Heterocyclyl tetracyclines. 2. 7-Methoxy-8-pyrrolidinyltetracyclines: discovery of TP-2758, a potent, orally efficacious antimicrobial against Gram-negative pathogens (original) (raw)
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The tetracycline antibiotic class has acquired new valuable members due to the optimisation of the chemical structure. The first modern tetracycline introduced into therapy was tigecycline, followed by omadacycline, eravacycline, and sarecycline (the third generation). Structural and physicochemical key elements which led to the discovery of modern tetracyclines are approached. Thus, several chemical subgroups are distinguished, such as glycylcyclines, aminomethylcyclines, and fluorocyclines, which have excellent development potential. The antibacterial spectrum comprises several resistant bacteria, including those resistant to old tetracyclines. Sarecycline, a narrow-spectrum tetracycline, is notable for being very effective against Cutinebacterium acnes. The mechanism of antibacterial action from the perspective of the new compound is approached. Several severe bacterial infections are treated with tigecycline, omadacycline, and eravacycline (with parenteral or oral formulations)....
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Expert Opinion on Therapeutic Patents, 1995
The patent status of tetracycline research for the period of 1991 to 1995 is presented. Topics covered include new tetracyclines with intrinsic antibacterial activity against tetracycline-resistant bacteria or which potentiate the activity of the older tetracyclines, new natural products, new chemical methods, and non-infectious disease uses for tetracyclines.
Journal of Infection and Public Health, 2015
Treatment of infectious diseases with antimicrobials constituted a great achievement in the history of medicine. Unfortunately, the emergence of resistant strains of bacteria to all classes of antimicrobials limited their efficacy. The present study was aimed at evaluating the effect of combinations of antibiotics on multi-drug resistant Gram-negative (MDRGN) bacteria. A liquid micro-broth dilution method was used to evaluate the antibacterial activity of 10 different classes of antimicrobials on 20 bacterial strains belonging to six different species. The antimicrobials were associated with phenylalanine ˇnaphthylamide (PAN), an efflux pump inhibitor, and with other antimicrobials at their sub-inhibitory concentrations. The effectiveness of each combination was monitored using the minimal inhibitory concentration (MIC) and the fractional inhibitory concentration (FIC). Most of the antimicrobials tested showed low antibacterial activity with a MIC value of 128 mg/L on a majority of the bacterial strains, justifying their multidrugresistant (MDR) profile. Synergistic effects were mostly observed (FIC ≤ 0.5) when ampicillin (AMP), cloxacillin (CLX), erythromycin (ERY), chloramphenicol (CHL), kanamycin (KAN) and streptomycin (STR) were combined with tetracycline (TET) at the sub-inhibitory concentration of MIC/5 or MIC/10. The results of the present work suggest that the association of several antimicrobials with TET could improve the fight against MDRGN bacterial species.
Journal of Medicinal Chemistry, 1994
This report describes the discovery of a new generation of tetracycline antibacterial agents, the "glycylcyclines". These agents are notable for their activity against a broad spectrum of tetracyclinesusceptible and-resistant Gram-negative and Gram-positive aerobic and anaerobic bacteria possessing various classes of tetracycline-resistant determinants [ tet B (efflux), tet M (ribosomal protection)]. The design and synthesis of a number of 7-substituted 9-substituted-amido 6-demethyl-6-deoxytetracyclines are described.
ChemTexts, 2021
Tetracyclines belong to the first broad-spectrum, well-tolerated, and easy-to-administer antibiotics, which are effective against plague, cholera, typhoid, syphilis, Legionnaire’s disease, and anthrax. Some can also be used to treat malaria, Lyme disease, tuberculosis, Rocky Mountain spotted fever, and leprosy. Humans first encountered these chemical species involuntarily in ancient times, as evidenced from the analysis of bone samples dating back more than 1500 years. Shortly after World War II, they were “rediscovered” at Lederle Laboratories and Pfizer as a result of an intense search for new antibiotics. Their bacteriostatic action is based on the inhibition of protein biosynthesis. Since the structure elucidation by Robert Woodward, Lloyd Hillyard Conover, and others in the 1950s, tetracyclines have become preferred targets for natural product synthesis. However, on industrial scale, they became readily available by fermentation and partial synthesis. Their casual and thoughtle...
American Journal of Physiology-Cell Physiology, 2010
There must be something unique about a class of drugs (discovered and developed in the mid-1940s) where there are more than 130 ongoing clinical trials currently listed. Tetracyclines were developed as a result of the screening of soil samples for antibiotic organisms. The first of these compounds chlortetracycline was introduced in 1948. Soon after their development tetracyclines were found to be highly effective against various pathogens including rickettsiae, Gram-positive, and Gram-negative bacteria, thus, becoming a class of broad-spectrum antibiotics. The mechanism of action of tetracyclines is thought to be related to the inhibition of protein synthesis by binding to the 30S bacterial ribosome. Tetracyclines are also an effective anti-malarial drug. Over time, many other “protective” actions have been described for tetracyclines. Minocycline, which can readily cross cell membranes, is known to be a potent anti-apoptotic agent. Its mechanism of action appears to relate to spec...
In Vitro and In Vivo Antibacterial Activities of Omadacycline, a Novel Aminomethylcycline
Antimicrobial Agents and Chemotherapy, 2014
ER-35786 is a new parenteral 1-methyl carbapenem with a broad antibacterial spectrum and a potent antipseudomonal activity. It showed high in vitro activity, comparable to those of meropenem and a new carbapenem, BO-2727, against methicillin-susceptible Staphylococcus aureus and streptococci, with MICs at which 90% of strains tested are inhibited (MIC 90 s) of <0.39 g/ml. Against methicillin-resistant S. aureus, ER-35786 was the most active among the compounds tested, yet its MIC 90 was 12.5 g/ml. Against members of the family Enterobacteriaceae, Moraxella catarrhalis, and Haemophilus influenzae, ER-35786 inhibited 90% of strains tested at a concentration of <1.56 g/ml. The MIC 90 of ER-35786 for Pseudomonas aeruginosa was 3.13 g/ml, and the compound was more active than meropenem. In addition, the activity of ER-35786 against imipenem-, meropenem-, cefclidin-, or ceftazidime-resistant P. aeruginosa was equal to or higher than that of the most active reference compound. The in vivo activity of ER-35786 was consistent with this in vitro activity.
The glycylcyclines: a comparative review with the tetracyclines
Drugs, 2004
The tetracycline class of antimicrobials exhibit a broad-spectrum of activity against numerous pathogens, including Gram-positive and Gram-negative bacteria, as well as atypical organisms. These compounds are bacteriostatic, and act by binding to the bacterial 30S ribosomal subunit and inhibiting protein synthesis. The tetracyclines have been used successfully for the treatment of a variety of infectious diseases including community-acquired respiratory tract infections and sexually transmitted diseases, as well in the management of acne. The use of tetracyclines for treating bacterial infections has been limited in recent years because of the emergence of resistant organisms with efflux and ribosomal protection mechanisms of resistance. Research to find tetracycline analogues that circumvented these resistance mechanisms has lead to the development of the glycylcyclines. The most developed glycylcycline is the 9-tert-butyl-glycylamido derivative of minocycline, otherwise known as t...
Diagnostic Microbiology and Infectious Disease, 2000
The in vitro activity of GAR-936, a new semisynthetic glycylcycline, was evaluated in comparison with two tetracyclines and several other antimicrobial agents. A total of 1, 203 recent clinical isolates were tested by reference broth or agar dilution methods. Among the members of the family Enterobacteriaceae, GAR-936 was generally two-to four-fold more active than minocycline, and two-to 16-fold more active than tetracycline. All enteric bacilli MIC 90 results were Յ 4 g/mL; the exception being Proteus mirabilis and indole-positive Proteae (Ն 8 g/mL). GAR-936 demonstrated excellent activity against all Gram-positive cocci with 90% of the penicillin-resistant Streptococcus pneumoniae isolates inhibited at 0.03 g/ml, while the same isolates had a MIC 90 of 8 and Ͼ 8 g/mL for minocycline and tetracycline, respectively. All Enterococcus spp., including vancomycin-resistant isolates, were inhibited at 0.25 g/mL of GAR-936 (MIC 90 , 0.12 or 0.25 g/mL). Although GAR-936 (MIC 50 , 0.25 g/mL) was two-fold less active than minocycline (MIC 50 , 0.12 g/mL) against oxacillin-resistant Staphylococcus aureus, all isolates were inhibited at Յ 0.25 g/mL. GAR-936 demonstrated good activity against nonfermentative bacteria such as Acinetobacter spp. (MIC 90 , 2 g/ml) and Stenotrophomonas maltophilia (MIC 90 , 4 g/mL), but the compound exhibited only modest activity against Pseudomonas aeruginosa (MIC 50 , 8 g/mL). Haemophilus influenzae (MIC 90 , 1-2 g/mL), Moraxella catarrhalis (MIC 90 , 0.12 g/mL), and various Neisseria spp. (MIC 90 , 0.12-0.5 g/mL) were susceptible to GAR-936. These results indicate that GAR-936 has potent in vitro activity against a wide range of clinically important pathogenic bacteria, and that several Gram-positive and -negative isolates resistant to older tetracyclines and other drug classes remain susceptible to GAR-936, the newest glycylcycline candidate for clinical use.
Omadacycline: A Novel Tetracycline Derivative With Oral and Intravenous Formulations
Clinical Infectious Diseases, 2019
Omadacycline, an aminomethylcycline, is a novel member of the tetracycline class of antibiotics. It has received approval by the US Food and Drug Administration for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections, and is available in both oral and intravenous formulations. It is also being evaluated in clinical trials for the treatment of cystitis and pyelonephritis. The omadacycline molecule was designed to overcome tetracycline resistance and has broad-spectrum activity that includes gram-positive bacteria, gram-negative bacteria, anaerobes, atypicals, and other drug-resistant strains, like methicillin-resistant Staphylococcus aureus, as well as Yersinia pestis and Bacillus anthracis, organisms of biodefense interest. Omadacycline has minimal drug-drug pharmacokinetic interactions and a favorable safety profile, with the most common adverse events being gastrointestinal symptoms.