Bacteriostatic actions of some tetracyclines

Benbough, J. E.; Morrison, G. A.

doi:10.1111/j.2042-7158.1965.tb07696.x

Cited by 17 publications

(3 citation statements)

References 9 publications

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“…Tetracyclines are bacteriostatic agents with broad-spectrum antimicrobial activity (3). Doxycycline is a semisynthetic, longacting, second-generation tetracycline which is absorbed rapidly and penetrates well into the brain and CSF (48).…”

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Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

et al. 2006

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Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 M in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats. Pneumococcal meningitis has a high level of mortality (up to 30%), and brain and/or cochlear damage occurs in up to 50% of the survivors (2). Inflammatory mediators, such as tumor necrosis factor alpha (TNF-␣) and matrix metalloproteinases (MMPs), are produced during the host response to bacteria and contribute to the pathophysiology that can ultimately lead to death, brain damage, and hearing impairment (23,26,29,36). The role of cytokines and MMPs in the pathophysiology of the cochlear damage associated with pneumococcal meningitis is still unknown. However, it has been demonstrated that MMPs are constitutively expressed at high levels in the cochlea (8) and that in meningitis pneumococci and polymorphonuclear leukocytes (PMNs) extend from the cerebrospinal fluid (CSF) to the perilymph via the cochlear aqueduct (5).Tetracyclines are bacteriostatic agents with broad-spectrum antimicrobial activity (3). Doxycycline is a semisynthetic, longacting, second-generation tetracycline which is absorbed rapidly and penetrates well into the brain and CSF (48). Doxycycline has been shown to have anti-inflammatory effects that are separate and distinct from its antimicrobial action (13,16,35,43). These effects include the reduction of cytokine release and the inhibition of MMPs (7, 38). Experimental and clinical studies have indicated that treatment with doxycycline may be beneficial in inflammatory diseases associated with excessive MMP activity (7,13,35).In pneumococcal meningitis massive subarachnoid and ventricular space inflammation is triggered by the presence of bacteria in the CSF space (7,1...

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Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

et al. 2006

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“…Mode II inhibition, under aeration conditions, is considered a derangement of protein synthesis. Subsequently, BENBOUGH and MoRRISON (1965) proposed a third mode of action for the chlorinated derivatives related to the metabolism of D-glutamate (see also SNELL and CHENG, 1961). (also see HAHN, 1959 and demonstrated that the effects of mixtures of chloramphenicol and either OTC or CTC on the growth rate of E. coli were additive.…”

Section: Protein Synthesismentioning

confidence: 98%

Antibiotics

1967

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AII rights, especially that of tnmslation into foreign languages, reserved. It is also forbidden to reproduce this book, either whole DedicationFor most areas of scientific pursuit, there is usually that rare investigator who has the imagination to conceive ideas, who has faith in his visions, and who has the ability to critically test his concepts in the laboratory. Almost invariably, this scientist also inspires younger men to enthusiastically enter into his research program. To him should go the accolades and the recognitions of the esteem in which he is held. As only a small part of this esteem, we wish to dedicate these books to Professor SELMAN A. W AKSMAN in appreciation of his leadership and contributions in all facets of antibiotic research. PrefaceThe idea for publishing these books on the mechanism of action and on the biosynthesis of antibiotics was born of frustration in our attempts to keep abreast of the literature. Gone were the years when we were able to keep a bibliography on antibiotics and feel confident that we could find everything that was being published on this subject. These fields of investigation were moving forward so rapidly and were encompassing so wide a range of specialized areas in microbiology and chemistry that it was almost impossible to keep abreast of developments. In our naivete and enthusiasm, however, we were unaware that we were toying with an idea that might enmesh us, that we were creating an entity with a life of its own, that we were letting loose a Golom who instead of being our servant would be our master.That we set up ideals for these books is obvious; they would be current guides to developments and information in the areas of mechanism of action and biosynthesis of antibiotics. For almost every subject, we wished to enlist the aid of an investigator who himself had played a part in determining the nature of the phenomena that were being discussed. One concept for the books was that they include only antibiotics for which a definitive, well-documented mechanism of action or biosynthetic pathway was known. Yet, such an approach would not entirely serve the purpose we projected, for it would not encompass all of the information available in these fields of antibiotic investigations and blind searches for the original literature would still have to be made. We therefore chose to include any and all antibiotics about which some pertinent information had been published. It was obvious even at the start that such a compilation, integration, and analysis of information could never be complete unless scientific investigations ceased at the moment the last manuscript was submitted-an end that was neither desirable nor possible. An addendum was therefore included at the end of the volume and left open for the addition of new information until the last pages of the regular articles had been printed.The original concept has also been further expanded as the authors of several papers found it advisable to elaborate on their subject. Some of the articles included discussions...

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“…Some authors suppose that their primary site of action is the bacterial synthesis of proteins (HAHN 1960, FRANKLIN andGODFREY 1965). Others think that electron transfer and energy yielding metabolism are the first reaction inhibited owing to the structural pecularities of the tetracyclines (SAZ andMARTINEZ 1958, PLAKUNOV 1964, GRUNERTOVA 1964, BENBOUGH andMORRISON 1965).…”

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The loss of inducibility for β‐galactosidase in Escherichia coli accompanying oxytetracycline resistance

Krčméry

Drobnica

Parráková

1967

J of Basic Microbiology

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The mechanisms of the action of tetracycline antibiotics are far from being elucidated. Some authors suppose that their primary site of action is the bacterial synthesis of proteins (HAHN 1960, FRANKLIN and GODFREY 1965). Others think that electron transfer and energy yielding metabolism are the first reaction inhibited owing to the structural pecularities of the tetracyclines (SAZ and MARTINEZ 1958, PLAKUNOV 1964, KRCMERY and GRUNERTOVA 1964, BENBOUGH and MORRISON 1965.Since tetracyclines inhibit in low concentrations the synthesis of specific proteins in cell-free preparations of microorganisms at the level of ribosomes (FRANKLIN and GODFREY 1965), it could be supposed that the process of induct,ion of some inducible enzymes in bacteria should also be influenced in some way by these antibiotics. The impairment of energy metabolism too should interfere with the formation of inducible enzymes (NEIDHARDT 1963). OTCresistant mutants of Escherichia coli and Staphylococcus aurews are devoid of malate dehydrogenase (KRCMERY and KELLEN 1966). It would be interesting, therefore, to know whether the induction of 8-galactosidase in malate-cultivated sensitive and resistant variants of E . coli would be altered in some way.We used two strains of E . coli and their OTC-resistant mutants. Strain H was kindly supplied us by Dr. SECKAROVA from this Institute. Strain B was supported by Dr. BETINOVA from Research Institute of Epidemiology, Bratislava. Their resistant mutants were prepared by serial transfer of parent strains on VH agar (VYMOLA and HEJZLAR 1964)) containing increasing concentrations of oxytetracycline (supplied by Dr. VLCEK, Research Institute of Antibiotics, Roztoky near Prague) until they grew well a t 250.0 pg OTC /ml.The strains were grown in the malete-containing synthetic medium of Max-DELSTAM (1962). In the original medium malate in equal amounts was substituted for glucose. Tubes containing each 10 ml of the medium were inoculated with lo6 bacteria from a culture 18 hours old and were shaken a t 37 "C until the beginning of the logarithmic phase of growth (usually 4-5 hours). After 45 minutes the antibiotic (0.05 ml) and the inducer (0.05 ml) were added to the cells as described by MCFALL, PARDEE and STENT (1958). After another 20 minutes, the detector (o-Nitrophenyl-j3-galactopyranoside, generously supplied by P. TAUSSIK from KOCH and LIGHT Co.) was added and exactly after 32 minutes thereafter (see MCFALL et al. 1958) the extinctions were measured with a PREXA spectrophotometer a t 430 mp.

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Bacteriostatic actions of some tetracyclines

Cited by 17 publications

References 9 publications

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

Antibiotics

The loss of inducibility for β‐galactosidase in Escherichia coli accompanying oxytetracycline resistance

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