Tetracycline; protein synthesis of bacteria

体外活性：Omadacycline 是一种新型氨甲基四环素抗生素，正在开发用于口服和静脉 (IV) 给药，用于治疗社区获得性细菌感染，例如急性细菌性皮肤和皮肤结构感染 (ABSSSI)、社区获得性细菌性肺炎 (CABP)和尿路感染（UTI）。在体外，omadacycline 对革兰氏阳性和革兰氏阴性需氧菌、厌氧菌和非典型病原体（包括军团菌和衣原体属）具有活性。奥马达环素提供每日一次的口服和静脉注射给药方式，其临床耐受性和安全性与当前用于治疗严重社区获得性感染的抗生素相比具有优势，而在这些感染中，耐药性已大大降低了有效性。在针对复杂皮肤和皮肤结构感染（包括 MRSA 感染患者）的研究中，omadacycline 表现出与利奈唑胺相当的疗效和耐受性。正在进行和计划中的临床研究正在评估 omadacycline 作为治疗严重社区获得性细菌感染的单一疗法，包括急性细菌性皮肤和皮肤结构感染 (ABSSSI) 和社区获得性细菌性肺炎 (CABP)。本综述概述了奥马环素的发现、微生物学、非临床数据以及可用的临床安全性和有效性数据，并参考了其他当代四环素衍生抗生素。细胞测定：omadacycline 对 MRSA、VRE 和 β-溶血性链球菌的 MIC90 分别为 1.0 μg/mL、0.25 μg/mL 和 0.5 μg/mL，omadacycline 对 PRSP 和流感嗜血杆菌的 MIC90 为 0.25 μg/ml分别为2.0μg/mL和2.0μg/mL。 Omadacycline 对生物体具有活性，表现出两种主要的耐药机制：核糖体保护和活性四环素外排[1]。 Omadacycline 抑制蛋白质合成，但对 RNA、DNA 和肽聚糖合成无明显影响。此外，omadacycline 与细菌核糖体 30S 亚基上的四环素结合位点结合，基于额外的分子相互作用，其结合增强，类似于替加环素。

使用小鼠腹膜内感染模型证明了omadacycline的体内功效。单次静脉注射剂量的 omadacycline 对肺炎链球菌、大肠杆菌和金黄色葡萄球菌（包括含有 tet (M) 和 tet (K) 外排的菌株和 MRSA 菌株）具有疗效。获得的肺炎链球菌的50%有效剂量（ED50）范围为0.45 mg/kg至3.39 mg/kg，获得的金黄色葡萄球菌的ED50范围为0.30 mg/kg至1.74 mg/kg，大肠杆菌的ED50为2.02毫克/公斤。

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使用小鼠腹腔感染模型证明了奥美他环素的体内疗效。单次静脉注射奥马达环素对肺炎链球菌、大肠杆菌和金黄色葡萄球菌具有疗效，包括含有tet（M）和tet（K）外排的菌株和MRSA菌株。获得的肺炎链球菌的50%有效剂量（ED50s）范围为0.45 mg/kg至3.39 mg/kg，获得的金黄色葡萄球菌的ED50s范围为0.30 mg/kg至1.74 mg/kg，大肠杆菌的ED50为2.02 mg/kg。这些结果表明了强大的体内疗效，包括对含有常见耐药决定因素的菌株的活性。奥马达环素在体外表现出对多种革兰氏阳性和选择性革兰氏阴性病原体的活性，包括含有耐药性决定簇的菌株，这种活性在体内转化为强效疗效[2]。

奥马环素的体外稳定性及药物相互作用潜力[2] 测定了4.8 μM和48 μM的奥马环素在人微粒体和肝细胞中的稳定性。奥马大环素在人微粒体中孵育30分钟后，>90%的奥马环素被完整地回收。同样，奥马环素在人肝细胞中孵育24小时后，>86%的细胞恢复完好。这些结果表明，奥马环素没有代谢到任何显著程度。使用混合人肝微粒体制剂、S9、肝细胞质或重组黄素单加氧酶(FMO1、FMO3、FMO5)评估与奥马环素药物相互作用的可能性。在原代人肝细胞中，用1-100 μM的奥马环素和底物探针孵育24和48小时，评估CYP450同工酶的诱导作用。在浓度为1-50 μM的奥马环素和浓度近似于每个底物Km的同工酶特异性底物的混合人微粒体中，评估CYP450同工酶的抑制作用。评估的同工酶包括CYP 1A1、1A2、1B1、2A6、2B6、2C8、2C9、2C19、2D6、2E1、2J2和3A4/5。奥马环素没有诱导CYP同工酶，并且没有或很少(<40%的最大阳性对照反应)诱导它们的mrna。奥马达环素对CYP同工酶活性无明显抑制作用。此外，奥马环素及其可能的代谢物对CYP1A2 2C9、2D6或3A4/5没有时间依赖性的抑制作用。 Bioorg Med Chem.2016 Dec 15;24(24):6409-6419.

omadacycline 对 MRSA、VRE 和 β-溶血性链球菌的 MIC90 分别为 1.0 μg/mL、0.25 μg/mL 和 0.5 μg/mL，omadacycline 对 PRSP 和流感嗜血杆菌的 MIC90 分别为 0.25 μg/ml 和 2.0 μg /mL，分别。 Omadacycline 对生物体具有活性，表现出两种主要的耐药机制：核糖体保护和活性四环素外流。 Omadacycline 抑制蛋白质合成，但对 RNA、DNA 和肽聚糖合成无明显影响。此外，omadacycline 与细菌核糖体 30S 亚基上的四环素结合位点结合，基于额外的分子相互作用，其结合增强，类似于替加环素。

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]

The pharmacokinetics of omadacycline are best described by a linear, three-compartment model following a zero-order intravenous infusion or first-order oral administration with transit compartments to account for delayed absorption. Omadacycline has a volume of distribution (Vd) ranging from 190 to 204 L, a terminal elimination half-life (t½) of 13.5-17.1 h, total clearance (CLT) of 8.8-10.6 L/h, and protein binding of 21.3% in healthy subjects. Oral bioavailability of omadacycline is estimated to be 34.5%. A single oral dose of 300 mg (bioequivalent to 100 mg IV) of omadacycline administered to fasted subjects achieved a maximum plasma concentration (Cmax) of 0.5-0.6 mg/L and an area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) of 9.6-11.9 mg h/L. The free plasma area under concentration-time curve divided by the minimum inhibitory concentration (i.e., fAUC24h/MIC), has been established as the pharmacodynamic parameter predictive of omadacycline antibacterial efficacy. Several animal models including neutropenic murine lung infection, thigh infection, and intraperitoneal challenge model have documented the in vivo antibacterial efficacy of omadacycline. A phase II clinical trial on complicated skin and skin structure infection (cSSSI) and three phase III clinical trials on ABSSSI and CABP demonstrated the safety and efficacy of omadacycline. The phase III trials, OASIS-1 (ABSSSI), OASIS-2 (ABSSSI), and OPTIC (CABP), established non-inferiority of omadacycline to linezolid (OASIS-1, OASIS-2) and moxifloxacin (OPTIC), respectively. Omadacycline is currently approved by the FDA for use in treatment of ABSSSI and CABP. Phase II clinical trials involving patients with acute cystitis and acute pyelonephritis are in progress. Mild, transient gastrointestinal events are the predominant adverse effects associated with use of omadacycline. Based on clinical trial data to date, the adverse effect profile of omadacycline is similar to studied comparators, linezolid and moxifloxacin. Unlike tigecycline and eravacycline, omadacycline has an oral formulation that allows for step-down therapy from the intravenous formulation, potentially facilitating earlier hospital discharge, outpatient therapy, and cost savings. Omadacycline has a potential role as part of an antimicrobial stewardship program in the treatment of patients with infections caused by antibiotic-resistant and multidrug-resistant Gram-positive [including methicillin-resistant Staphylococcus aureus (MRSA)] and Gram-negative pathogens. [https://pubmed.ncbi.nlm.nih.gov/31970713/]

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of omadacycline during breastfeeding. It is unknown how much omadacycline is excreted into breastmilk, but the drug is only about 35% absorbed orally under optimal circumstances, and is probably less from milk because of its calcium content. The manufacturer states that breastfeeding is not recommended during treatment and for 4 days after the last dose. If an infant is breastfed, monitor the infant for possible effects on the gastrointestinal flora, such as diarrhea, candidiasis (e.g., thrush, diaper rash) or rarely, blood in the stool indicating possible antibiotic-associated colitis. As a theoretical precaution, avoid prolonged or repeat courses during nursing.
◉ 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.

[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.

Omadacycline (Nuzyra®) is a new aminomethylcycline, approved by the U. S. Food and Drug Administration in 2018, as a tetracycline antibacterial. It can be used in community-acquired pneumonia and in acute bacterial skin and skin-structure infections. It was developed and is commercialized by Paratek Pharmaceuticals. It is a semisynthetic compound, derived from minocycline, capable of evading widely distributed efflux and target protection antibacterial resistance mechanisms and has demonstrated activity in a broad spectrum of bacteria.[1]

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Omadacycline is the first intravenous and oral 9-aminomethylcycline in clinical development for use against multiple infectious diseases including acute bacterial skin and skin structure infections (ABSSSI), community-acquired bacterial pneumonia (CABP), and urinary tract infections (UTI). The comparative in vitro activity of omadacycline was determined against a broad panel of Gram-positive clinical isolates, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Lancefield groups A and B beta-hemolytic streptococci, penicillin-resistant Streptococcus pneumoniae (PRSP), and Haemophilus influenzae (H. influenzae). The omadacycline MIC90s for MRSA, VRE, and beta-hemolytic streptococci were 1.0 μg/ml, 0.25 μg/ml, and 0.5 μg/ml, respectively, and the omadacycline MIC90s for PRSP and H. influenzae were 0.25 μg/ml and 2.0 μg/ml, respectively. Omadacycline was active against organisms demonstrating the two major mechanisms of resistance, ribosomal protection and active tetracycline efflux. 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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Omadacycline is a novel aminomethylcycline antibiotic developed as a once-daily, intravenous and oral treatment for acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP). Omadacycline, a derivative of minocycline, has a chemical structure similar to tigecycline with an alkylaminomethyl group replacing the glycylamido group at the C-9 position of the D-ring of the tetracycline core. Similar to other tetracyclines, omadacycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Omadacycline possesses broad-spectrum antibacterial activity against Gram-positive and Gram-negative aerobic, anaerobic, and atypical bacteria. Omadacycline remains active against bacterial isolates possessing common tetracycline resistance mechanisms such as efflux pumps (e.g., TetK) and ribosomal protection proteins (e.g., TetM) as well as in the presence of resistance mechanisms to other antibiotic classes.[3]

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Paratek Pharmaceuticals are developing omadacycline (NUZYRA™), a first-in-class orally active aminomethylcycline antibacterial, as a treatment for various bacterial infections. The drug, which is available in intravenous and oral formulations, has a broad spectrum of antibacterial activity and was recently approved in the USA as a treatment for the treatment of community acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in adults. This article summarizes the milestones in the development of omadacycline leading to this first global approval for the treatment of CABP and ABSSSI.[4]

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

177Ų

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

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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)

配方 1 中的溶解度: ≥ 2.62 mg/mL (4.42 mM) (饱和度未知) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 2 中的溶解度: 50 mg/mL (84.30 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
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