Omadacycline: Development of a Novel Aminomethylcycline Antibiotic for Treating Drug-Resistant Bacterial Infections

Villano, Stephen; Steenbergen, Judith N.; Loh, Evan

doi:10.2217/fmb-2016-0100

Cited by 96 publications

(130 citation statements)

References 14 publications

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…Tetracyclines have been used extensively in clinical and veterinary medicine and in agriculture and for a variety of noninfectious conditions (e.g., acne) for many years (7,8). Broad use of tetracyclines has resulted in emergence of tetracycline-resistant bacteria and limited the use of the older members of this class (tetracycline, doxycycline, and minocycline) in treating bacterial disease (7,8).…”

Section: Downloaded Frommentioning

confidence: 99%

“…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. and Stenotrophomonas maltophilia (8). Omadacycline does not have useful activity against Pseudomonas aeruginosa (8).…”

mentioning

confidence: 97%

“…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).…”

mentioning

confidence: 99%

“…A great deal is known about resistance mechanisms that bacterial strains have developed to the tetracyclines. 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)(8)(9)(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).…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

See 4 more Smart Citations

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

View full text Add to dashboard Cite

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...

show abstract

Section: Downloaded Frommentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

View full text Add to dashboard Cite

show abstract

Considerations and Caveats in Combating ESKAPE Pathogens against Nosocomial Infections

et al. 2019

View full text Add to dashboard Cite

ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are among the most common opportunistic pathogens in nosocomial infections. ESKAPE pathogens distinguish themselves from normal ones by developing a high level of antibiotic resistance that involves multiple mechanisms. Contemporary therapeutic strategies which are potential options in combating ESKAPE bacteria need further investigation. Herein, a broad overview of the antimicrobial research on ESKAPE pathogens over the past five years is provided with prospective clinical applications.

show abstract

Peptoid drug discovery and optimization via surface X‐ray scattering

2019

View full text Add to dashboard Cite

Synthetic polymers mimicking antimicrobial peptides have drawn considerable interest as potential therapeutics. N‐substituted glycines, or peptoids, are recognized by their in vivo stability and ease of synthesis. Peptoids are thought to act primarily on the negatively charged lipids that are abundant in bacterial cell membranes. A mechanistic understanding of lipid–peptoid interaction at the molecular level will provide insights for rational design and optimization of peptoids. Here, we highlight recent studies that utilize synchrotron liquid surface X‐ray scattering to characterize the underlying peptoid interactions with bacterial and eukaryotic membranes. Cellular membranes are highly complex, and difficult to characterize at the molecular level. Model systems including Langmuir monolayers, are used in these studies to reduce system complexity. The general workflow of these systems and the corresponding data analysis techniques are presented alongside recent findings. These studies investigate the role of peptoid physicochemical characteristics on membrane activity. Specifically, the roles of cationic charge, conformational constraint via macrocyclization, and hydrophobicity are shown to correlate their membrane interactions to biological activities in vitro. These structure–activity relationships have led to new insights into the mechanism of action by peptoid antimicrobials, and suggest optimization strategies for future therapeutics based on peptoids.

show abstract

Omadacycline: Development of a Novel Aminomethylcycline Antibiotic for Treating Drug-Resistant Bacterial Infections

Cited by 96 publications

References 14 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

Considerations and Caveats in Combating ESKAPE Pathogens against Nosocomial Infections

Peptoid drug discovery and optimization via surface X‐ray scattering

Contact Info

Product

Resources

About