Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines

Sum, Phaik‐Eng; Lee, Ving J.; Testa, R. T.; Hlavka, Joseph J.; Ellestad, George A.; Bloom, Jonathan D.; Gluzman, Y; Tally, Francis P.

doi:10.1021/jm00027a023

Cited by 116 publications

(73 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To restore the potential of the tetracyclines as a class of useful broad-spectrum agents, a systematic search was undertaken during the early 1990s to discover new analogs that might possess activity against organisms resistant to older members of the class while retaining activity against tetracycline-susceptible organisms (295). This resulted in the discovery of the 9-glycinyltetracyclines (glycylcyclines) (15,286,287,295) (Tables 1 and 2). Previous attempts to introduce substituents at position 9 of the molecule, e.g., 9-nitro, 9-amino, and 9-hydroxy, led to analogs with poor antibacterial activity (179,250).…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

“…However, during the 1990s, a team at Lederle Laboratories (now American Home Products) noted that 9-acylamido derivatives of minocycline exhibited antibacterial activities typical of earlier tetracyclines but without activity against tetracycline-resistant organisms (15). Nevertheless, when the acyl group was modified to include an N,N-dialkylamine moiety, e.g., as in the 6-demethyl-6-deoxytetracycline and minocycline derivatives (GAR-936) shown in Table 2, not only was antibacterial activity retained but also the compounds displayed activity against bacteria containing tet genes (Tables 3 to 5 (15,286,287,295). These findings were extended to the 9-t-butylglycylamido derivative of minocycline (Tables 1 and 2) (208).…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

See 1 more Smart Citation

Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance

Chopra

Roberts

2001

Microbiol Mol Biol Rev

3,635

2,643

View full text Add to dashboard Cite

Tetracyclines were discovered in the 1940s and exhibited activity against a wide range of microorganisms including gram-positive and gram-negative bacteria, chlamydiae, mycoplasmas, rickettsiae, and protozoan parasites. They are inexpensive antibiotics, which have been used extensively in the prophlylaxis and therapy of human and animal infections and also at subtherapeutic levels in animal feed as growth promoters. The first tetracycline-resistant bacterium, Shigella dysenteriae, was isolated in 1953. Tetracycline resistance now occurs in an increasing number of pathogenic, opportunistic, and commensal bacteria. The presence of tetracycline-resistant pathogens limits the use of these agents in treatment of disease. Tetracycline resistance is often due to the acquisition of new genes, which code for energy-dependent efflux of tetracyclines or for a protein that protects bacterial ribosomes from the action of tetracyclines. Many of these genes are associated with mobile plasmids or transposons and can be distinguished from each other using molecular methods including DNA-DNA hybridization with oligonucleotide probes and DNA sequencing. A limited number of bacteria acquire resistance by mutations, which alter the permeability of the outer membrane porins and/or lipopolysaccharides in the outer membrane, change the regulation of innate efflux systems, or alter the 16S rRNA. New tetracycline derivatives are being examined, although their role in treatment is not clear. Changing the use of tetracyclines in human and animal health as well as in food production is needed if we are to continue to use this class of broad-spectrum antimicrobials through the present century

show abstract

Section: Structure-activity Relationshipsmentioning

confidence: 99%

Section: Structure-activity Relationshipsmentioning

confidence: 99%

Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance

Chopra

Roberts

2001

Microbiol Mol Biol Rev

3,635

2,643

View full text Add to dashboard Cite

show abstract

“…Glycylcyclines are novel semisynthetic compounds that contain a glycylamido substitution at position 9 of various tetracycline derivatives (27,28). Tigecycline ( Fig.…”

mentioning

confidence: 99%

Functional, Biophysical, and Structural Bases for Antibacterial Activity of Tigecycline

Olson

Ruzin

Feyfant

et al. 2006

Antimicrob Agents Chemother

181

148

View full text Add to dashboard Cite

Tigecycline is a novel glycylcycline antibiotic that possesses broad-spectrum activity against many clinically relevant species of bacterial pathogens. The mechanism of action of tigecycline was delineated using functional, biophysical, and molecular modeling experiments in this study. Functional assays showed that tigecycline specifically inhibits bacterial protein synthesis with potency 3-and 20-fold greater than that of minocycline and tetracycline, respectively. Biophysical analyses demonstrated that isolated ribosomes bind tigecycline, minocycline, and tetracycline with dissociation constant values of 10 ؊8 , 10 ؊7 , and >10 ؊6 M, respectively. A molecular model of tigecycline bound to the ribosome was generated with the aid of a 3.40-angstrom resolution X-ray diffraction structure of the 30S ribosomal subunit from Thermus thermophilus. This model places tigecycline in the A site of the 30S subunit and involves substantial interactions with residues of H34 of the ribosomal subunit. These interactions were not observed in a model of tetracycline binding. Modeling data were consistent with the biochemical and biophysical data generated in this and other recent studies and suggested that tigecycline binds to bacterial ribosomes in a novel way that allows it to overcome tetracycline resistance due to ribosomal protection.

show abstract

“…Glycylcyclines inhibit both tetracycline-resistant and sensitive fractions exhibiting ribosomal protection factors i.e. tetM and tetO or efflux determinants Tet A, E L and K [70]. The MIC 90 of [(dimethylamino)glycylamido]-6-desmethyl-6-deoxytetracycline (DMG-DMOT) against MRSA was 2μg/ml whereas minocycline had a value of 16 µg/ml.…”

Section: Glycylcyclinesmentioning

confidence: 99%

Surmounting antimicrobial resistance in the Millennium Superbug: Staphylococcus aureus

Saxena

Gomber

2010

Open Medicine

View full text Add to dashboard Cite

AbstractStaphylococcus aureus is the third most dreaded pathogen posing a severe threat due to its refractory behavior against the current armamentarium of antimicrobial drugs. This is attributed to the evolution of an array of resistance mechanisms responsible for morbidity and mortality globally. Local and international travel has resulted in the movement of drug resistant S. aureus clones from hospitals into communities and further into different geographical areas where they have been responsible for epidemic outbreaks. Thus, there is a dire necessity to refrain further cross movement of these multidrug resistant clones across the globe. The plausible alternative to prevent this situation is by thorough implementation of regulatory aspects of sanitation, formulary usage and development of new therapeutic interventions. Various strategies like exploring novel antibacterial targets, high throughput screening of microbes, combinatorial and synthetic chemistry, combinatorial biosynthesis and vaccine development are being extensively sought to overcome multidrug resistant chronic Staphylococcal infections. The majority of the antibacterial drugs are of microbial origin and are prone to being resisted. Anti-staphylococcal plant natural products that may provide a new alternative to overcome the refractory S.aureus under clinical settings have grossly been unnoticed. The present communication highlights the new chemical entities and therapeutic modalities that are entering the pharmaceutical market or are in the late stages of clinical evaluation to overcome multidrug resistant Staphylococcal infections. The review also explores the possibility of immunity and enzyme-based interventions as new therapeutic modalities and highlights the regulatory concerns on the prescription, usage and formulary development in the developed and developing world to keep the new chemical entities and therapeutic modalities viable to overcome antimicrobial resistance in S. aureus.

show abstract

Glycylcyclines. 1. A new generation of potent antibacterial agents through modification of 9-aminotetracyclines

Cited by 116 publications

References 8 publications

Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance

Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance

Functional, Biophysical, and Structural Bases for Antibacterial Activity of Tigecycline

Surmounting antimicrobial resistance in the Millennium Superbug: Staphylococcus aureus

Contact Info

Product

Resources

About