Antibiotics: Current Innovations and Future Trends | Book
"packed full of useful information" (MicroToday)
"genuinely a brilliant resource" (ChemMedChem)
"a useful resource" (Book News)
"insightful reading" (Biospektrum)
"I thoroughly recommend this textbook" (Aus. J. Med. Sci.)
Caister Academic Press
Sergio Sánchez and Arnold L. Demain
Departamento de Biología Molecular y Biotecnología, Universidad Nacional Autónoma de México, México and Research Institute for Scientists Emeriti (RISE), Drew University, Madison, USA; respectively
xii + 430
January 2015Buy book
GB £219 or US $360Ebook:
January 2015Buy ebook
GB £180 or US $360
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The 'golden age' for antibiotic discovery, from 1940 until the early 1970s, ushered in a new era in human- and animal-health and the associated dramatic increase in human life expectancies. Indeed the possibility of eradicating infectious disease seemed feasible. However it soon became apparent that microorganisms wouldn't be defeated so easily. Their weapon: antibiotic resistance. Today microbial antibiotic resistance is rapidly exhausting our supply of effective compounds and making the possibility of a global public health disaster seems likely. The urgency of this situation has spawned a plethora of new multi-disciplinary research initiatives looking for novel antibiotics and other antimicrobial agents.
In this timely book respected international experts summarize the most important research to provide a timely overview of the field. Opening chapters define 'antibiotic', explain why we need new compounds, outline the applications of antibiotics, both old and new, and describe the producing microbes. These are followed by chapters that cover antibiotic resistance, toxicity, overuse, new antimicrobial sources, new targets, novel technologies for antibiotic discovery (e.g. silent gene clusters), lantibiotics, natural antivirals, new macrolide derivatives, and antibiotics in the pipeline.
This book is essential reading for everyone working in antimicrobial research in academia, biotechnology companies, and the pharmaceutical industry and a recommended volume for all microbiology libraries.
"a useful resource for anyone involved in that research as well as biotechnology companies and the pharmaceutical industry" from Book News (Dec 2014)
"The timing is absolutely perfect for the publication of this informative and inspirational collection of articles on antibiotics. One would expect no less from Arnold Demain, for long one of the world's leading microbiologists, ably assisted by Sergio Sanchez. The book is remarkably good value due to the breadth of the articles, which range from historical perspectives on antibiotics, through to perspectives on the current state of the art in antibiotic drug discovery, antimicrobial resistance and perspectives on the reasons for lack of new antibiotics in recent decades. The book is genuinely a brilliant resource ... Overall this is an absolutely excellent book on antibiotics - almost every chapter has something of interest for researchers in the field and provides an outstanding overview of very widespread interest. " from ChemMedChem (2015) 925-928.
"packed full of useful information ... information which is difficult to find elsewhere ... I found the book informative and easy to read, and the scope is huge with a lot of coverage given to the new sources of antibiotics ... I recommend this book as an essential reference for anyone interested in the field of antimicrobial resistance and antibiotic discovery" from Microbiology Today (2015) 42: 86.
"...an updated overview of the field ... insightful reading ..." from BIOspektrum (2015) 21: 356-357.
"This text book is a structured compilation of scholarly papers ... vast amounts of new and relevant information are provided ... The list of the 50 contributors is distinguished and with a compelling international representation ... chapters are thoroughly referenced ... Diagrams and tables are plentiful ... I thoroughly recommend this textbook to thoughtful microbiologists and medical scientists" from Aus. J. Med. Sci. (2015) 36: 89.
Table of contents
1. What is an Antibiotic?
Joan Wennstrom Bennett
The word 'antibiotic' was originally used in the English language as an adjective. In 1947, Selman A. Waksman published a definition of 'antibiotic' as a noun: "An antibiotic is a chemical substance, produced by micro-organisms, which has the capacity to inhibit the growth of and even to destroy bacteria and other micro-organisms." The clinical efficacy of penicillin and streptomycin brought public attention to this group of life-saving drugs and the word "antibiotic" soon became commonplace in scientific and ordinary language. Waksman stressed that antibiotics were not only antimicrobial in action but also that they were products of microbial metabolism. He excluded compounds made by plants, animals or synthetic chemists. Contemporary usage makes no such distinction. Because most of the early antibiotics were effective only against bacteria, and because responsible health care workers warned patients against the asking for antibiotics to treat viral infections, nowadays 'antibiotic' is often used as a synonym for 'antibacterial' in order to simplify communication. Curiously, Waksman's original definition and most of the energy he subsequently devoted to defending his definition rarely included mention of the single most important property of a good antibiotic, namely that it does not harm the host. Many of the currently published definitions continue in the Waksman tradition and focus on the antimicrobial activity of the compounds, not on their selective action. The published literature can be an important resource in the search for new efficacious compounds with antimicrobial action. Thus, it is more important than ever to have an understanding of how the word 'antibiotic' is used in different contexts so as to guide contemporary information scientists to mine the vast scientific and patent literature.
2. Main Applications of Antibiotics
Biao Ren, Pei Huang, Jingyu Zhang, Wenni He, Jianying Han, Xueting Liu and Lixin Zhang
Antibiotics have been developed for more than 80 years since the investigation of the sulfonamides and β-lactams in 1930s. Meanwhile, the pathogenic bacteria developed resistance to antibiotics rapidly and have caused urgent threat to public health. In addition, many antibiotics are used commercially, or are potentially useful, in medicine for activities other than their antimicrobial action. They are used as antitumor agents, enzyme inhibitors including powerful hypocholesterolemic agents, immunosuppressive agents, and anti-migraine agents, etc. The purpose of this chapter is to focus on the application of anti-bacterials, antifungals, and anti-cancers with their clinical use to date, including the development history, side effects, and etc. The antibiotics summarized herein were classified by their uses, structure types, and molecular mechanisms.
3. Microorganisms Producing Antibiotics
The meaning of the definition of antibiotics, that is the bioactive secondary microbial metabolites, and specific features of the history of antibiotic research in the last eighty years shows continuous changing. The real role of the microbial metabolites in the various life processes in the Earth is far to be totally explored. Their importance, over the antibiotic effect, seems to be more significant than in was believed. They may be general regulatory and signally compounds in the most life processes and in the environment.
The main producers of the microbial metabolites, the actinobacteria, fungi and other filamentous bacteria, represent inexhaustible sources for the future. The connecting and increasing taxonomic, chemical and biodiversities of microbial metabolites certainly will give numerous new leads and drugs and other products not only for the chemotherapy but in other fields of human therapy and also for the agriculture to cure and feed the increasing population.
The numbers of known and possible secondary metabolite producing microorganisms, the produced new chemical compounds and their extremely wide range of bioactivities are discussed in details. Several new trends of the research, the full exploration of the living world of oceans and the discovery of endophytic microbes are also presented.
4. The Need for New Antibiotics
Arnold L. Demain and Sergio Sanchez
The large amounts of antibiotics used in human therapy, as well as those used for farm animals and aquaculture, have resulted in the selection of pathogenic bacteria resistant to multiple drugs. New antibiotics are continuously required to combat antibiotic-resistant bacteria and pathogenic yeast. Such resistance increasingly limits the effectiveness of current antimicrobial drugs. The problem is not just antibiotic resistance, but also the appearance of an increasing number of multidrug-resistant pathogenic bacteria. Resistant bacteria were detected in hospitals and nosocomial infections have become a major problem. Staphylococcus aureus is responsible for half of hospital-acquired infections and causes deaths of many people around the world. Besides the problem of antibiotic-resistance, new families of antibiotics are needed to enter the marketplace at regular intervals to face new diseases caused by evolving pathogens. At least 30 new diseases emerged in the 1980s and 1990s and they are growing in incidence. Also important are reemerging diseases such as influenza and hepatitis B. Due to the movement of the pharmaceutical industry away from natural products, especially antibiotics, the number of drug approvals in recent years has drastically dropped. However, antimicrobial pharmaceuticals are still big business and the search for new drugs must not be stopped. New screening approaches, including the search for novel targets and exploration of non-conventional places as sources of the producer microorganisms, are needed. In addition, metagenomic and genome- mining techniques have shown strong potential for discovery of new antibiotics. What is needed is a move back by the large companies to rational drug design and the use of more focused, more drug-like, compound libraries. In addition, it is desirable that small companies and academics, either in an independent manner or organized as biotechnology/university groups, increase their participation in a worldwide effort for new antibiotic discovery.
5. Tackling Antibiotic Resistance
Jaroslav Spizek and Vladimir Havlicek
Resistance to antibiotics and other antimicrobial compounds permanently increases and it appears that the struggle against antibiotic resistance is a war we can never win. The strength of the immense numbers of microorganisms appears to overpower our drugs. However, there are hopes and chances to at least improve the situation. In the present review we want to discuss certain steps to be used to tackle antibiotic resistance including: 1. Preparation of new vaccines against resistant bacterial strains, 2. Search for new antibiotics in both traditional and non-traditional sources 3. Search for genes specifying biosynthesis of antibiotics, 4. Use of forgotten natural compounds and their transformation, and 5. Search for new antibiotic targets. We want to devote a special attention to the search for new compounds that would inhibit the currently antibiotic resistant pathogenic bacteria.
6. Eradication of Dormant Pathogens
Kim Lewis, Brian Conlon and Michael LaFleur
Persisters are specialized survivor cells that protect bacterial and fungal populations from killing by antibiotics. Persisters are dormant phenotypic variants of regular cells rather than mutants. Most microbicidal antibiotics kill by corrupting their targets into producing toxic products; tolerance to antibiotics follows when targets are inactive. Mechanisms of persister formation are redundant, making it difficult to eradicate these cells. In Escherichia coli, toxins RelE and MazF cause dormancy by degrading mRNA; HipA inhibits translation by phosphorylating glutamyl tRNA synthase; and TisB forms an anion channel in the membrane, leading to a decrease in proton motive force (pmf) and ATP levels. Prolonged treatment of chronic infections with antibiotics selects for hip mutants that produce more persister cells. Eradication of tolerant persisters is a serious challenge. Existing antibiotics were developed to kill rapidly growing cells and have limited activity against dormant persisters. A number of compounds were recently described that have a capability of killing persisters. A potentiator of azoles, AC17, sterilizes a biofilm of Candida albicans. Prodrugs are converted into generally reactive compounds with bacteria-specific enzymes and kill growing and dormant cells. Lassomycin activates the ATPase of the ClpP1P2C1 protease of Mycobacterium tuberculosis, and kills persisters. Acyldepsipeptide (ADEP4) activates the ClpP protease, forcing the cell to self-digest, and kills both growing cells and persisters. These findings suggest a path towards developing sterilizing antibiotics.
7. Toxicity of Antibacterial Drugs
Steven J. Projan
Therapeutic antibacterial drugs are considered among the safest of pharmaceuticals but this was not always the case. Indeed prior to the discovery of penicillin and, subsequently, other antibiotics, the safety profile of antibacterial drugs more closely resembled that of today's cytotoxic, chemotherapeutic agents used in oncology with narrow therapeutic windows and considerable side effects. Today's antibiotics are, in fact, safe by design. Where agents have defined toxicities (e.g. photosensitivity induced by fluoroquinolones) they are usually class effects and, rather than "idiosyncratic" are more frequently predictable based on pharmacokinetics and tissue distribution. As newer antibacterial drugs are being designed to be more "pathogen specific" the expectation is that these future drugs will have even better safety profiles than today's therapeutics.
The common perception of antibacterial drugs is that they are very safe, very useful and very important therapeutic agents, indeed the safety and tolerability of antibacterials are, in general are among the best of all prescribed drugs. This is not a matter of chance and it was not always the case. In 1908 Paul Ehrlich shared the Novel Prize for Medicine or Physiology (with Ilya Metchnikoff) for his work on immunotherapeutics (indeed the first Nobel Prize in that category went to Emil von Behring, also for immunotherapy) but Ehrlich was unhappy both with the efficacy of immunotherapeutics as well as their safety (e.g. "serum sickness"). He embarked on a bona fide medicinal chemistry/drug discovery campaign to find novel organic molecules based on arsenical compounds that were active versus trypanosomes and spirochetes. It should be noted that at the turn of the twentieth century mercury was still being used as treatment for syphilis, a bacterial infection caused by Treponema pallidum. Even today, mercury toxicity remains an important issue. The compound that Ehrlich's group eventually discovered, arsphenamine ("606") became known as Salvarsan and was both more effective and far safer than mercury treatment (not to mention less expensive) but was not without its own safety and tolerability issues (which are a subject of controversy even today) (Baumler,1984). Eventually arsphenamine was supplanted by penicillin, where even a single, intramuscular dose was found to be effective in the early stages of the disease with a significantly better safety profile. It should be realized that today's antibacterial drugs are safe not as a matter of chance but by design; the result of decades of microbial research, the development of in vitro and animal models of infection, brute force science and inventive medicinal chemistry, and careful (as well as some careless) clinical research resulting in the successful treatment of hundreds of millions (if not billions) of people.
8. Overuse of Antibiotics: Non-medical Applications
The decreasing effectiveness of antibiotics in treating common infections results from the spread of antimicrobial resistance (AMR), and is building up to become an epic global public health crisis. Extended periods of antibiotic overuse and misuse since their introduction have applied strong selective pressure towards high level AMR and multiple drug resistance (MDR), rendering entire classes of antibiotics ineffective. The primary driving force for this global AMR pandemic is the widespread misuse and overuse of antibiotics, in both medical and non-medical applications. The introduction of every antibiotic product has been closely followed by emerging resistance to that antibiotic. Levels of antibiotic consumption correlate with levels of AMR. Antibiotics have been misused in all of their applications, including:
Hospital and outpatient use by physicians through unnecessary, indiscriminate or incorrect prescribing
By patients, through incorrect dosing and course durations
Large scale use in agriculture for disease treatment, prophylaxis and growth promotion in animal husbandry and food production
These actions not only have provoked the emergence of resistant microbes, but also have provided optimal environments for the spread of and selection of resistance determinants. It has been established in many countries that the levels of antibiotic consumption consistently correlate with levels of antibiotic resistance (i.e. the more antibiotics are being used in a population, the more resistance to antibiotics there will be in bacteria responsible for infections in that population). The increase in resistance from overuse of antibiotics in turn leads to cross transmission of AMR microbes between humans, between animals and between humans and animals and the environment. Almost two million Americans per year develop hospital acquired infections (HAI), resulting in 99,000 deaths per year. The vast majority of these HAI related deaths are due to AMR infections. Based on studies of the costs of infections caused by antibiotic resistant pathogens vs. antibiotic susceptible pathogens, the annual cost to the US health system of antibiotic resistant infections is to billion, and 8 million additional hospital days. This chapter will focus on the overuse of antibiotics through non- medical applications; by their extensive use in animal agriculture & aquaculture and their effect as environmental contaminants on land and water systems. These non-human medical applications are a primary cause of AMR and ultimately impact negatively on human health.
9. Antibiotics for Emerging and Re-emerging Diseases
Kazuro Shiomi and Satoshi Ōmura
Emerging and re-emerging infectious diseases are global problems, and a constant supply of new antibiotics is essential if we are to combat these diseases successfully. Among antibiotics currently used against these diseases, antiparasite antibiotics are to the fore and are the major focus of this chapter. For example, tetracyclines are used against malaria, acetylspiramycin and clindamycin are used for toxoplasmosis, amphotericin B is used for leishmaniasis, and trichomycin is deployed against trichomoniasis. Nitroimidazole compounds used for various protozoiasis are analogs of azomycin. Ivermectin is a great nematocide, used for onchocerciasis, lymphatic filariasis, and strongyloidiasis. Paromomycin is used for the treatment of cestodiasis. Recent research for new antiparasite antibiotics is also described. Viral diseases represent a significant and growing threat among the major emerging and re-emerging infectious diseases and studies in this line of research, particularly on antibiotics active against HIV and influenza virus, are briefly covered. Even within the human body, our own essential microbial flora can pose a considerable and extremely complicated threat, such as diarrheagenic Escherichia coli (O157:H7) which is responsible for an emerging disease. Fortunately, recent research has uncovered a new type of antibiotic that only inhibits pathogenicity and does not affect the growth of pathogenic E. coli. The new type of antibiotic is expected to avoid some problems of conventional antibiotics: development of resistant strains, expression of various toxins, and disruption of normal microbial flora.
10. Endophytes as a Potential Source of New Antibiotics
Silvia Guzmán-Trampe, Karol Rodríguez-Peña, Allan Espinosa-Gómez, Rosa E. Sánchez-Fernández, Martha L. Macías-Rubalcava, Luis B. Flores-Cotera and Sergio Sánchez
Antibiotics are useful compounds for treatment of human, farm animal and aquaculture infections. However, due to resistance development of pathogenic microbes to most of the useful antibiotics, there is a continuous necessity for new and powerful anti-infective compounds. This situation encourages the search for new alternatives for the isolation of new compounds with antimicrobial activity. Because of their proficiency in producing secondary metabolites with therapeutic properties, plants have attracted attention since ancient times. Recently, plant endophytic microorganisms have been also shown to be an important and novel source of natural bioactive products with antimicrobial, antiviral, antitumor, antiparasitic, and agricultural activities. Endophytes commonly live associated to the plant vascular tissues, without causing any apparent damage to their host or symptoms of disease. The bioactive compounds they produce, usually vary depending on the plant host taxonomy and forest type. Fungi and actinomycetes have been the main source of new bioactive natural products from endophytes. Occasionally, endophytes can synthesize the same metabolites produced by the host plant. This chapter mainly reviews the progress that has been achieved on the production, by endophytic microbes, of the same or similar bioactive compounds originated from their host plants, as well as other secondary metabolites apparently not produced by the plant, including antituberculosis and antiparasitic compounds. Furthermore, the potential agricultural uses of endophytic compounds as antifungal, nematicidal, antiviral, insecticidal and phytotoxic activities, is also reviewed. Finally, we mention some examples of new compounds with antimicrobial properties chemically derived from natural products produced by endophytes.
11. Antibiotics from Micro-organisms from Hot springs/Geysers
Girish B. Mahajan
Nature has provided mankind with abundant resources in the form of bioactive compounds which have been isolated from microbial resources. Novel natural products can have many innumerable potential uses, especially in the area of new drug discovery. Extensive research in this field has reported several terrestrial mesophilic sites. The marine environment has recently evinced more interest, and several thousands of novel bioactive compounds have been identified from various marine microorganisms. The constant need for new leads from the healthcare sector has sparked off a relentless quest for novel compounds. A difference in the habitat of the microorganisms yields different types of microorganisms, thus resulting in some variation in the types of compounds obtained from them. Physically and chemically extreme ecological units on the globe harbor special groups of microbes which are genetically well acclimatized to the stress conditions, and their adaptive ability makes them unique producers of different classes of compounds. Hot springs or geysers are such ecological niches, which have been studied mainly from their biodiversity point of view. There have been occasional reports of their harboring a huge cache of bioactive compounds from the drug discovery perspectives. In this article, we have tried to review present some such ecological niches.
12. New Sources of Antibiotics: Caves
Naowarat Cheeptham and Cesareo Saiz-Jimenez
Caves are regarded as extreme habitats according to their unique and harsh conditions for microbial life. Though demanding, these irreplaceable habitats have demonstrated to support a great diversity of microbial communities that are believed to hold great promises as new sources of antibiotics and industrially relevant compounds. This chapter highlights recent findings that convincingly solidify the concept that caves are potentially homes to novel and rare microorganisms and tomorrow's antibiotics.
13. Animal Venoms as Natural Sources of Antimicrobials
R. Perumal Samy, S. Satyanarayanajois, O. L. Franco, B. G. Stiles and P. Gopalakrishnakone
A number of naturally occurring proteins/peptides exert antimicrobial activities reported throughout the literature, of which snake venoms (SV) represent a vast natural source of protein/peptides not thoroughly explored to date. Snake venoms represent rich sources of bioactive compounds, which are produced by venom glands located around the snake's jawbone. In this review, we focus more on the basis of antimicrobial potential within SV and further need to search for novel antibiotic prototypes. Several enzymes [i.e. phospholipase A2 (PLA2) (these are part of PLA22) L-amino acid oxidase and metalloproteinase], as well as antimicrobial peptides (AMPs) such as cathelicidine and defensin, have been isolated by various groups from SV. Antimicrobial proteins/peptides work in various ways that include hydrolyzing phospholipids on the bacterial surface. The presence of unusual amino acids and structure motifs in AMPs confer unique structural properties that contribute their specific mode of action. The ability of these active AMPs to act as multifunctional effectors such as signaling molecules and antibacterial agents makes them interesting candidates for structural and biological studies for prophylactic and therapeutic applications. In this review, we focus on the diversity and antimicrobial activities of various SV-derived molecules potentially useful as drug candidates for the pharmaceutical industry.
14. New Targets for Antibacterial Compounds
Lynn L. Silver
Resistance to antibacterials underwent a noticeable rise starting in the mid-1980's, at a time when natural product screening for antibacterial antibiotics had become less productive. The advent of genome sequencing of bacteria, starting in 1995 seemed to provide an answer to the resistance problem: find new gene products to target in order to find antibacterial agents that were different from previous classes and unlikely to be cross-resistant with them. This plan relied on the assumption that the limitation to discovery was a lack of novel targets. As the search for antibacterials over the past twenty years has been largely directed toward finding inhibitors of novel targets, and that search has been largely unproductive, it seems likely that the assumption that targets are rate limiting is wrong. This chapter will discuss the characteristics that define good targets, with an emphasis on recognizing the potential for rapid resistance development with single-gene targets. Until it is robustly demonstrated that combinations of single-targeted agents can prevent or retard resistance development (as is seen with tuberculosis, HIV and HCV) and a regulatory pathway is established to develop such combinations, it may be that we will have to depend on the successful targets that have already been found and exploited.
15. Novel Antimicrobial and other Bioactive Metabolites Obtained from Silent Gene Clusters
Juan F. Martín and Paloma Liras
Hundreds of secondary metabolite gene clusters have been found in the genome sequence of filamentous fungi, Streptomyces
species and some rare actinomycetes (20 to 50 clusters per genome). However, the number of secondary metabolites found in the culture broths of each strain is much lower than the number of gene clusters in that particular strain. Many of the sequenced gene clusters are silent or very poorly expressed, and there is a high untapped potential for the discovery of novel antibiotics or other bioactive products. Classical strategies to trigger production of secondary metabolites rely on the use of nutritional stressing conditions such as phosphate starvation or ammonium limitation, and the addition of phosphate-precipitating or ammonium-trapping agents leads to formation of new products. Metal toxicity also triggers the production of novel secondary metabolites in some Streptomyces
strains. Modification of the rpsL
(for the ribosomal protein S12) or the rpoB
(for the RNA polymerase β subunit) genes enhance the expression of silent or poorly expressed secondary metabolite gene clusters in several Streptomyces
species. Addition of antibiotic biosynthesis "remodeling compounds" re-directs the metabolic flux to obtain new antibiotics. Modern strategies to awaken sleeping clusters include the modification of wide domain regulators that control related or even disparate pathways. Alteration of butyrolactone receptor proteins or of an oligopeptide-binding protein results also in awakening of silent gene clusters in some producer strains. Co-cultivation of Streptomyces
with other bacteria or fungi, involving contact between cells, frequently triggers silent gene clusters. The potential of these strategies to trigger the expression of silent clusters in poorly studied actinobacteria other than Streptomyces
, is very high.
In fungi, rearrangements of the chromatin structure by either directed mutations of some genes or by the use of "chromatin modifiers", has provided several new compounds in each of the tested fungi. Particularly, deletion or overexpression of the laeA gene that influences chromatin rearrangement, modifies the transcription of some low-expression gene clusters and awakens the expression of some silent clusters providing new compounds. Expression of the laeA gene is increased by the fungal autoinducer 1,3-diaminopropane, what may trigger some silent clusters.
Examples of new molecules synthesized by the enzyme encoded by different silent or "near-silent" gene clusters are provided in this article. Most of the novel products observed by HPLC or by bioassays still remain to be characterized chemically.
16. Combinatorial Biosynthesis for Antibiotic Discovery
Sung Ryeol Park and Yeo Joon Yoon
The rapid and increasing prevalence of antibiotic-resistant pathogenic microorganisms has heightened the need for development of novel antibiotics. Natural products have traditionally been a prolific source of therapeutic agents for infectious diseases and other illnesses. However, as searching for new antibiotics with desired properties from natural products has become increasingly challenging, researchers have turned towards a genetic approach known as combinatorial biosynthesis to generate novel bioactive compounds for antibiotic discovery. In this chapter, we will review the past and current attempts and achievements to discover potentially novel antibiotic derivatives through combinatorial biosynthesis, and discuss its role and importance as well as its challenges, giving insights into the future trends and possibilities. In addition, multiple approaches, including heterologous expression and in vitro glycorandomization, coupled with the combinatorial biosynthesis technique will be described. Moreover, although we will focus on antibacterial compounds and their derivatives, several other related compounds will be mentioned to enlighten the concept of combinatorial biosynthesis.
17. Lantibiotics and Other Antibacterial Peptides
Margherita Sosio and Stefano Donadio
Lantibiotics and other ribosomally synthesized peptides have attracted increasing attention in the search for new chemical classes of antibacterial agents effective against multidrug-resistant pathogens. Several factors have probably contributed to this resurgent interest. Among them, the realization that many different classes of ribosomally synthesized peptides are produced by almost all taxa of bacteria; that lantibiotics, being ribosomally synthesized, are amenable to the generation of analogs by codon substitutions in the structural gene; and that, by binding to biosynthetic intermediates and not directly to enzymes, resistance in bacterial pathogens cannot be simply acquired by mutations in the target enzymes. In this chapter, we will review the chemistry, biosynthesis, occurrence and mechanism of action of lanthipeptides, with particular focus on lantibiotics. We will also present three lantibiotics that are currently under advanced preclinical or early clinical development, as well as some recently discovered compounds which represent improved variants of known lantibiotics.
18. Antiviral Compounds of Natural Origin
P. Veiga-Crespo, M. Viñas and Tomas Gonzalez Villa
A great variety of plant-and-medicinal herb-derived active principles have been traditionally known by the Natural Medicine of many civilizations. Recent advances in Molecular Biology have allowed us to characterize those active principles, to understand their mode of action and finally to include many of these compounds in the arsenal of antiviral drugs used by Western medicine. The higher number of resistant-strains both in the bacterial and viral worlds makes mandatory the continuous search for new active principles to treat diseases. Many of the natural remedies used in medicine are now being characterized and will facility their use as regular chemotherapeutics.
19. New Compounds with Antibacterial Activity
P. Veiga-Crespo, A. Sánchez-Pérez, D. Piso and Tomas Gonzalez Villa
Infections caused by pathogenic microorganisms are among the major causes of global mortality and morbidity. The discovery and use of antibiotics revolutionized medicine as they constituted not only the first real therapeutic weapon against bacteria but also the possibility of eradication of bacterial disease in humans. However, the combination of antibiotic misuse and bacterial natural evolution rendered them less efective and resulted in the phenomenon known as antibiotic resistance. Although it is currently mandatory to search for new therapies, antibiotics still offer many potential uses, these range from enzybiotics to new nanotechnology-based delivery systems.
20. Use of Antibiotic Core Structures to Generate New and Useful Macrolide Antibiotics
Macrolides, such as erythromycin, are safe and effective antibiotics that are broadly used in adults and children. Clarithromycin and azithromycin were introduced in the 1990s and became popular because of improved gastrointestinal tolerability and pharmacokinetics but they exhibit cross resistance with erythromycin. Intense efforts in many pharmaceutical companies led to the third-generation macrolide, telithromycin, a 3-keto aglycone of clarithromycin with an extended 11, 12-carbamate side chain. Telithromycin was invented using two lessons learned from older macrolides:(i) additional side chains on the macrolide ring, as found on 16-membered macrolides, can gain activity against resistant organisms, and (ii) an aglycone with a keto group as noted in picromycin, instead of erythromycin's cladinose can retain antibacterial activity. Although active against drug-resistant bacteria, telithromycin failed in the clinic due to serious adverse events. Solithromycin is a fourth generation macrolide, a fluoroketolide, in late stage development that is differentiated from telithromycin in lacking the latter's pyridine containing side chain, which interacts with human nicotinic acetylcholine receptors to produce treatment-limiting side effects, and in having a third binding region in the bacterial ribosome to help overcome resistance. Solithromycin is in late-stage clinical development. Molecular mode of action studies could lead to even more potent molecules in the future, perhaps with uses beyond antiinfectives.
21. Antibiotics in the Pipeline
Hyunjun Park and Michael Thomas
The enormous success of using antibiotics to save lives is being challenged by the steady evolution of resistance to these antibiotics by the targeted bacteria. This resistance has led to predictions that we will soon be returning to the pre-antibiotic era whereby even the most minor infection has the potential to have severe consequences on the infected person. Fortunately, there has been a steady increase in the efforts to combat this rise in antibiotic resistance. This chapter discusses antibiotics for treating bacterial infections that were in the clinical pipeline at the beginning of 2014. While a list of the drugs that have recently been approved for clinical use or are in various phases of clinical trials is provided, a select few are highlighted in more detail to show how drug development itself is evolving to generate the next generation of antibiotics so the pre-antibiotic era stays in the past.
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(EAN: 9781908230546 9781908230553 Subjects: [microbiology] [bacteriology] [virology] [medical microbiology] [parasitology] )