β-Lactam resistance in Staphylococcus aureus: the adaptive resistance of a plastic genome

Staphylococci have two mechanisms for resistance to β-lactam antibiotics. One is the production of β-lactamases, enzymes that hydrolytically destroy β-lactams. The other is the expression of penicillin-binding protein 2a (PBP 2a), which is not susceptible to inhibition by β-lactam antibiotics. Strains of S. aureus exhibiting either β-lactamase or PBP 2a-directed resistance (or both) have established a considerable ecological niche among human pathogens. The emergence and subsequent spread of bacterial strains designated as methicillin-resistant S. aureus (MRSA), from the 1960s to the present, has created clinical difficulties for nosocomial treatment on a global scale. The recent variants of MRSA that are resistant to glycopeptide antibiotics (such as vancomycin) have ushered in a new and disconcerting chapter in the evolution of this organism. Received 2 April 2005; received after revision 15 July 2005; accepted 25 July 2005     

Über eisenhaltige Wachstumsfaktoren,die Sideramine,und ihre Antagonisten,die eisenhaltigen Antibiotika Sideromycine

Summary A new group of iron-containing metabolites, with growth stimulating properties for a number of microorganisms, has been isolated from streptomycetes and namedferrioxamines. It is proposed to include them, together with some known substances, like ferrichrome, coprogen and the terregens factor, which either contain or bind iron, in a new class of growth factors, thesideramines.The biological property of the sideramines is counteracted by iron-containing antibiotics from streptomycetes, thesideromycins. They comprise, besides known products like grisein and albomycin, two new groups of antibiotics, among them the highly potentferrimycins.

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22. Mitteilung, Stoffwechselprodukte von Actinomyceten; 21. Mitteilung: Helv. chim. acta43, im Druck (1960).     

Mobile genetic elements of Staphylococcus aureus

Bacteria such as Staphylococcus aureus are successful as commensal organisms or pathogens in part because they adapt rapidly to selective pressures imparted by the human host. Mobile genetic elements (MGEs) play a central role in this adaptation process and are a means to transfer genetic information (DNA) among and within bacterial species. Importantly, MGEs encode putative virulence factors and molecules that confer resistance to antibiotics, including the gene that confers resistance to beta-lactam antibiotics in methicillin-resistant S. aureus (MRSA). Inasmuch as MRSA infections are a significant problem worldwide and continue to emerge in epidemic waves, there has been significant effort to improve diagnostic assays and to develop new antimicrobial agents for treatment of disease. Our understanding of S. aureus MGEs and the molecules they encode has played an important role toward these ends and has provided detailed insight into the evolution of antimicrobial resistance mechanisms and virulence.     

Beyond natural antimicrobial peptides: multimeric peptides and other peptidomimetic approaches

Naturally occurring antimicrobial peptides (AMPs) present several drawbacks that strongly limit their development into therapeutically valuable antibiotics. These include susceptibility to protease degradation and high costs of manufacture. To overcome these problems, researchers have tried to develop mimics or peptidomimetics endowed with better properties, while retaining the basic features of membrane-active natural AMPs such as cationic charge and amphipathic design. Protein epitope mimetics, multimeric (dendrimeric) peptides, oligoacyllysines, ceragenins, synthetic lipidated peptides, peptoids and other foldamers are some of the routes explored so far. The synthetic approach has led to compounds that have already entered clinical evaluation for the treatment of specific conditions, such as Staphylococcus (MRSA) infections. Should these trials be successful, an important proof-of-concept would be established, showing that synthetic oligomers rather than naturally occurring molecules could bring peptide-based antibiotics to clinical practice and the drug market for local and systemic treatment of medical conditions associated with multi-drug resistant pathogens.     

Role of fungal statling growth products in inter-specific competition among phylloplane fungi

Summary The effect of fungal staling growth products on leaf-inhabiting microfungi, with special reference to a leaf spot pathogenPestalotiopsis funerea Desm. ofEucalyptus globulus Labill. was studied. Results depict that antibiotics produced by competing microfungi caused the phenomenon of mycostasis on the leaf surfaces.Acknowledgments. I would like to express my thanks to Professor R.S. Dwivedi for his encouragement and to CSIR (Indian Govt.) for financial assistance.     

Male production induced by antibiotic treatment inEncarsia formosa (Hymenoptera: Aphelinidae), an asexual species

The production of large numbers of males in the thelytokous speciesEncarsia formosa was induced by feeding antibiotics to their mothers. The males induced by antibiotic treatment produce sperm and sometimes mate with females, but insemination does not occur.     

Über den Wirkungscharakter verschiedener Antibiotikain vitro

Summary The mode of action of penicillin onBact. coli is the same as that on staphylococci.The mode of action of 6 different antibiotics was found in 5 cases to be different from that of penicillin.Streptomycin, however, was shown to have at least a very similar action to penicillin on staphylococci, and the same action as penicillin onBact. coli.     

Two sulfur-containing ansamycin antibiotics fromStreptomyces albolongus

Summary Two sulfur-containing ansamycin antibiotics were isolated from the culture broth ofStreptomyces albolongus C-46366; the major one was identical with awamycin and the minor one was a new ansamycin antibiotic, ansathiazin. Their structures were elucidated from their reactions and spectroscopic analyses. These antibiotics were active against gram-positive bacteria, acid-fast bacteria and a protozoan.We thank Dr I. Umezawa for his generous gift of awamycin. We are grateful to Drs K. Morita, Y. Nakao, H. Okazaki and H. Ono for their interest throughout this work. Thanks are also due to Messrs Y. Kono, K. Koyama, H. Fujiuchi and Y. Nakano, and Mrs K. Jinno for their skillful technical assistance.     

Flow microcalorimetric bioassay of polyene antibiotics: Interaction with growingSaccharomyces cerevisiae

Summary Microcalorimetric investigation of the interaction of polyene antibiotics with mid-exponential cells of a growing culture ofSaccharomyces cerevisiae has been used as the basis of a bioassay procedure. The assay is rapid, sensitive and reproducible. The results are compared to classical assays and potency ranking orders.This work was supported by the Science Research Council. (Studentship for B.Z. Chowdhry). We are grateful to the Central Research Fund of London University for funds to purchase the flow nephelometer used to support this study.     

Plant growth stimulation by inoculation with symbiotic and associative rhizosphere microorganisms

SelectedRhizobium bacteria, arbuscular mycorrhiza-forming (AM) fungi and associative bacteria have been shown to stimulate the growth of legumes, gramineae and cruciferae in field experiments on different soil types in temperate regions. A combination of microorganisms with different metabolic capacities (N₂-fixation, P-mobilization; production of phytohormones and antibiotics) can partly surpass the effect of single inoculations, or can produce a positive effect where single inoculations are ineffective. Growth stimulation by inoculation requires microorganisms with phytoeffective metabolic characteristics and the ability to survive in the rhizosphere during the growth period. Another prerequisite is an adequate supply of plant assimilates for the production of microbial phytoeffective metabolites. Type of inoculum, method of inoculation and agricultural measures can influence the effect of the inoculation. Research is necessary to extend our knowledge both of basic principles, and about using microorganisms in practice.     

Versuche zur Wirkungssteigerung der Kombination Sulfamethoxazol/Trimethoprim durch EDTA und Levallorphan anEscherichia coli

Summary EDTA, which is reported to potentiate the action of some antibiotics and chemotherapeutics in various bacterial strains, showed only additive effects inE. coli, when combined with trimethoprim or sulfamethoxazole, eithersingly or together. Neither was a potentiation seen with sulfanilamide, the permeation and effectiveness of which is less pronounced than that of sulfamethoxazole. The same negative results were obtained with levallorphan, which leads to alterations in the cell membrane. EDTA may therefore be of chemotherapeutic interest only in special cases, e.g. inPsuedomonas species which possess a highly EDTA-sensitive cell wall.     

Gramicidin S and polymyxins: the revival of cationic cyclic peptide antibiotics

Gramicidin S and polymyxins are small cationic cyclic peptides and act as potent antibiotics against Gram-negative and Gram-positive bacteria by perturbing integrity of the bacterial membranes. Screening of a natural antibiotics library with bacterial membrane vesicles identified gramicidin S as an inhibitor of cytochrome bd quinol oxidase and an alternative NADH dehydrogenase (NDH-2) and polymyxin B as an inhibitor of NDH-2 and malate: quinone oxidoreductase. Our studies showed that cationic cyclic peptide antibiotics have novel molecular targets in the membrane and interfere ligand binding on the hydrophobic surface of enzymes. Improvement of the toxicity and optimization of the structures and clinical uses are urgently needed for their effective application in combating drug-resistant bacteria.     

Substrate binding and catalytic mechanism of class B β-lactamases: a molecular modelling study

Increased resistance to β-lactam antibiotics is mainly due to β-lactamases whose production by pathogenic bacteria makes their broad activity spectrum especially frightening. X-ray structures of several zinc β-lactamases have revealed the coordination of the two metal ions, but their mode of action remains unclear. Geometry optimisation of stable complexes along the reaction pathway of benzylpenicillin hydrolysis highlighted a proton shuttle occurring from D120 of the Bacillus cereus β-lactamase to the β-lactam nitrogen via Zn2 which is central to the network. First, the Zn1 ion has a structural role maintaining Zn-bound waters, WAT1 and WAT2, either directly or through the Zn1 tetrahedrally coordinated histidine ligands. The Zn2 ion has a more catalytic role, stabilising the tetrahedral intermediate, accepting the β-lactam nitrogen atom as a ligand. The role of Zn2 and the flexibility in the coordination geometry of both Zn ions is of crucial importance for catalysis. Received 14 August 2001; received after revision 19 October 2001; accepted 30 October 2001     

Resistance to association of antibiotics (polymyxin and penicillin) in relation to cell concentration of two bacterial species in the same inoculum. Complementary inoculum effect]

Dense suspensions of Sa. typhi (Polys Penr) and of St. aureus (Polyr Pens) proliferate on gelose medium added with the two antibiotics only if the inoculum is mixed. The growth is probably due to the partial neutralization of the antibiotics following the formation of complexes between these antibiotics and some constituents of the two strains.     

Über die Chemie des Enniatins

Summary Judging by the physical and chemical properties and bacterial spectra, the antibiotic substance, Enniatin, previously isolated from a strain ofFusarium by the authors, appears to be identical with that which was recently reported byCook et al. derived from another strain and designated by them as Lateritiin-I, although the reported empirical formulæ differ. Numerous physical and chemical characteristics of Enniatin and its degradation products are given, and, further, two relatedFusarium antibiotics, here designated as Enniatin B and C, are briefly described.

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Ausgeführt mit einem Beitrag aus den eidg. Arbeitsbeschaffungskrediten.     

Tetracyclines inhibit parathyroid hormone-induced bone resorption in organ culture

Summary Several tetracyclines (minocycline, doxycycline, tetracycline), in levels approximating physiologic concentrations, were found to inhibit parathyroid hormone-induced bone resorption in organ culture; the specificity of this effect was demonstrated by comparison with other (non-tetracycline) types of antibiotics. The ability of tetracyclines to inhibit bone resorption is consistent with the recent proposal by Golub et al². that these antibiotics can inhibit mammalian collagenolytic enzymes by a mechanism unrelated to the drug's antibacterial efficacy, a property which could be therapeutically useful in diseases characterized by excessive collagen breakdown.     

Bromelain: biochemistry, pharmacology and medical use

Bromelain is a crude extract from the pineapple that contains, among other components, various closely related proteinases, demonstrating, in vitro and in vivo, antiedematous, antiinflammatory, antithrombotic and fibrinolytic activities. The active factors involved are biochemically characterized only in part. Due to its efficacy after oral administration, its safety and lack of undesired side effects, bromelain has earned growing acceptance and compliance among patients as a phytotherapeutical drug. A wide range of therapeutic benefits has been claimed for bromelain, such as reversible inhibition of platelet aggregation, angina pectoris, bronchitis, sinusitis, surgical traumas, thrombophlebitis, pyelonephritis and enhanced absorption of drugs, particularly of antibiotics. Biochemical experiments indicate that these pharmacological properties depend on the proteolytic activity only partly, suggesting the presence of nonprotein factors in bromelain. Recent results from preclinical and pharmacological studies recommend bromelain as an orally given drug for complementary tumor therapy: bromelain acts as an immunomodulator by raising the impaired immunocytotoxicity of monocytes against tumor cells from patients and by inducing the production of distinct cytokines such as tumor necrosis factor-α, interleukin (Il)-1β, Il-6, and Il-8. In a recent clinical study with mammary tumor patients, these findings could be partially confirmed. Especially promising are reports on animal experiments claiming an antimetastatic efficacy and inhibition of metastasis-associated platelet aggregation as well as inhibition of growth and invasiveness of tumor cells. Apparently, the antiinvasive activity does not depend on the proteolytic activity. This is also true for bromelain effects on the modulation of immune functions, its potential to eliminate burn debris and to accelerate wound healing. Whether bromelain will gain wide acceptance as a drug that inhibits platelet aggregation, is antimetastatic and facilitates skin debridement, among other indications, will be determined by further clinical trials. The claim that bromelain cannot be effective after oral administration is definitely refuted at this time. Received 25 August 2000; received after revision 29 March 2001; accepted 30 March 2001     

Antibiotic activity of organic compounds and their average quasi-valence number

Summary It is shown that the average quasi-valence numbers of antibiotics inhibiting protein synthesis are well defined and lie in the region of average quasi-valence numbers of amino acids, while the average quasi-valence numbers of antibiotics inhibiting DNA or RNA synthesis have higher values. Possible explanations of these findings and their implications on the design and selection of antibiotics are discussed.     

Early microbiota,antibiotics and health

The colonization of the neonatal digestive tract provides a microbial stimulus required for an adequate maturation towards the physiological homeostasis of the host. This colonization, which is affected by several factors, begins with facultative anaerobes and continues with anaerobic genera. Accumulating evidence underlines the key role of the early neonatal period for this microbiota-induced maturation, being a key determinant factor for later health. Therefore, understanding the factors that determine the establishment of the microbiota in the infant is of critical importance. Exposure to antibiotics, either prenatally or postnatally, is common in early life mainly due to the use of intrapartum prophylaxis or to the administration of antibiotics in C-section deliveries. However, we are still far from understanding the impact of early antibiotics and their long-term effects. Increased risk of non-communicable diseases, such as allergies or obesity, has been observed in individuals exposed to antibiotics during early infancy. Moreover, the impact of antibiotics on the establishment of the infant gut resistome, and on the role of the microbiota as a reservoir of resistance genes, should be evaluated in the context of the problems associated with the increasing number of antibiotic resistant pathogenic strains. In this article, we review and discuss the above-mentioned issues with the aim of encouraging debate on the actions needed for understanding the impact of early life antibiotics upon human microbiota and health and for developing strategies aimed at minimizing this impact.     

The Sushi peptides: structural characterization and mode of action against Gram-negative bacteria

The compositional difference in microbial and human cell membranes allows antimicrobial peptides to preferentially bind microbes. Peptides which specifically target lipopolysaccharide (LPS) and palmitoyl-oleoyl-phosphatidylglycerol (POPG) are efficient antibiotics. From the core LPS-binding region of Factor C, two 34-mer Sushi peptides, S1 and S3, were derived. S1 functions as a monomer, while S3 is active as a dimer. Both S1 and S3 display detergent-like properties in disrupting LPS aggregates, with specificity for POPG resulting from electrostatic and hydrophobic forces between the peptides and the bacterial lipids. During interaction with POPG, the S1 transitioned from a random coil to an α-helix, while S3 resumed a mixture of α-helix and β-sheet structures. The unsaturated nature of POPG confers fluidity and enhances insertion of the peptides into the lipid bilayer, causing maximal disruption of the bacterial membrane. These parameters should be considered in designing and developing new generations of peptide antibiotics with LPS-neutralizing capability. Received 2 October 2007; received after revision 2 November 2007; accepted 4 December 2007 J. L. Ding, B. Ho: Co-senior authors.