Structure-Activity Relationship of the Aminomethylcyclines and the Discovery of Omadacycline

Honeyman, Laura; Ismail, Mohamed; Nelson, Mark L.; Bhatia, Beena; Bowser, Todd E.; Chen, Jackson; Mechiche, Rachid; Ohemeng, Kwasi A.; Verma, Atul Kumar; Cannon, E. Pat; Macone, Ann B.; Tanaka, Sébastien; Levy, Stuart B.

doi:10.1128/aac.01536-15

Cited by 109 publications

(90 citation statements)

References 11 publications

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“…Omadacycline is a semisynthetic derivative of minocycline and the first member of the novel aminomethylcycline class (9,12,13). Similar to the older tetracyclines (doxycycline, minocycline, and tetracycline), omadacycline binds to the 30S ribosomal subunit of target GPC and GNB with resultant inhibition of protein synthesis (7,9,12).…”

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“…Similar to the older tetracyclines (doxycycline, minocycline, and tetracycline), omadacycline binds to the 30S ribosomal subunit of target GPC and GNB with resultant inhibition of protein synthesis (7,9,12). Notably, omadacycline remains active against ribosomal protection and efflux tetracycline resistance genes (8,9,13). Omadacycline also maintains its activity against difficult-to-treat pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Enterobacteriaceae strains that produce a wide array of extended-spectrum ␤-lactamases (ESBLs) and carbapenemases, in addition to multidrug-resistant (resistant to Ն3 classes of agents) strains of Acinetobacter spp.…”

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“…Genes encoding for efflux pumps and ribosomal protection proteins have been described in both GPC and GNB and confer resistance to tetracycline, doxycycline, and minocycline (7-10). Chemical modification of minocycline has led to the development of tigecycline, a glycylcycline (11), and omadacycline, an aminomethylcycline (9), both of which specifically overcome tetracycline resistance mechanisms and are not affected by resistance to other classes of antibiotics (8,9,11).Omadacycline is a semisynthetic derivative of minocycline and the first member of the novel aminomethylcycline class (9, 12, 13). Similar to the older tetracyclines (doxycycline, minocycline, and tetracycline), omadacycline binds to the 30S ribosomal subunit of target GPC and GNB with resultant inhibition of protein synthesis (7,9,12).…”

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Surveillance of Omadacycline Activity against Clinical Isolates from a Global Collection (North America, Europe, Latin America, Asia-Western Pacific), 2010-2011

Pfaller

Huband

Rhomberg

et al. 2017

Antimicrob Agents Chemother

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Omadacycline is a broad-spectrum aminomethylcycline in late-stage clinical development for the treatment of acute bacterial skin and skin structure infections and community-acquired pneumonia as an oral and an intravenous oncedaily formulation. In this study, omadacycline and comparators were tested against 69,246 nonduplicate bacterial isolates collected prospectively during 2010 and 2011 from medical centers in Asia-Pacific (11,397 isolates), Europe (23,490 isolates), Latin America (8,038 isolates), and North America (26,321 isolates). Omadacycline was tested by broth microdilution following Clinical and Laboratory Standards Institute M07-A10 (2015) methods. A total of 99.9% of Staphylococcus aureus isolates were inhibited by Յ2 g/ml of omadacycline (MIC 50/90 , 0.12/0.25 g/ml), including 100.0% of methicillin-susceptible S. aureus isolates and 99.8% of methicillin-resistant S. aureus isolates. Omadacycline potencies were comparable for Streptococcus pneumoniae (MIC 50/90 , 0.06/0.06 g/ml), viridans group streptococci (MIC 50/90 , 0.06/0.12 g/ml), and beta-hemolytic streptococci (MIC 50/90 , 0.06/0.12 g/ml) regardless of species and susceptibility to penicillin. Omadacycline was active against Enterobacteriaceae and was most active against Escherichia coli (MIC 50/90 , 0.5/2 g/ml), Enterobacter aerogenes (MIC 50/90 , 2/4 g/ml), Klebsiella oxytoca (MIC 50/90 , 1/4 g/ml), and Citrobacter spp. (MIC 50/90 , 1/4 g/ml). Omadacycline was active against Haemophilus influenzae (MIC 50/90 , 1/1 g/ml) regardless of ␤-lactamase status and against Moraxella catarrhalis (MIC 50/90 , 0.12/0.25 g/ml). The potent activity of omadacycline against Gram-positive and Gramnegative bacteria indicates that omadacycline merits further study in serious infections in which multidrug resistance and mixed Gram-positive and Gram-negative infections may be a concern.KEYWORDS aminomethylcycline, omadacycline, resistance, surveillance A ntimicrobial resistance (AMR) is a global problem that requires a coordinated response to prevent further erosion of the ability to address established and emerging threats to human health (1). In the United States, AMR infections cost an estimated additional $20 billion annually and associated production losses of $35 billion per year (2). In the United Kingdom, it is estimated that drug-resistant infections might account for 10 million deaths per year by 2050, with total costs of $100 trillion in lost output (1). Collection of AMR surveillance and antibiotic consumption data is an essential approach to both defining the scope of the resistance problem and developing interventions that improve appropriate use of antibiotics and decrease resistance selection pressure (1, 3). Another important effort is to understand the mechanisms of resistance whereby bacteria avoid the effects of antibiotics and to use this information to develop new agents, or modify older agents, such that potent activity is retained against the key target pathogens (4-6). Downloaded fromTetracyclines are broad-spectrum age...

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Surveillance of Omadacycline Activity against Clinical Isolates from a Global Collection (North America, Europe, Latin America, Asia-Western Pacific), 2010-2011

Pfaller

Huband

Rhomberg

et al. 2017

Antimicrob Agents Chemother

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Effect of Food on the Bioavailability of Omadacycline in Healthy Participants

Tzanis

Manley

Villano

et al. 2016

The Journal of Clinical Pharma

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Omadacycline is a first‐in‐class aminomethylcycline antibiotic being evaluated in phase 3 studies as oral and intravenous monotherapy for bacterial infections. This was a phase 1, randomized, open‐label, 4‐period, crossover study that evaluated the effect of food consumption on the bioavailability of omadacycline. Healthy participant were randomized to 1 of 4 sequences, which included the following predose conditions in different orders (A) ≥6‐hour fast, (B) high‐fat, nondairy meal 4 hours before dosing, (C) high‐fat, nondairy meal 2 hours before dosing, and (D) high‐fat meal containing dairy 2 hours before dosing. Participants received a single 300‐mg oral dose of omadacycline during each treatment period; periods were separated by ≥5 days. Blood samples for pharmacokinetic (PK) analysis were collected over 24 hours after each dose, and safety assessments were performed during each treatment period. Least‐squares mean and 90% confidence intervals were compared for fed state vs fasted state. Thirty‐one participants were included in the PK analysis. Fasted AUC0‐∞, AUC0‐t, and AUC0‐24 were 10.2, 7.2, and 7.2 μg·h/mL, respectively, and Cmax was 0.6 μg/mL. Compared with a fasted dose, bioavailability was reduced by 15% to 17% by a nondairy meal 4 hours before dosing, 40% to 42% by a nondairy meal 2 hours before dosing, and 59% to 63% for a dairy meal 2 hours before dosing. Two participants experienced adverse events (mild nausea, mild somnolence). A 300‐mg oral dose of omadacycline administered within 2 to 4 hours after food had reduced bioavailability compared with the fasted state. Oral omadacycline should be administered in a fasted state.

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Ribosome‐targeting antibacterial agents: Advances, challenges, and opportunities

Zhang

Bai

et al. 2021

Medicinal Research Reviews

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Ribosomes, which synthesize proteins, are critical organelles for the survival and growth of bacteria. About 60% of approved antibiotics discovered so far combat pathogenic bacteria by targeting ribosomes. However, several issues, such as drug resistance and toxicity, have impeded the clinical use of ribosome‐targeting antibiotics. Moreover, the complexity of the bacteria ribosome structure has retarded the discovery of new ribosome‐targeting agents that are considered as the key to the drug‐resistance and toxicity. To deal with these challenges, efforts such as medicinal chemistry optimization, combination treatment, and new drug delivery system have been developed. But not enough, the development of structural biology and new screening methods bring powerful tools, such as cryo‐electron microscopy technology, advanced computer‐aided drug design, and cell‐free in vitro transcription/translation systems, for the discovery of novel ribosome‐targeting antibiotics. Thus, in this paper, we overview the research on different aspects of bacterial ribosomes, especially focus on discussing the challenges in the discovery of ribosome‐targeting antibacterial drugs and advances made to address issues such as drug‐resistance and selectivity, which, we believe, provide perspectives for the discovery of novel antibiotics.

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Structure-Activity Relationship of the Aminomethylcyclines and the Discovery of Omadacycline

Cited by 109 publications

References 11 publications

Surveillance of Omadacycline Activity against Clinical Isolates from a Global Collection (North America, Europe, Latin America, Asia-Western Pacific), 2010-2011

Surveillance of Omadacycline Activity against Clinical Isolates from a Global Collection (North America, Europe, Latin America, Asia-Western Pacific), 2010-2011

Effect of Food on the Bioavailability of Omadacycline in Healthy Participants

Ribosome‐targeting antibacterial agents: Advances, challenges, and opportunities

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