bacteria. Against Gram-positive bacteria, it is active against Staphylococcus aureus (including methicillin-resistant MRSA) with MIC ranges of 0.125–1 µg/mL for strains carrying the tet(M) gene and 0.125–0.25 µg/mL for strains carrying the tet(K) gene. For Enterococcus faecalis and E. faecium (including vancomycin-resistant strains), MICs were as low as 0.125–0.5 µg/mL against ribosomal protection strains and 0.25 µg/mL against efflux strains. Against Streptococcus pneumoniae (including penicillin- and macrolide-resistant strains), MIC values were ≤0.06 µg/mL. For Gram-negative bacteria such as Escherichia coli carrying the tet(A) efflux gene, the MIC was 2 µg/mL. It also shows activity against anaerobes (e.g., Clostridium difficile MIC range 0.25-8 µg/mL), atypical pathogens (e.g., Legionella pneumophila MIC range 0.06–1 µg/mL; Chlamydia pneumoniae MIC range 0.03–0.5 µg/mL), and rapidly growing mycobacteria (e.g., Mycobacterium abscessus MIC50 1 µg/mL, MIC90 2 µg/mL). Its activity is largely unaffected by common tetracycline resistance determinants. [1]

In a mouse systemic infection model, omadacycline (0.11–18 mg/kg; a single intravenous dose) shows effectiveness against Streptococcus pneumonia, Escherichia coli, and Staphylococcus aureus, with ED50s ranging from 0.30 mg/kg to 3.39 mg/kg[2].

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In vivo efficacy of omadacycline was demonstrated using an intraperitoneal infection model in mice. A single intravenous dose of omadacycline exhibited efficacy against Streptococcus pneumoniae, Escherichia coli, and Staphylococcus aureus, including tet(M) and tet(K) efflux-containing strains and MRSA strains. The 50% effective doses (ED50s) for Streptococcus pneumoniae obtained ranged from 0.45 mg/kg to 3.39 mg/kg, the ED50s for Staphylococcus aureus obtained ranged from 0.30 mg/kg to 1.74 mg/kg, and the ED50 for Escherichia coli was 2.02 mg/kg. These results demonstrate potent in vivo efficacy including activity against strains containing common resistance determinants. Omadacycline demonstrated in vitro activity against a broad range of Gram-positive and select Gram-negative pathogens, including resistance determinant-containing strains, and this activity translated to potent efficacy in vivo[2].

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Clinical studies (Phase II and III) demonstrated the efficacy of omadacycline in human patients. In the OASIS-1 and OASIS-2 trials for acute bacterial skin and skin structure infections, intravenous (IV) or oral omadacycline was non-inferior to linezolid, with high clinical success rates against pathogens including MRSA. In the OPTIC trial for community-acquired bacterial pneumonia, IV omadacycline was non-inferior to moxifloxacin. [1]

In vitro stability and drug–drug interaction potential of omadacycline[2] The stability of omadacycline (4.8 and 48 μM) was assessed in human microsomes and hepatocytes. After 30 min incubation of omadacycline in human microsomes, >90% of omadacycline was recovered intact. Similarly, after incubation of omadacycline up to 24 h in human hepatocytes, >86% was recovered intact. These results indicate that omadacycline is not metabolized to any significant extent.The potential for drug-drug-interactions with omadacycline was assessed using either pooled human liver microsome preparations, S9, liver cytosol, or recombinant flavin monooxygenases (FMO1, FMO3, FMO5). Induction of CYP450 isozymes was evaluated in primary human hepatocytes incubated with omadacycline 1–100 μM and a substrate probe for 24 and 48 h. Inhibition of CYP450 isozymes was evaluated with pooled human microsomes at omadacycline concentrations of 1–50 μM and isozyme specific substrates at concentrations approximating the Km of each substrate. Isozymes evaluated included CYP 1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2, and 3A4/5.Omadacycline did not induce CYP isozymes, and no or minimal (<40% of maximal positive control response) induction of their mRNAs was observed. Omadacycline demonstrated no significant inhibition of CYP isozyme activity. In addition, there was no time-dependent inhibition of omadacycline or its possible metabolites for CYP1A2 2C9, 2D6 or 3A4/5.Bioorg Med Chem.2016 Dec 15;24(24):6409-6419.

The omadacycline MIC90s for MRSA, VRE, and beta-hemolytic streptococci are 1.0 μg/mL, 0.25 μg/mL, and 0.5 μg/mL, respectively, and the omadacycline MIC90s for PRSP and H. influenzae are 0.25 μg/ml and 2.0 μg/mL, respectively. Omadacycline is active against organisms demonstrating the two major mechanisms of resistance, ribosomal protection and active tetracycline efflux. Omadacycline inhibits protein synthesis while having no significant effect on RNA, DNA and peptidoglycan synthesis. Further, omadacycline binds to the tetracycline binding site on the 30S subunit of the bacterial ribosome with enhanced binding similar to tigecycline based on additional molecular interactions.

Mice: Sterile saline is used to dissolve omadacycline. A 3-mL lock-top sterile syringe with a sterile 25-gauge, 5/8-in. needle is used to infect mice. Mice are given an intravenous (i.v.) dose of omadacycline or relevant comparator compounds at a volume of 10 ml/kg at one hour post-infection (p.i.). Each experiment involves testing a minimum of four dose levels on five mice per group. With a few notable exceptions, the usual dose range tested is 0.11 to 18 mg/kg of body weight[1]. Significantly higher or lower doses are needed for comparators to achieve 50% efficacy.

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Systemic i.p. challenge model. Six-week-old, specific-pathogen-free, male CD-1 mice, weighing 18 to 30 g were used for all experiments. At 1 h postinfection (p.i.), mice were dosed intravenously (i.v.) with omadacycline or comparator compounds of interest, dissolved in sterile saline for injection at a volume of 10 ml/kg. All drug doses were formulated fresh immediately prior to administration and adjusted to account for percent activity. A minimum of four dose levels were tested per experiment with 5 mice/group. The typical doses tested ranged from 0.11 to 18 mg/kg of body weight, with exceptions for comparators that required significantly higher or lower doses to achieve 50% efficacy (dose range minimum-maximum, 0.08 to 54 mg/kg). Each study also included an untreated control group. Mice were housed in filter-topped cages in an isolated room and monitored for morbidity at least every 24 h for 7 days. Efficacy was determined by calculating the 50% effective dose (ED50) for all drugs tested. The ED50 is defined as the dose required to achieve 50% survival at 7 days p.i. and was estimated when possible using the formula y = 1/[1 + 10(log(k)-log(x)× 4.2)], where k = 0.5, by nonlinear regression analysis with Prism, version 3.0 software. [2]

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The provided protocols are from human clinical trials. For example, in the OASIS-1 skin infection study, patients received an IV loading dose of 100 mg omadacycline twice on day one, followed by 100 mg IV once daily, with an option to switch to oral 300 mg once daily. The comparator was linezolid 600 mg IV/oral twice daily. Treatment duration was 7-14 days. [1]
In the OPTIC pneumonia study, patients received IV omadacycline 100 mg twice on day one, then 100 mg IV once daily, with an option to switch to oral therapy. The comparator was moxifloxacin 400 mg IV/oral once daily. [1]

Omalia cycline's pharmacokinetic profile best conforms to a linear three-compartment model, with zero-order kinetics for intravenous infusion and first-order kinetics for oral administration, taking into account the transport compartment to explain delayed absorption. The volume of distribution (Vd) of omaalia cycline is 190–204 L, the terminal elimination half-life (t½) is 13.5–17.1 h, the total clearance (CLT) is 8.8–10.6 L/h, and the protein binding rate in healthy subjects is 21.3%. The estimated oral bioavailability of omaalia cycline is 34.5%. Following a single oral dose of 300 mg (bioequivalent to 100 mg intravenously) of omaalia cycline, the peak plasma concentration (Cmax) in fasting subjects is 0.5–0.6 mg/L, and the area under the plasma concentration-time curve (AUC0–∞) is 9.6–11.9 mg·h/L. The area under the free plasma concentration-time curve divided by the minimum inhibitory concentration (fAUC24h/MIC) has been identified as a pharmacodynamic parameter for predicting the antibacterial efficacy of omalicycline. Multiple animal models, including neutropenic mouse models of lung infection, thigh infection, and intraperitoneal infection, have demonstrated the in vivo antibacterial efficacy of omalicycline. A phase II clinical trial for complicated skin and soft tissue infections (cSSSI) and three phase III clinical trials for acute bacterial skin and soft tissue infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) have confirmed the safety and efficacy of omalicycline. The phase III clinical trials OASIS-1 (ABSSSI), OASIS-2 (ABSSSI), and OPTIC (CABP) demonstrated that omalicycline is non-inferior to linezolid (OASIS-1, OASIS-2) and moxifloxacin (OPTIC) in the treatment of ABSSSI and CABP, respectively. Currently, omalicycline is approved by the FDA for the treatment of ABSSSI and CABP. Phase II clinical trials for patients with acute cystitis and acute pyelonephritis are ongoing. Mild, transient gastrointestinal reactions are the main adverse reactions of omalicycline. Based on clinical trial data to date, the adverse reaction profile of omalicycline is similar to that of the study control drugs linezolid and moxifloxacin. Unlike tigecycline and eracycline, omalicycline is available in an oral formulation, allowing for a gradual transition from intravenous to oral administration, which may help patients be discharged earlier, receive outpatient treatment, and save on healthcare costs. Omalicycline has potential in antimicrobial management regimens for the treatment of infections caused by drug-resistant and multidrug-resistant Gram-positive bacteria (including methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative bacteria. [https://pubmed.ncbi.nlm.nih.gov/31970713/]

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Phase I studies have shown that omalicycline can be administered once daily, either orally or intravenously. Intravenous doses exceeding 300 mg can cause a reversible increase in alanine aminotransferase. Oral doses exceeding 400 mg may cause mild nausea. This reference does not detail specific pharmacokinetic parameters such as half-life, bioavailability, absorption, distribution, metabolism, and excretion. [1]

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information regarding the use of omalicycline during lactation. It is unclear how much omalicycline is excreted into breast milk, but even under optimal conditions, the oral absorption rate is only about 35%, and the amount of omalicycline in breast milk may be even lower due to its calcium content. The manufacturer states that breastfeeding is not recommended during treatment and for 4 days after the last dose. If the infant is being breastfed, the infant's gut microbiota should be monitored for any impact, such as diarrhea, candidiasis (e.g., thrush, diaper rash), or rare hematochezia (suggesting possible antibiotic-associated colitis). As a theoretical precaution, prolonged or repeated use should be avoided during lactation.
◉ 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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Omacycline is generally well tolerated in clinical studies. Common side effects include mild and transient nausea, especially at higher oral doses. Alanine aminotransferase (ALT) levels are reversibly elevated at intravenous doses >300 mg. In a phase I study of female patients with cystitis, the incidence of gastrointestinal side effects (vomiting, nausea) was higher than expected, but the symptoms were mild and did not lead to patient withdrawal from the trial. Information on LD50, organ toxicity, drug interactions, or plasma protein binding was not provided. [1]

[1]. Pharmaceuticals (Basel). 2019 Apr 21;12(2):63.

[2]. Antimicrob Agents Chemother. 2014;58(2):1127-35.

[3]. Drugs. 2020 Feb;80(3):285-313.

[4]. Drugs. 2018 Dec;78(18):1931-1937.

Omaliacycline (Nuzyra®) is a novel aminomethylcycline drug approved by the U.S. Food and Drug Administration (FDA) in 2018. It is a tetracycline antibiotic. It is used to treat community-acquired pneumonia and acute bacterial skin and soft tissue infections. The drug was developed and commercialized by Paratek Pharmaceuticals. Omaliacycline is a semi-synthetic compound derived from minocycline that can evade a wide range of resistance mechanisms, including efflux pumps and targeted protection mechanisms, and has been shown to be active against a variety of bacteria. [1]

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Omaliacycline is the first intravenous and oral 9-aminomethylcycline drug to enter clinical development for the treatment of a variety of infectious diseases, including acute bacterial skin and soft tissue infections (ABSSSI), community-acquired bacterial pneumonia (CABP), and urinary tract infections (UTI). This study determined the in vitro activity of omalicycline against a variety of Gram-positive clinical isolates, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), group A and B β-hemolytic streptococci, penicillin-resistant Streptococcus pneumoniae (PRSP), and Haemophilus influenzae. The MIC90 values of omalicycline against MRSA, VRE, and β-hemolytic streptococci were 1.0 μg/ml, 0.25 μg/ml, and 0.5 μg/ml, respectively, while the MIC90 values against PRSP and Haemophilus influenzae were 0.25 μg/ml and 2.0 μg/ml, respectively. Omalicycline is effective against pathogens exhibiting two main resistance mechanisms (ribosomal protection and active tetracycline efflux). The in vivo efficacy of omalicycline was confirmed using a mouse intraperitoneal infection model. A single intravenous injection of omalicycline is effective against Streptococcus pneumoniae, Escherichia coli, and Staphylococcus aureus, including strains carrying tet(M) and tet(K) efflux genes, as well as methicillin-resistant Staphylococcus aureus (MRSA) strains. The median effective dose (ED50) against Streptococcus pneumoniae ranges from 0.45 mg/kg to 3.39 mg/kg, against Staphylococcus aureus from 0.30 mg/kg to 1.74 mg/kg, and against Escherichia coli from 2.02 mg/kg. These results demonstrate that omalicycline possesses potent in vivo efficacy, including activity against strains containing common resistance determinants. In vitro studies have shown that omalicycline is active against a variety of Gram-positive bacteria and some Gram-negative pathogens, including strains containing resistance determinants, and this activity translates into potent in vivo efficacy. [2]

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Omalacycline is a novel aminomethylcycline antibiotic developed for the treatment of acute bacterial skin and soft tissue infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), administered once daily via intravenous or oral administration. Omalacycline is a derivative of minocycline, with a chemical structure similar to tigecycline, but the glycine group at the C-9 position of the tetracycline core D ring is replaced by an alkyl aminomethyl group. Similar to other tetracycline antibiotics, omaalacycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Omalacycline has broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic, anaerobic, and atypical bacteria. Omalacycline remains effective against bacterial isolates with common tetracycline resistance mechanisms (such as efflux pumps (e.g., TetK) and ribosomal protective proteins (e.g., TetM)) and bacterial isolates resistant to other antibiotic classes. [3] Paratek Pharmaceuticals is developing omphacycline (NUZYRA™), a first-in-class oral active aminomethylcycline antibiotic for the treatment of a variety of bacterial infections. Available in intravenous and oral formulations, it has broad-spectrum antibacterial activity and was recently approved in the United States for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and soft tissue infections (ABSSSI) in adults. This article summarizes the key milestones in the development of omphacycline that ultimately led to its first approval for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and soft tissue infections (ABSSSI). [4] Omphacycline (Nuzyra®) is a novel aminomethylcycline antibiotic, a semi-synthetic derivative of minocycline, and was approved by the U.S. Food and Drug Administration (FDA) in 2018. It is indicated for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and soft tissue infections. Its main advantage lies in its ability to bypass major tetracycline resistance mechanisms (efflux and ribosome protection), thereby maintaining activity against a variety of multidrug-resistant bacteria. It only needs to be administered once daily, which is more convenient than some older generation tetracyclines. Clinical trials are currently underway for its use in the treatment of urinary tract infections (cystitis and acute pyelonephritis). [1]

C29H41CLN4O7

593.1114

592.266

C, 58.73; H, 6.97; Cl, 5.98; N, 9.45; O, 18.88

1196800-39-1

Omadacycline;389139-89-3;Omadacycline tosylate;1075240-43-5;Omadacycline-d9;2272886-41-4;Omadacycline mesylate;1196800-40-4

54746487

Brown to black solid powder

7

10

7

41

1140

4

CC(C)(C)CNCC1=CC(=C2C[C@H]3C[C@H]4[C@@H](C(=O)C(=C([C@]4(C(=O)C3=C(C2=C1O)O)O)O)C(=O)N)N(C)C)N(C)C.Cl

HXMCZSICOWSBRX-XGLFQKEBSA-N

InChI=1S/C29H40N4O7.ClH/c1-28(2,3)12-31-11-14-10-17(32(4)5)15-8-13-9-16-21(33(6)7)24(36)20(27(30)39)26(38)29(16,40)25(37)18(13)23(35)19(15)22(14)34;/h10,13,16,21,31,34,36-37,40H,8-9,11-12H2,1-7H3,(H2,30,39);1H/t13-,16-,21-,29-;/m0./s1

(4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-9-((neopentylamino)methyl)-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide hydrochloride

Omadacycline HCl; Omadacycline hydrochloride; PTK 0796; PTK-0796; PTK0796; Amadacyclin; Omadacycline (hydrochloride); (4S,4aS,5aR,12aR)-4,7-bis(dimethylamino)-9-[(2,2-dimethylpropylamino)methyl]-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide;hydrochloride; PTK0796 hydrochloride; CHEMBL3942449; Omadacycline; Nuzyra.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

H2O : 200 mg/mL (~!337.21 mM)
DMSO : 50 mg/mL (~84.30 mM)

Solubility in Formulation 1: ≥ 2.62 mg/mL (4.42 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: 50 mg/mL (84.30 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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