Current Topics in Medicinal Chemistry, Volume 1, No. 1, 2001
Contents
Novel Biochemical, Microbiological and Analytical
Developments Concerning Pathogenic Bacteria: Focus on Pyoverdines and Receptor
Proteins of Pseudomonads
Executive Editor: Mathias Schafer
Foreword
Allen B. Reitz
Preface
Mathias Schafer
Siderophores of
the Human Pathogenic Fluorescent Pseudomonads Pp.1-6
Herbert Budzikiewicz
[Abstract]
Structural
Biology of Bacterial Iron Uptake Systems Pp.7-30
Teresa E. Clarke, Leslie W. Tari and Hans J. Vogel
[Abstract]
Siderotyping –
A Powerful Tool for the Characterization of Pyoverdines Pp.31-57
Regine Fuchs, Mathias Schafer, Valerie Geoffroy and
Jean-Marie Meyer
[Abstract]
Multidrug Efflux
in Pseudomonas aeruginosa: Components, Mechanisms and Clinical
Significance Pp.59-71
Keith Poole and Ramakrishnan Srikumar
[Abstract]
Siderophore-Antibiotic
Conjugates Used as Trojan Horses Against Pseudomonas aeruginosa Pp.73-82
Herbert Budzikiewicz
[Abstract]
Abstracts
[Back to top] Foreword
Allen B. Reitz
This is the first issue of Current Topics in Medicinal Chemistry (CTMC), published by Bentham Science Publishers (http://www.bentham.org/ctmc). This new journal adopts the format of the very popular “hot topics” issues that were formerly published in Current Medicinal Chemistry. Additional information about CTMC can be found on the internet at http://www.bentham.org/ctmc. There will be six issues of CTMC published in 2001, and then the journal will appear as a monthly thereafter. Both print and online subscriptions are available. The entire first issue of the journal can be viewed without charge by going to the homepage of the publisher and following the simple instructions listed there (http://www.bentham.org).
As all of us know, it is a constant challenge for practicing medicinal chemists and those in allied disciplines to stay abreast of new and important research developments. CTMC seeks to fill this void by thoroughly reviewing in each issue a single important topic by a group of experts in the field. The areas covered include new and emerging drug targets, structure-activity relationships, rational drug design, bioorganic chemistry, combinatorial chemistry, early drug evaluation, and compound diversity measurements.
This first issue addresses an anti-infective target, bacteria of the genus Pseudomonas. The next issue is devoted to inhibition of Factor Xa for the treatment of ischemic cardiovascular and cerebrovascular disease. Future issues include “Compound Optimization in Early- and Late-Phase Drug Discovery”, “From Genes to Leads: Medicinal Chemistry in the Postgenomic Era”, and “Purinergic P2 Receptors: Medicinal Chemistry and Therapeutic Potential”. There are presently ca. 15 Guest Editors that have committed to preparing issues for CTMC, and I want to thank each of them for their efforts. If any reader wishes to suggest possible topics for the future, or volunteer as a potential Guest Editor, then please go the CTMC website and send me an email directly from there.
I wish to thank Bentham Science Publishers and Dr. Matthew Honan for the creation of this new journal. I also thank the many distinguished scientists who are members of the CTMC Editorial Advisory Board, and several of these have already made invaluable contributions. In addition, I thank Ambreen Aqil, Mahmood Alam, and their associates at the Bentham office in Pakistan for their continuing assistance and support, and Sandy McCarthy, my Editorial Assistant here in Spring House.
Finally, I believe that here has never been a more exciting time to engage in scientific research, and that medicinal and bioorganic chemistry are especially rewarding fields of study. Medicinal chemists have the opportunity to apply the “central science” of chemistry to pressing problems of human need. I wish all of my colleagues the best of success in the discovery of new therapeutic agents, whether it be through combinatorial chemistry and high throughput screening or computer assisted rational drug design.
[Back to top] Preface
Mathias Schafer
The genus Pseudomonas (P.) is a large group of medically and environmentally important bacteria. A strong interest in the drug discovery community is directed to pathogenic bacteria such as P. aeruginosa, as reflected in the large number of publications devoted to original research, reviews, and books devoted to this subject.
In this first issue of Current Topics in Medicinal Chemistry, a selection of scholarly Pseudomonas research papers is presented by researchers who have been active in the field over many years.
Novel biochemical, microbiological, and analytical developments are reviewed which cover iron chelating siderophores (pyoverdines), the active export mechanism of low molecular weight compounds out of the bacterial cell, and the mechanism of iron uptake into the cell. In this way, medicinal chemists have an updated survey of the fundamentals of the complex problem of multidrug resistance associated with P. aeruginosa.
The first contribution in this issue describes the siderophores of the human pathogenic fluorescent pseudomonads. Herbert Budzikiewicz gives an overview of the structural aspects of the variety of siderophores produced and utilized by P. aeruginosa.
The biology of the ferri-pyoverdine mediated microbacterial iron uptake is carefully and thoroughly reviewed by Hans Vogel.
A variety of accurate, rapid, and easily-applicable methods for bacterial identification of Pseudomonas are discussed and evaluated by Regine Fuchs and co-workers. These methods, termed siderotyping, are very important for taxonomical purposes and are based directly on the presence and structural diversity of the siderophores.
The multidrug resistance of P. aeruginosa is discussed in detail in the last two contributions. The microbial drug efflux system is highlighted by Keith Poole and colleagues, and its key role for the resistance phenomenon is documented.
Finally, the synthesis of conjugates involving both siderophores and antibiotics is reviewed by Herbert Budzikiewicz as a promising strategy to overcome the resistance of P. aeruginosa against treatment with conventional antibiotics.
[Back to top] Siderophores
of the Human Pathogenic Fluorescent Pseudomonads
Herbert Budzikiewicz
Bacteria need a sufficient supply of iron in ionic form for their metabolism. When living in an environment where this is not possible (as in the soil due to the presence of highly unsoluble ferric oxide hydrates, or in living organisms where iron is bound to peptidic chelators) Fe3+ complexing compounds, called siderophores, are produced. The siderophores of Pseudomonas aeruginosa, a dangerous opportunistic human pathogen, and of related potentially pathogenic species will be presented.
[Back to top] Structural
Biology of Bacterial Iron Uptake Systems
Teresa E. Clarke, Leslie W. Tari and Hans J. Vogel
Numerous bacterial proteins are involved in microbial iron uptake and transport and considerable variation has been found in the uptake schemes used by different bacterial species. However, whether extracting iron from host proteins such as transferrin, lactoferrin or hemoglobin or importing low molecular weight iron-chelating compounds such as heme, citrate or siderophores, Gram-negative pathogenic bacteria typically employ a specific outer membrane receptor, a periplasmic binding protein and two inner membrane associated proteins: a transporter coupled with an ATP-hydrolyzing protein. Often, studies have shown that proteins with similar function but little amino acid sequence homology are structurally related. Elucidation of the structures of the Escherichia coli outer membrane siderophore transport proteins FepA and FhuA have provided the first insights into the conformational changes required for ligand transport through the bacterial outer membrane. The variations between the structures of the prototypical periplasmic ferric binding protein FbpA from Neisseria and Haemophilus influenzae and the unusual E. coli periplasmic siderophore binding protein FhuD reveal that the different periplasmic ligand binding proteins exercise distinct mechanisms for ligand binding and release. The structure of the hemophore HasA from Serratia marcescens shows how heme may be extracted and utilized by the bacteria. Other biochemical evidence also shows that the proteins that provide energy for iron transport at the outer membrane, such as the TonB-ExbB-ExbD system, are structurally very similar across bacterial species. Likewise, the iron-sensitive gene regulatory protein Fur is found in most bacteria. To date, no structural information is available for Fur, but the structure for the related protein DxtR has been determined. Together, these three-dimensional structures complement our knowledge of iron transport systems from other pathogenic bacteria, including Pseudomonas aeruginosa, which has a number of homologous iron uptake proteins. More importantly, the current structures for iron transport proteins provide rational starting points for design of novel antimicrobial agents.
[Back to top] Siderotyping – A
Powerful Tool for the Characterization of Pyoverdines
Regine Fuchs, Mathias Schafer, Valerie Geoffroy and Jean-Marie
Meyer
Tools for the identification of bacteria are of great importance especially for taxonomical and medical purposes. In the case of fluorescent pseudomonads a quick and unambiguous identification is possible by methods that are referred to as “siderotyping”. All of them are based upon the characterization of the bacterial siderophores or the receptors expressed for the uptake of these compounds. Different microbiological and bioanalytical tests that are accurate, rapid and easy to use will be described.
[Back to top] Multidrug Efflux
in Pseudomonas aeruginosa: Components, Mechanisms and Clinical Significance
Keith Poole and Ramakrishnan Srikumar
Pseudomonas aeruginosa is an opportunistic human pathogen characterized by an intrinsic resistance to multiple antimicrobial agents and the ability to develop high-level (acquired) multidrug resistance during antibiotic therapy. Much of this resistance is promoted by highly homologous three-component efflux systems of broad substrate specificity, of which four have been identified to date. These include MexA-MexB-OprM and MexX-MexY-OprM, which are expressed constitutively in wild type cells and, thus, provide for intrinsic multidrug resistance, and MexC-MexD-OprJ and MexE-MexF-OprN, whose expression so far has only been seen in acquired multidrug resistant mutant strains. Additional homologues of these efflux systems are identifiable in the recently released genome sequence, though their roles, if any, in antimicrobial efflux are unknown. These tripartite pumps are composed of an integral cytoplasmic membrane drug-proton antiporter of the resistance-nodulation-cell division (RND) family of exporters, a channel-forming outer membrane efflux protein (or outer membrane factor [OMF]) and a periplasmic membrane fusion protein (MFP) that links the other two. In addition to a number of antimicrobials of clinical significance, these pumps also export dyes, detergents, disinfectants, organic solvents and acylated homoserine lactones involved in quorum-sensing. While the natural functional of these pumps remains undefined, the fact that they contribute to antimicrobial resistance in P. aeruginosa makes them reasonable targets for therapeutic intervention.
[Back to top] Siderophore-Antibiotic
Conjugates Used as Trojan Horses Against Pseudomonas aeruginosa
Herbert Budzikiewicz
Pseudomonas aeruginosa is a dangerous opportunistic bacterium responsible for frequently lethal hospital (nosocomial) infections. It endangers especially severely injured patients suffering from large wounds or severe burns, as well as persons whose immune system is weakened. An extremely critical situation exists for patients suffering from mucoviscidosis (cystic fibrosis), when P. aeruginosa infects the bronchial tubes. P. aeruginosa is resistant against many desinfecting agents and, more important, an increasing number of strains especially from hospital isolates have become highly resistant against most antibiotics. The low permeability of the outer membrane and an active export mechanism for low molecular weight substances are the main reasons for the resistance. In addition, b-lactamase activity affects treatment with b-lactam antibiotics. An approach to overcome the problem of resistance lies in the synthesis of antibiotics conjugated with compounds active as siderophores. In this way the transport ways for iron complexes into the cell can be used ("Trojan Horse strategy"), and the presence of large substituents reduces the export and the b-lactamase activity. The results obtained with natural (pyoverdins) and synthetic (mainly catecholate) siderophores will be reviewed.