Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023241 (Legionella)
 6,990 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A series of N-benzyl-substituted 3'-(R)-3'-aminomethyl-3'-hydroxy spectinomycins was developed on the basis of a computational analysis of the aminomethyl spectinomycin binding site and structure-guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against the common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis, as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome-binding 3'-(S) isomers of the lead compounds demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target against the ribosome. Compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series exhibited excellent chemical stability superior to spectinomycin; no interaction with a panel of human receptors and drug metabolism enzymes, suggesting low potential for adverse reactions or drug-drug interactions in vivo; activity in vitro against a panel of penicillin-, macrolide-, and cephalosporin-resistant S. pneumoniae clinical isolates; and the ability to cure mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate that N-benzyl aminomethyl spectinomycins are suitable for further development to treat drug-resistant respiratory tract and sexually transmitted bacterial infections.
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PMID:Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections. 2599 21

Omadacycline is novel, aminomethyl tetracycline antibiotic being developed for oral and intravenous (IV) administration for the treatment of community-acquired bacterial infections. Omadacycline is characterized by an aminomethyl substituent at the C9 position of the core 6-member ring. Modifications at this position result in an improved spectrum of antimicrobial activity by overcoming resistance known to affect older generation tetracyclines via ribosomal protection proteins and efflux pump mechanisms. In vitro, omadacycline has activity against Gram-positive and Gram-negative aerobes, anaerobes, and atypical pathogens including Legionella and Chlamydia spp. Omadacycline offers once daily oral and IV dosing and a clinical tolerability and safety profile that compares favorably with contemporary antibiotics used across serious community-acquired infections where resistance has rendered many less effective. In studies in patients with complicated skin and skin structure infections, including those with MRSA infections, omadacycline exhibited an efficacy and tolerability profile that was comparable to linezolid. Ongoing and planned clinical studies are evaluating omadacycline as monotherapy for treating serious community-acquired bacterial infections including Acute Bacterial Skin and Skin Structure Infections (ABSSSI) and Community-Acquired Bacterial Pneumonia (CABP). This review provides an overview of the discovery, microbiology, nonclinical data, and available clinical safety and efficacy data for omadacycline, with reference to other contemporary tetracycline-derived antibiotics.
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PMID:Discovery, pharmacology, and clinical profile of omadacycline, a novel aminomethylcycline antibiotic. 2746 81