In vitro and in vivo antibacterial activities of the glycylcyclines, a new class of semisynthetic tetracyclines

Testa, R. T.; Petersen, Peter J.; Jacobus, Nilda V.; Sum, Phaik‐Eng; Lee, V. J.; Tally, Francis P.

doi:10.1128/aac.37.11.2270

Cited by 117 publications

(101 citation statements)

References 26 publications

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“…In our system, we assume that P tot and drug diffusion across the inner membrane ( D 2 ) remain constant. Here, TetB more readily pumps out TET compared to DOX and MCN, which is consistent with previous studies performed with tet(B) (Testa et al , 1993; Nguyen et al , 2014). Figure 2C shows how the final steady‐state concentration of TET in the cytoplasm relates to a given concentration in the media based on equation (8).…”

Section: Resultssupporting

confidence: 92%

Using cellular fitness to map the structure and function of a major facilitator superfamily effluxer

Perez

Gomez

Kalvapalle

et al. 2017

Molecular Systems Biology

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The major facilitator superfamily (MFS) effluxers are prominent mediators of antimicrobial resistance. The biochemical characterization of MFS proteins is hindered by their complex membrane environment that makes in vitro biochemical analysis challenging. Since the physicochemical properties of proteins drive the fitness of an organism, we posed the question of whether we could reverse that relationship and derive meaningful biochemical parameters for a single protein simply from fitness changes it confers under varying strengths of selection. Here, we present a physiological model that uses cellular fitness as a proxy to predict the biochemical properties of the MFS tetracycline efflux pump, TetB, and a family of single amino acid variants. We determined two lumped biochemical parameters roughly describing K m and V max for TetB and variants. Including in vivo protein levels into our model allowed for more specified prediction of pump parameters relating to substrate binding affinity and pumping efficiency for TetB and variants. We further demonstrated the general utility of our model by solely using fitness to assay a library of tet(B) variants and estimate their biochemical properties.

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Section: Resultssupporting

confidence: 92%

Using cellular fitness to map the structure and function of a major facilitator superfamily effluxer

Perez

Gomez

Kalvapalle

et al. 2017

Molecular Systems Biology

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“…Most of these efflux proteins confer resistance to tetracycline but not to minocycline or glycylcyclines. In contrast, the gram-negative tet(B) gene codes for an efflux protein which confers resistance to both tetracycline and minocycline but not glycylcyclines (44,295 (173,291). The tetracycline resistance proteins in this group have 41 to 78% amino acid identity.…”

Section: Genetic and Biochemical Mechanisms Of Tetracycline Resistancementioning

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%

“…clines (1,2,19,38,44,70,85,103,120,122,150,165,(227)(228)(229)307). 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).…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

“…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%

See 2 more Smart Citations

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

Chopra

Roberts

2001

Microbiol Mol Biol Rev

3,644

2,643

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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

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Tetracyclines

Sum

2004

Kirk-Othmer Encyclopedia of Chemical Technology

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The tetracyclines are a group of antibiotics having an identical 4‐ring carbocyclic structure as a basic skeleton and differing from each other chemically only by substituent variation. The first tetracycline discovered was produced by a soil organism, Streptomyces aureofaciens , and is now known as chlorotetracycline. This compound ushered in a new era in antibacterial chemotherapy because it was effective orally and against a broad range of Gram‐positive and Gram‐negative bacteria. The three marketed tetracyclines were made by a semisynthetic pathway. The first of these were methacycline (6‐methylene oxytetracycline), and its reduction product doxycycline. The latest addition is minocycline. Minocycline showed superior antibacterial activity over other older tetracyclines and was active against many tetracycline‐resistant strains of gram‐positive bacteria when it was first discovered. In general, the tetracyclines are yellow crystalline compounds that have amphoteric properties. Most of the fermentation and isolation processes for manufacture of the tetracyclines are described in patents. Manufacture begins with the cultivated growth of selected strains of Streptomyces in a medium chosen to produce growth and maximum antibiotic production. Most of the clinically useful tetracyclines have been prepared either semi‐synthetically or isolated from fermentation. Tetracyclines inhibit bacterial growth by blocking protein synthesis and are bacteriostatic. The crystal structure of complex of Thermus thermophilius 30S ribosomal subunit with tetracycline has recently been determined. The emergence of bacterial resistance to tetracyclines has limited the use of these agents. Nevertheless, they are still the treatment of first choice for bacterial infections causing brucellosis, cholera, chancroid, granuloma inguinale, and lyme disease; for rickettsial and chlamydial infections, in the treatment of nonspecific urethritis, and in the treatment of acne vulgaris and rosacea. Tetracyclines are used as alternative drugs in a variety of circumstances when patient is unable to take the drug of choice, eg, in patients allergic to penicillin. Tetracyclines are widely used for veterinary therapy. The types of pathogens encountered are frequently different from those for which tetracyclines are used in humans. The discovery of glycylcyclines represents a significant advance in combating highly resistant organisms. One of the compounds, tigecycline, is current in phase III clinical trials. Tigecycline exhibits potent antibacterial activity against a broad‐spectrum of both tetracycline‐susceptible and tetracycline‐resistant organisms, including organisms resistant to other class of antibiotics. Most notably, it is active against multiply‐resistant staphylococci, vancomycin‐resistant enterococci, penicillin‐resistant streptococci and methicillin‐resistant S. aureous .

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In vitro and in vivo antibacterial activities of the glycylcyclines, a new class of semisynthetic tetracyclines

Cited by 117 publications

References 26 publications

Using cellular fitness to map the structure and function of a major facilitator superfamily effluxer

Using cellular fitness to map the structure and function of a major facilitator superfamily effluxer

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

Tetracyclines

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