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Winning the war against antibiotic resistance
Literature
MOLECULAR MEDICINE TODAY, JULY 1998
non-human primates after exposure to replicating retroviruses. Furthermore, the recombinogenic properties of retroviral sequences might offer the possibility of creating a hybrid retrovirus between the incoming porcine retrovirus and silent retrosequences or ERVs in the human genome. Implications for the emergence of a new type of retroviral pathogen are already documented by the story of HIV, and this underscores the important considerations in assessing the safety risks associated with xenotransplantation. Roger Hewson PhD Centre for Applied Microbiology and Research, Porton Down, Salisbury, Wiltshire, UK SP4 0JG.
New evidence for neuroprotection by estrogen Estrogen reduces neuronal generation of Alzheimer -amyloid peptides Xu, H. et al. (1998)
Nat. Med. 4, 447–451
Nuclear estrogen receptor-independent neuroprotection by estratrienes: a novel interaction with glutathione Green, P.S. et al. (1998)
Neuroscience 84, 7–10 Recent epidemiological and clinical studies suggest that estrogen-replacement therapy might protect postmenopausal women from Alzheimer’s disease and improve their cognitive function. The substantial potential for prevention and therapy of this devastating disease by estrogen hormones is now beginning to emerge. Estrogen’s Alzheimerbusting potential should be enhanced by discerning the mechanisms underlying its neuroprotective properties. Previous studies have demonstrated that treating cultured neuronal cells with 17-estradiol, the physiological estrogen hormone, increased the secretion to the culture medium of -APP, the membrane-spanning precursor for -amyloid peptides, which are the major component of the amyloid plaques found in postmortem brains of individuals with Alzheimer’s disease. Because secreted -APP, unlike full-length membrane -APP, cannot serve as a precursor for -amyloid peptides, researchers reasoned that increasing secretion of soluble -APP should
reduce the yield of -amyloid peptides in the aging brain. An important lead in this direction has now been supplied by Xu et al., who showed that treating cultured neuronal cells with 17-estradiol diminishes the production of -amyloid peptides to almost half the control levels. This effect was long-lasting, as it was observed in cultures treated with physiological concentrations of 17-estradiol for periods of several weeks. This observation is particularly encouraging compared with previous in vitro strategies, in which increased soluble -APP secretion or decreased -amyloid production usually lasted only a few hours to a few days. Other putative neuroprotective effects of estrogen hormones might include modulation of basal forebrain cholinergic activity and prevention of oxidative stress and -amyloid-mediated toxicity. Green et al. have now shown that the latter effect is unrelated to the known nuclear estrogen receptor: treatment of HT-22 murine neuronal cells with either 17-estradiol, 17␣-estradiol, or estratrien-3-ol protected them from -amyloid toxicity. Notably, adding reduced glutathione to the culture medium increases the neuroprotective potency of estrogens by about 400-fold, suggesting an antioxidant-related mechanism of neuroprotection. Together, the new studies raise hopes for a combined estrogen/antioxidant therapy for Alzheimer’s disease, and possibly for other neurodegenerative diseases, in the future.
Chem. Biol. 5, 185–196
clinician. Even the antibiotic of last resort, vancomycin, is no longer all conquering [see, for example, Healy, V.L. et al. (1998) Chem. Biol. 5, 197–207]. In these papers, two approaches to getting around this problem are described. Species of Bacteroides, including B. fragilis, are commonly found in clinical isolates from suppurative or surgical infections. Simultaneous resistance to metronidazole, co-amoxiclav and imipenem in a single clinical isolate of B. fragilis was recently found to be due to a metallo--lactamase-like enzyme produced by the bacteria. Toney et al. set out to determine whether combination therapy with antibiotics and inhibitors of metallo--lactamases might revive the activity of the antibiotics. By screening of a large chemical library and modelling based on X-ray crystallography, the authors identified a series of biphenyl tetrazoles (BPTs) that inhibited -lactamase activity. In a simple assay of antibiotic activity, in which zones of growth inhibition on lawns of bacteria were measured, they were able to show synergistic inhibition by a BPT and imipenem – thus converting a clinically resistant strain of B. fragilis to a sensitive one. In a strikingly different approach, Balaban et al. have targeted the production of bacterial toxins by Staphylococcus aureus. The synthesis of virulence factors in S. aureus is controlled by the regulatory RNAmolecule RNAIII, which is itself auto-induced by the RNAIII-activating protein (RAP). In a mouse model, the authors showed that vaccination of the animals with purified RAP had the effect of dramatically reducing both the mortality and morbidity associated with the S. aureus infection. Only one out of 33 vaccinated mice died, whereas five of 22 untreated animals died. The lesions in surviving mice were much smaller in the vaccinated group than those in the controls. In addition, a non-pathogenic strain of S. aureus was found to produce a peptide, YSPXTNF, that inhibited RAP and has therefore been called RIP. Injection of purified RIP and S. aureus protected mice against a sub-lethal dose of the bacterium. Further good news is that regulatory mechanisms involving auto-inducers have been described for other bacterial species. Together, these papers give hope to the clinician that the war against antibiotic-resistant bacteria is far from lost.
Autoinducer of virulence as a target for vaccine and therapy against Staphylococcus aureus
Ian A. McKay MA, PhD Senior Lecturer in Dermatology, Centre for Cutaneous Research, 2 Newark Street, London, UK E1 2AT.
David Gurwitz PhD ([email protected]) National Laboratory for the Genetics of Israeli Populations, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
Winning the war against antibiotic resistance Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo--lactamase Toney, J.H. et al. (1998)
Balaban, N. et al. (1998)
Science 280, 438–440 Multiple antibiotic resistance among bacteria is becoming an increasingly alarming problem for the
Copyright ©1998 Elsevier Science Ltd. All rights reserved. 1357 - 4310/98/$19.00
The literature page is designed to alert readers to recent primary papers that are relevant to molecular medicine. A panel of senior active researchers is commissioned to select one or two recent papers within their area of expertise. If you are interested in joining this panel, send an e-mail message to the Editor at: [email protected]
281
MOLECULAR MEDICINE TODAY, JULY 1998
non-human primates after exposure to replicating retroviruses. Furthermore, the recombinogenic properties of retroviral sequences might offer the possibility of creating a hybrid retrovirus between the incoming porcine retrovirus and silent retrosequences or ERVs in the human genome. Implications for the emergence of a new type of retroviral pathogen are already documented by the story of HIV, and this underscores the important considerations in assessing the safety risks associated with xenotransplantation. Roger Hewson PhD Centre for Applied Microbiology and Research, Porton Down, Salisbury, Wiltshire, UK SP4 0JG.
New evidence for neuroprotection by estrogen Estrogen reduces neuronal generation of Alzheimer -amyloid peptides Xu, H. et al. (1998)
Nat. Med. 4, 447–451
Nuclear estrogen receptor-independent neuroprotection by estratrienes: a novel interaction with glutathione Green, P.S. et al. (1998)
Neuroscience 84, 7–10 Recent epidemiological and clinical studies suggest that estrogen-replacement therapy might protect postmenopausal women from Alzheimer’s disease and improve their cognitive function. The substantial potential for prevention and therapy of this devastating disease by estrogen hormones is now beginning to emerge. Estrogen’s Alzheimerbusting potential should be enhanced by discerning the mechanisms underlying its neuroprotective properties. Previous studies have demonstrated that treating cultured neuronal cells with 17-estradiol, the physiological estrogen hormone, increased the secretion to the culture medium of -APP, the membrane-spanning precursor for -amyloid peptides, which are the major component of the amyloid plaques found in postmortem brains of individuals with Alzheimer’s disease. Because secreted -APP, unlike full-length membrane -APP, cannot serve as a precursor for -amyloid peptides, researchers reasoned that increasing secretion of soluble -APP should
reduce the yield of -amyloid peptides in the aging brain. An important lead in this direction has now been supplied by Xu et al., who showed that treating cultured neuronal cells with 17-estradiol diminishes the production of -amyloid peptides to almost half the control levels. This effect was long-lasting, as it was observed in cultures treated with physiological concentrations of 17-estradiol for periods of several weeks. This observation is particularly encouraging compared with previous in vitro strategies, in which increased soluble -APP secretion or decreased -amyloid production usually lasted only a few hours to a few days. Other putative neuroprotective effects of estrogen hormones might include modulation of basal forebrain cholinergic activity and prevention of oxidative stress and -amyloid-mediated toxicity. Green et al. have now shown that the latter effect is unrelated to the known nuclear estrogen receptor: treatment of HT-22 murine neuronal cells with either 17-estradiol, 17␣-estradiol, or estratrien-3-ol protected them from -amyloid toxicity. Notably, adding reduced glutathione to the culture medium increases the neuroprotective potency of estrogens by about 400-fold, suggesting an antioxidant-related mechanism of neuroprotection. Together, the new studies raise hopes for a combined estrogen/antioxidant therapy for Alzheimer’s disease, and possibly for other neurodegenerative diseases, in the future.
Chem. Biol. 5, 185–196
clinician. Even the antibiotic of last resort, vancomycin, is no longer all conquering [see, for example, Healy, V.L. et al. (1998) Chem. Biol. 5, 197–207]. In these papers, two approaches to getting around this problem are described. Species of Bacteroides, including B. fragilis, are commonly found in clinical isolates from suppurative or surgical infections. Simultaneous resistance to metronidazole, co-amoxiclav and imipenem in a single clinical isolate of B. fragilis was recently found to be due to a metallo--lactamase-like enzyme produced by the bacteria. Toney et al. set out to determine whether combination therapy with antibiotics and inhibitors of metallo--lactamases might revive the activity of the antibiotics. By screening of a large chemical library and modelling based on X-ray crystallography, the authors identified a series of biphenyl tetrazoles (BPTs) that inhibited -lactamase activity. In a simple assay of antibiotic activity, in which zones of growth inhibition on lawns of bacteria were measured, they were able to show synergistic inhibition by a BPT and imipenem – thus converting a clinically resistant strain of B. fragilis to a sensitive one. In a strikingly different approach, Balaban et al. have targeted the production of bacterial toxins by Staphylococcus aureus. The synthesis of virulence factors in S. aureus is controlled by the regulatory RNAmolecule RNAIII, which is itself auto-induced by the RNAIII-activating protein (RAP). In a mouse model, the authors showed that vaccination of the animals with purified RAP had the effect of dramatically reducing both the mortality and morbidity associated with the S. aureus infection. Only one out of 33 vaccinated mice died, whereas five of 22 untreated animals died. The lesions in surviving mice were much smaller in the vaccinated group than those in the controls. In addition, a non-pathogenic strain of S. aureus was found to produce a peptide, YSPXTNF, that inhibited RAP and has therefore been called RIP. Injection of purified RIP and S. aureus protected mice against a sub-lethal dose of the bacterium. Further good news is that regulatory mechanisms involving auto-inducers have been described for other bacterial species. Together, these papers give hope to the clinician that the war against antibiotic-resistant bacteria is far from lost.
Autoinducer of virulence as a target for vaccine and therapy against Staphylococcus aureus
Ian A. McKay MA, PhD Senior Lecturer in Dermatology, Centre for Cutaneous Research, 2 Newark Street, London, UK E1 2AT.
David Gurwitz PhD ([email protected]) National Laboratory for the Genetics of Israeli Populations, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
Winning the war against antibiotic resistance Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of Bacteroides fragilis metallo--lactamase Toney, J.H. et al. (1998)
Balaban, N. et al. (1998)
Science 280, 438–440 Multiple antibiotic resistance among bacteria is becoming an increasingly alarming problem for the
Copyright ©1998 Elsevier Science Ltd. All rights reserved. 1357 - 4310/98/$19.00
The literature page is designed to alert readers to recent primary papers that are relevant to molecular medicine. A panel of senior active researchers is commissioned to select one or two recent papers within their area of expertise. If you are interested in joining this panel, send an e-mail message to the Editor at: [email protected]
281