安普霉素(Apramycin) - 药物靶点：30S subunit_在研适应症：革兰氏阴性菌感染_专利_临床

概要

基本信息

药物类型

小分子化药

别名

4-O-((8R)-2-amino-8-O-(4-amino-4-deoxy-α-D-glucopyranosyl)-2,3,7-trideoxy-7-(methylamino)-D-glycero-α-D-allo-octodialdo-1,5:8,4-dipyranos-1-yl)-2-deoxy-D-streptamine、4-O-(3α-amino-6α-((4-amino-4-deoxy-α-D-glucopyranosyl)oxy)-2,3,4,5aβ,6,7,8,8aα-octahydro-8β-hydroxy-7β-(methylamino)pyrano(3,2-b)pyran-2α-yl)-2-deoxy-D-streptamine、Apramycin (USAN/INN)

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靶点

30S subunit

作用机制

30S subunit抑制剂(30S核糖体亚基抑制剂)

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

Uppsala University Hospital

University of Zurich

非在研机构

Juvabis GmbHAventis SA

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C21H41N5O11

InChIKeyXZNUGFQTQHRASN-XQENGBIVSA-N

CAS号37321-09-8

关联

2

项与安普霉素相关的临床试验

NCT05590728 / Completed临床1期IIT

A Phase I, Open-label Study to Assess Lung Pharmacokinetics and Safety of a Single Dose of Apramycin Administered Intravenously in Healthy Adult Subjects

A Phase I, open label study of a single dose of 30 mg/kg of apramycin administered intravenously (IV) over 30 (+/- 5) minutes. Twenty subjects will be enrolled in the study to one of 5 cohorts, T1-T5, each corresponding to a timepoint after initiation of infusion at which a single fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is performed. There will be 4 subjects per cohort. Cohort T5 will be enrolled after plasma and lung apramycin concentrations and preliminary PK data analysis are completed in cohorts T1-T4. Enrollment and dosing will be determined by bronchoscopy schedule. For each cohort, if 2 subjects are scheduled to receive study drug on the same day, the dose will be administered sequentially at least 2 hours apart. The primary objective is to assess plasma pharmacokinetic (PK) profile of apramycin and lung penetration of apramycin in epithelial lining fluid (ELF) and alveolar macrophages (AM) after single intravenous (IV) apramycin dose of 30 mg/kg in healthy subjects.

开始日期2023-06-16

申办/合作机构

National Institute of Allergy & Infectious Diseases

NCT04105205 / Completed临床1期

A Phase I, Randomized, Double-blind, Placebo-controlled, Single Ascending Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of Apramycin Administered Intravenously in Healthy Adults.

This is a first-in-human study to assess the safety, tolerability and pharmacokinetics of escalating single doses of apramycin. This trial will be conducted as a single ascending dose trial in up to 5 sequential dose cohorts (group-comparison). Each cohort will consist of 8 healthy subjects, 6 will receive apramycin and 2 placebo.

开始日期2019-09-25

申办/合作机构

Juvabis GmbH

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100 项与安普霉素相关的临床结果

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100 项与安普霉素相关的转化医学

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100 项与安普霉素相关的专利（医药）

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387

项与安普霉素相关的文献（医药）

2024-12-01·Applied Microbiology and Biotechnology

Improving the production of carbamoyltobramycin by an industrial Streptoalloteichus tenebrarius through metabolic engineering

Article

作者: Chen, Xutong ; Yu, Haoran ; Feng, Yun ; Lin, Jianping ; Xue, Hailong ; Jiang, Yiqi ; Yang, Lirong ; Zhu, Li ; Wu, Mianbin

AbstractTobramycin is an essential and extensively used broad-spectrum aminoglycoside antibiotic obtained through alkaline hydrolysis of carbamoyltobramycin, one of the fermentation products of Streptoalloteichus tenebrarius. To simplify the composition of fermentation products from industrial strain, the main byproduct apramycin was blocked by gene disruption and constructed a mutant mainly producing carbamoyltobramycin. The generation of antibiotics is significantly affected by the secondary metabolism of actinomycetes which could be controlled by modifying the pathway-specific regulatory proteins within the cluster. Within the tobramycin biosynthesis cluster, a transcriptional regulatory factor TobR belonging to the Lrp/AsnC family was identified. Based on the sequence and structural characteristics, tobR might encode a pathway-specific transcriptional regulatory factor during biosynthesis. Knockout and overexpression strains of tobR were constructed to investigate its role in carbamoyltobramycin production. Results showed that knockout of TobR increased carbamoyltobramycin biosynthesis by 22.35%, whereas its overexpression decreased carbamoyltobramycin production by 10.23%. In vitro electrophoretic mobility shift assay (EMSA) experiments confirmed that TobR interacts with DNA at the adjacent tobO promoter position. Strains overexpressing tobO with ermEp* promoter exhibited 36.36% increase, and tobO with kasOp* promoter exhibited 22.84% increase in carbamoyltobramycin titer. When the overexpressing of tobO and the knockout of tobR were combined, the production of carbamoyltobramycin was further enhanced. In the shake-flask fermentation, the titer reached 3.76 g/L, which was 42.42% higher than that of starting strain. Understanding the role of Lrp/AsnC family transcription regulators would be useful for other antibiotic biosynthesis in other actinomycetes.Key points• The transcriptional regulator TobR belonging to the Lrp/AsnC family was identified. • An oxygenase TobO was identified within the tobramycin biosynthesis cluster.• TobO and TobR have significant effects on the synthesis of carbamoyltobramycin.

2024-11-06·Antimicrobial Agents and Chemotherapy

The point mutation A1387G in the 16S rRNA gene confers aminoglycoside resistance in Campylobacter jejuni and Campylobacter coli

Article

作者: Golz, Julia C. ; Werckenthin, Christiane ; Zarske, Michael ; Stingl, Kerstin

ABSTRACT Thermotolerant Campylobacter spp. are the most frequent cause of foodborne bacterial diarrhea and high-priority antibiotic-resistant pathogens, according to the World Health Organization (WHO). Monitoring revealed current low prevalence of gentamicin resistance in European Campylobacter spp. isolates but substantial presence of gentamicin modifying genes circulating globally. Using a combined approach of natural transformation and whole-genome sequencing, we revealed a novel gentamicin resistance mechanism, namely the point mutation A1387G in the 16S rRNA gene, originally identified in a C. coli isolate from turkey caecal content. The transformation rate of the resistance using genomic DNA of the resistant donor to sensitive recipient C. jejuni and C. coli was ~2.5 log 10 lower compared to the control rpsL -A128G point mutation conferring streptomycin resistance. Antimicrobial susceptibility tests showed cross-resistance to apramycin, kanamycin, and tobramycin, with transformants exhibiting more than 4- to 8-fold increased MICs to apramycin and tobramycin and over 64-fold higher MICs to kanamycin compared to wild-type isolates. Although transformants showed 177–1,235 variations relative to the recipient, only the A1387G point mutation in the 16S rRNA was in common. This mutation was causal for resistance, as transformation of a 16S rRNA_A1387G PCR fragment into susceptible isolates also led to resistant transformants. Sanger sequencing of the 16S rRNA genes and Oxford nanopore whole-genome sequencing of transformants identified clones harboring either all three copies with A1387G or a mixed population of wild-type and mutated 16S rRNA gene alleles. Within 15 passages on non-selective medium, transformants with mixed populations of the 16S rRNA gene copies partially reverted to wild type, both geno- and phenotypically. In contrast, transformants harboring the A1387G point mutation in all three 16S rRNA gene copies kept full resistance within at least 45 passages. We speculate that partial acquisition and rapid loss of the point mutation limited its spread among C . spp. isolates. In-depth knowledge on resistance mechanisms contributes to optimal diagnosis and preventative measures.

2024-08-01·Talanta

Dual-ligand lanthanide metal-organic framework based ratiometric fluorescent platform for visual monitoring of aminoglycoside residues in food samples

Article

作者: Yan, Xiaoxia ; He, Haibo ; Luo, Liqiang ; Lei, Yunyi ; Peng, Xitian ; Li, Hongbo ; Chen, Huinan ; Deng, Tingting

Herein, a dual-emission Eu metal-organic framework (Eu-MOF) is prepared and used as the ratiometric fluorescence probe for ultrasensitive detection of aminoglycoside antibiotics (AGs). Due to the strong hydrogen bond interactions between AGs and Eu-MOF, the blue emission is enhanced while the red emission has little fluctuation in Eu-MOF with the addition of AGs, thus a good linear relationship with the logarithm of AGs concentrations from 0.001 to 100 μg/mL can be established for quantitative analysis. Good sensitivity with the detection limit of 0.33 ng/mL for apramycin, 0.32 ng/mL for amikacin and 0.30 ng/mL for kanamycin is achieved. The proposed assay demonstrates good selectivity and applicability for determination of AGs in real milk and honey samples. The Eu-MOF materials are further fabricated as fluorescent test papers for facile visual detection. The as-established ratio fluorescence platform offers a portable and economical way for rapid monitoring AGs residues in complex food samples.

100 项与安普霉素相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D02322	安普霉素	-	DB04626

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
革兰氏阴性菌感染	临床1期	-	Sanofi	-
革兰氏阴性菌感染	临床1期	-	Uppsala University Hospital	-
革兰氏阴性菌感染	临床1期	-	University of Zurich	-
肿瘤	临床1期	法国	Aventis SA	-