Quinolones

12 Key excerpts on "Quinolones"

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  Antibacterial Agents

  Chemistry, Mode of Action, Mechanisms of Resistance and Clinical Applications

  • Rosaleen Anderson, Paul W. Groundwater, Adam Todd, Alan Worsley(Authors)
  • 2012(Publication Date)
  • Wiley

    (Publisher)

  Section 2 Agents Targeting DNA Antibacterial agents which target nucleic acids belong to the Quinolones (DNA gyrase/DNA topoisomerase IV inhibitors), rifamycins (DNA-dependent RNA polymerase inhibitors), or nitroimidazoles. Passage contains an image Chapter 2.1 Quinolone Antibacterial Agents

  Key Points

  • The Quinolones are synthetic antibacterial agents which show greatest activity against Gram negative bacteria and are used in the treatment of urinary tract and respiratory infections.
  • Resistance to Quinolones arises due to alterations in the DNA gyrase (via mutations in the quinolone resistance-determining region (QRDR) of the gyrA gene), and similar mutations which decrease quinolone binding have been described in topoisomerase IV (in the parC gene).
  • The Quinolones are generally well tolerated, but some of the newer generations have been associated with serious adverse effects, such as hepatotoxicity and QT interval prolongation (cardiotoxicity).
  • Some Quinolones should not be routinely used in combination with theophylline because of the risk of developing theophylline toxicity.
  • For further information, see Emmerson and Jones (2003) and Hooper (1998).

  Antibacterial Quinolones used clinically include nalidixic acid, ciprofloxacin, ofloxacin (racemic mixture of levofloxacin enantiomers), levofloxacin, norfloxacin, besifloxacin, and moxifloxacin; their structures are shown in Figure 2.1.1 and their therapeutic indications are listed in Table 2.1.1 .

  Figure 2.1.1

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  Antimicrobial Agents

  • Varaprasad Bobbarala(Author)
  • 2012(Publication Date)
  • IntechOpen

    (Publisher)

  Trovafloxacin N N COOH O F N F F H 2 N H H Clinafloxacin H 2 N Cl N COOH O F N Sitafloxacin N F O COOH N F H 2 N Cl S R S Moxifloxacin OCH 3 N COOH O F N HN H H S S BAY y 3118 Cl N COOH O F N HN H H S S Fig. 4. Fourth- generation Quinolones. Until now a large number of antibacterial substances belonging to the above mentioned class have been used in medicine. Quinolones are used when treating infections of the urinary tract, the respiratory tract, intestinal infections, ear/nose/throat infections, STD’s, soft tissue and skin infections, meningitis caused by gram negative and Staphilococci bacteria, liver and bile infections, septicemia and endocarditis, prophylaxis and surgical infections and on patients with immune deficiencies. Antimicrobial Agents 258 The mechanism of action of quinolone antibacterial agents involves the inhibition of DNA gyrase (a bacterial topoisomerase II) resulting in a rapid bactericidal effect. The antibacterial activity of Quinolones (measured in terms of MIC), however, is the result of the combination of bacterial cell penetration and DNA gyrase inhibitory activity. The antibacterial activity of Quinolones depends not only on the bicyclic heteroaromatic system combining the 1,4-dihydro-4-pyridine-3-carboxylic acid moiety and an aromatic ring, but also on the nature of the peripheral substituents and their spatial relationships. These substituents exert their influence on bacterial activity by providing additional affinity for bacterial enzimes, enhancing cell penetration or altering the pharmacokinetics. The research for an ideal quinolone continues worldwide. Such a quinolone must be biologically active on a large spectrum of gram positive and gram negative bacteria, aerobes and anaerobes and mycobacteria, must have as few side effects as possible, excellent solubility in water and oral bioavailability.

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  Synthesis of Best-Seller Drugs

  • Ruben Vardanyan, Victor Hruby(Authors)
  • 2016(Publication Date)
  • Academic Press

    (Publisher)

  The sulfonamides competitively inhibit dihydropteroate synthetase, a vital enzyme that facilitates p-aminobenzoic acid as a substrate for the synthesis of dihydrofolic acid. Dihydrofolate is a precursor for formation of tetrahydrofolate, an essential methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. When the folate synthesis is inhibited in bacteria the bacteria can no longer grow.

  Sulfonamides are the oldest and remain among the widely used antibacterials.

  Quinolones are synthetic, bactericidal, antibacterial agents with broad-spectrum activity. They inhibit the enzyme topoisomerase II (named DNA gyrase), which is necessary for the replication of the bacteria. By inhibiting topoisomerase II in bacteria, the DNA replication and transcription of the bacteria are blocked, thereby stopping bacterial multiplication.

  The unique mechanism of action of this class of antibacterial agents with its economically and clinically proven track record generated considerable scientific efforts and resulted in creation of a new family of synthetic broad-spectrum antibacterial drugs—the nitrofurans.

  The nitrofurans are a class of synthetic antibacterials characterized by the 5-nitro-2-furanyl scaffold. The basic mechanism of action of nitrofuran antibacterials remains unclear. Nitrofurans inhibit many microbial enzyme systems, including those involved in carbohydrate metabolism. None of nitrofurans is included in the list of Top 200 Drugs by sales for the 2010s.

  Keywords

  Nitrofurans; Quinolones; Sulfonamides

  31.1. Sulfonamides

  Antibacterial drugs is a general term that refers to a group of drugs that includes antibiotics, antifungals, antivirals, and antiprotozoals.

  The term antibacterials also includes antibiotics, but antibiotics are more often referred to as substances produced by microorganisms. The story of antimicrobials begins with the observations of Louis Pasteur and Jules Francois Joubert, who discovered that one type of bacteria could prevent the growth of another.

  Another significant milestone event in the field of antimicrobials, was the discovery of sulfonamides, synthetic compounds that have activity against both Gram-positive and Gram-negative bacteria [1 -5] .

  Early in the 1930s, Bayer chemists Josef Klarer and Fritz Mietzsch synthesized some azo dyes. The potential antiinfectious properties of the azo dyes was studied by the bacteriologist and pathologist Gerhard Domagk, the appointed director of Bayer’s Institute of Pathology and Bacteriology. Domagk began testing the effect of each newly synthesized dye on streptococci in vitro.

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  Antibiotics

  Challenges, Mechanisms, Opportunities

  • Christopher Walsh, Timothy Wencewicz(Authors)
  • 2016(Publication Date)
  • ASM Press

    (Publisher)

  7.3a). A third generation (Fig. 7.3b) includes such approved molecules as moxifloxacin (Drlica and Zhao, 1997), gatifloxacin, and trovafloxacin, which was withdrawn due to life-threatening side effects. As of 2011, there was another set of FQs in clinical development (Fig. 7.3c). Because the Quinolones are fully synthetic scaffolds, amenable to synthesis, and because of the success of the early FQs, some tens of thousands of fluoroquinolone derivatives have been reported and more than two dozen have gone through clinical trials, reflecting the central place they have had over the past decades in the antibiotic space (Andriole, 2005). Figure 7.2 Structures of chloroquine and nalidixic acid. Nalidixic acid is an impurity isolated during the synthesis of chloroquine that was shown to have antibiotic properties. It is considered to be the first of the Quinolones. Figure 7.3 Second generation (a) and third generation (b) fluoroQuinolones and fluoroQuinolones currently in development (c). Each generation introduced different modifications (shown in red) to the original fluoroquinolone scaffold (shown in black) designed to improve efficacy. The targets of the various generations of quinolone antibiotics are type II topoisomerases (topo), and the antibiotics have played an important part in elucidation of the physiologic role of this topoisomerase class and in studies of mechanism of action (Wang, 1996). Bacteria have two related sets of topo II enzymes, DNA gyrase and topoisomerase IV. Each is an A 2 B 2 -type heterotetramer, with the gyrase subunits provided by GyrA and GyrB and the topo IV subunits composed of ParC and ParE. Some bacteria predominantly express the gyrAB genes, some the parCE genes, and some use both with overlap of apparent functions. DNA gyrase is the major enzyme regulating the supercoiling state of DNA in circular bacterial chromosomes (Higgins, 2007)

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  A Search for Antibacterial Agents

  • Varaprasad Bobbarala(Author)
  • 2012(Publication Date)
  • IntechOpen

    (Publisher)

  12 New Improved Quinlone Derivatives Against Infection Urooj Haroon 1 , M. Hashim Zuberi 1 , M. Saeed Arayne 2 and Najma Sultana 2 1 Federal Urdu University for Arts, Science and Technology, 2 Department of Chemistry, University of Karachi, Pakistan 1. Introduction There had been a tremendous advancement in the quality and quantity of worldwide research production in the field of microbiology. Among various biomedical fields, microbiology has been the subject of extensive study due to the problems imposed on human health by countless infectious diseases known so far. Identification of infectious agents and to adapt measures for its eradication is considered a major tool for alleviating human from the burden of infections. Progressively it is important to modulate the structure of earlier marketed antibacterial agents to produce newer agents with superior antimicrobial profile. FluoroQuinolones, useful in the treatment of many bacterial infections, attacks DNA gyrase and topoisomerase IV on bacterial chromosomal DNA (Ball et al., 1998, Blandeau, 1999). However, widespread use of fluoroQuinolones has caused the resistant rates of various Gram-negative bacilli (e.g., Pseudomonas aeruginosa , Escherichia coli , and Salmonella ), to approach the critical points. To solve the problem of increasing antimicrobial resistance, it is crucial to design and produce new Quinolones that could provide effective therapy for infections caused by organisms resistant to older agents. Most of the Quinolones currently on the market or those which are under development, displays only moderate activity against many Gram-positive cocci, including Staphylococci and Streptococci. This insufficient activity has not only limited their use in infections caused by these organisms, such as respiratory tract infections, but has also been believed to be one of the reasons for the rapidly developing quinolone resistance.

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  Molecular Genetics of Mycobacteria

  • Graham F. Hatfull, William R. Jacobs, Graham F. Hatfull, William R. Jacobs, Jr.(Authors)
  • 2014(Publication Date)
  • ASM Press

    (Publisher)

  This review will describe the current use of FQs to treat TB, their interaction with the drug target, their mechanism of action, and the mutations known to confer resistance. It will also describe limitations to the rapid detection of resistance mutations and additional potential mechanisms of resistance.

  FQs AND THEIR INTRODUCTION INTO ANTI-TB THERAPY

  The first quinolone, nalidixic acid, was discovered in 1962 (9 ) and introduced into clinical use in 1967 for the treatment of Gram-negative urinary tract infections (10 ). The Quinolones are synthetic molecules that contain a 4-oxo-1,4-dihydroquinoline ring system with a carboxylic acid attached at position 3 (Fig. 1 ), and are amenable to multiple modifications. After it was found that the addition of a fluorine atom at the 6-position of the quinoline ring greatly improved their antibacterial potency and broadened their activity, the other side groups were modified, and thousands of different FQs were synthesized. They are classically divided into two subfamilies: the “older” agents, such as ciprofloxacin, ofloxacin, norfloxacin, and pefloxacin, and the “newer” FQs that were developed after 1990, such as levofloxacin, sparfloxacin, gatifloxacin, moxifloxacin, and gemifloxacin. Garenoxacin, one of the last quinolone generation, is a des-F(6)-quinolone. Among the side groups the three positions R1, R7, and R8 are the most variable and have been exploited to design FQs with increased efficacy.

  Figure 1 Chemical structures of FQs. doi:10.1128/microbiolspec.MGM2-0009-2013.f1

  When the first “blockbuster” FQ, ciprofloxacin, was introduced, its heralded broad-spectrum activity raised hopes that it might even be capable of replacing injected drugs for the treatment of serious infections such as Staphylococcus aureus osteomyelitis. Unfortunately, it soon became apparent that the usefulness of ciprofloxacin would be limited by the development of resistant strains. Within just a few years after it was introduced, a high percentage of nosocomial isolates (11 ), especially Gram-positive bacteria, were found to be resistant (12 ). Ciprofloxacin remained effective against some enteric Gram-negative bacteria, such as Escherichia coli , for much longer (13 ), probably because their innate MICs for ciprofloxacin were much lower than those of the Gram-positive bacteria. From in vitro studies, it appears that as the FQ concentration increases, the frequency of FQ-resistant colonies decreases, eventually reaching a “mutant prevention concentration,” generally >8 times the MIC, at which point resistant colonies are rare (<1 in 109-10 ) (14 –16

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  Bacterial Resistance to Antibiotics

  From Molecules to Man

  • Boyan B. Bonev, Nicholas M. Brown, Boyan B. Bonev, Nicholas M. Brown(Authors)
  • 2019(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  [3] . By this criterion, moxifloxacin would be a fourth‐generation quinolone and gatifloxacin would be in the first or second generation. Moreover, several important Quinolones lie outside our generational scheme. One is levofloxacin, a popular compound that shows activity with both Gram‐negative and Gram‐positive bacteria. The distinctive feature of levofloxacin is the fusion between the N‐1 and C‐8 substituents. This fused ring structure places levofloxacin between the third and fourth generations. Two newer agents, garenoxacin and gemifloxacin, also differ from the ciprofloxacin‐based lineage. Garenoxacin is noteworthy because it lacks the C‐6 fluorine characteristic of fluoroQuinolones.

  A variety of related compounds also form drug–topoisomerase–DNA complexes (Figure 6.1 , Table 6.2 ). We briefly comment on the quinazolinediones, because they have been used in resistance studies. Two general classes emerged from initial work, the 2,4‐diones and the 1,3‐diones. Both dione types lack the carboxyl group that is characteristic of the Quinolones. The absence of the carboxyl moiety renders the diones insensitive to the major resistance mutations in gyrA and parC [4 , 5 ].

  6.2 Mechanism of Action

  6.2.1 Overview

  Knowing how the Quinolones act provides a context for understanding resistance. A key observation is that the compounds are “concentration‐dependent killers.” Thus, raising their concentration improves the ability to eradicate an infecting pathogen population, to reduce the chance that new mutants will arise, and to kill resistant mutants that might already be present. Below we describe several steps in quinolone action that occur at different drug concentrations.

  At low quinolone concentrations, the drugs form bacteriostatic ternary complexes with DNA and either gyrase or topoisomerase IV; at higher concentrations, roughly above five‐times the MIC, the compounds kill rapidly growing cells within an hour or two. Rapid killing occurs by two lethal pathways (Figure 6.2 ). In one, bacteria respond to lethal lesions by generating ROS that accelerate cell death [7 , 8 ]. Killing by this pathway requires ongoing protein synthesis, which is required for ROS accumulation. Protein synthesis is also required for the chromosome fragmentation associated with nalidixic acid treatment. The second mode of killing, which is most prominent with the newest Quinolones (e.g., PD161144 with E. coli), occurs in the absence of growth, protein synthesis, or oxygen. Factors affecting rapid lethality are summarized in Table 6.3

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  The Quinolones

  • Vincent T. Andriole(Author)
  • 2000(Publication Date)
  • Academic Press

    (Publisher)

  It is this process of DNA end release, and not inhibition of DNA synthesis, that is thought to produce the bactericidal effect of these agents. This process may not function to the same degree with all Quinolones, however, because the lethal action of the newer potent fluoroQuinolones is only partially blocked by protein and RNA synthesis inhibi-tors [242]. This alternative mechanism could still involve the release of free DNA ends from the quinolone–gyrase–DNA complex; it has been shown that treatment Chemistry and Mechanism of Action 77 of cells with ciprofloxacin disrupts the ability of chromosomal DNA to maintain normal supercoiling even in the presence of chloramphenicol [247]. Another property of fluoroQuinolones may help to explain how such free DNA ends could be generated from the ternary complex. Quinolones have been shown to stimulate illegitimate recombination and deletions that may result from the dissociation–reassociation of the gyrase–DNA complex. Also, oxolinic acid stimulated formation of λ biotransducing phage by two to three orders of magnitude via illegitimate recombination [248]. The production of phage stimu-lated by oxolinic acid was prevented in bacterial host cells containing a mutation in gyrA that conferred quinolone resistance. The ability of Quinolones to induce illegitimate recombination may provide a mechanism by which the same ternary complex could produce free DNA ends on the bacterial chromosome, which would result in lethality. As reviewed by Drlica [179], all of these properties of Quinolones could be consistent with earlier results describing the multiple mechanisms of bacterial cell killing as outlined by Smith and Lewin [242,243]. The first mechanism of cell killing (mechanism A) is common to many Quinolones and is inhibited by chloramphenicol [243]. This mechanism is consistent with the removal of the gyrase–quinolone complexes formed with DNA, creating free DNA ends.

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  Small Animal Clinical Pharmacology and Therapeutics

  • Dawn Merton Boothe(Author)
  • 2011(Publication Date)
  • Saunders

    (Publisher)

  Drugs that Target Nucleic Acids

  Fluorinated Quinolones

  The fluorinated Quinolones (FQs) are among the most recent classes of antimicrobials to be developed for treatment of bacterial infections. These synthetic drugs are minimally toxic yet have been effective in the treatment of many aerobic gram-negative organisms and selected gram-positive organisms. The desire to expand their spectrum of activity and the advent of resistance has led to innovated structural changes.

  Structure–Activity Relationship

  A review of the development of FQs is worthwhile, not only to facilitate understanding of their actions but also to provide insight regarding the advantages of so-called designer drugs. Two decades elapsed between the development of nalidixic acid, the progenitor of the FQs, and norfloxacin, the first of the FQs to be approved for use. Among the FQs currently used for treatment of susceptible infections in dogs and cats, ciprofloxacin was first approved for use in humans in 1986, with its veterinary counterpart, enrofloxacin, rapidly following in 1991. Extensive use of these drugs has exposed the need for improvements and newer clinical indications; pharmaceutical companies have been attentive to addressing these needs.

  Nalidixic acid is the progenitor of the FQs (Figure 7-8 ). Synthetic manipulations, including but not limited to the addition of a fluorine atom, have broadened the antibacterial spectrum; enhanced tissue penetrability; reduced (some) side effects (perhaps while contributing to others); and, most recently, decreased the risk of resistance. Currently marketed FQs generally consist of a quinolone ring nucleus, the target of most initial structural manipulations (Figure 7-9 ), or a napthyridone ring structure, which replaces the nitrogen at carbon 8 on the quinolone structure (enoxacin, tosufloxacin, trovafloxacin, and gemifloxacin). The quinolone nucleus contains a carboxylic acid group at position 3 and an exocyclic oxygen at position 4 (hence the term “4-Quinolones”); these are the active DNA gyrase binding sites, and thus these sites generally are not chemically manipulated. The structures yield two pKas for most FQs, rendering them amphoteric; they can act as weak bases, weak acids, or neutral compounds. For example, the carboxylic acid of enrofloxacin has a pKa of 6 and the amine group a pKa of 8.8. The side chain attached to the nitrogen at position 1 affects potency. The ethyl group at this position on nalidixic acid and the first of the clinically used FQs, norfloxacin, was replaced with a bulkier group (e.g., the cyclopropyl group of ciprofloxacin), which enhanced both gram-negative and -positive spectra. Substitution at position 5 also improved the gram-positive spectrum; however, it was the addition of a fluorine atom at position 6 that profoundly enhanced the gram-positive spectrum. The addition of a piperazyl ring, containing a heterocyclic nitrogen, at position 7 also was a critical improvement. This addition improved bacterial penetration (potency) and added P. aeruginosa

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  Analogue-based Drug Discovery

  • János Fischer, C. Robin Ganellin, János Fischer, C. Robin Ganellin(Authors)
  • 2006(Publication Date)
  • Wiley-VCH

    (Publisher)

  Part 1. Pharmazie, 1991, 46, 485–501. 53 Leysen DC, et al. Synthesis of antibac- terial 4-quinolone-3-carboxylic acids and their derivatives. Part 2. Pharmazie, 1991, 46, 557–572. 54 Mitscher LA, et al. Recent advances on quinolone antimicrobial agents. In: Hor- izons on Antibiotic Research. Davis BD, et al. (Eds.) Japan Antibiotics Research Association: Tokyo, 1988, pp. 166–193. 55 Rádl S, Bouzard D. Recent advances in the synthesis of antibacterial quino- lones. Heterocycles, 1992, 34, 2143–2177. 56 Mitscher LA. Bacterial topoisomerase inhibitors: quinolone and pyridone anti- bacterial agents. Chem. Rev ., 2005, 105, 559–592. 57 Andriole VT. The Quinolones. Academic Press: London, San Diego, New York, Berkeley, Boston, Sydney, Tokyo, Toronto, 1988. 58 Asahina Y, Ishizaki T, Suzue S. Recent advances in structure activity relation- ships in new Quinolones. In: Fluorinated Quinolones – new quinolone antimicro- bials; Progress in Dug Research – Fortschritte der Arzneimittelforschung. Jucker E (Ed.), Vol. 38. Mitsuhashi (Ed.) Birkhäuser: Basel Stuttgart, 1992, pp. 57–106. 59 Domagala JM. Review: Structure–activ- ity and structure–side-effect relation- ships for the quinolone antibacterials. J. Antimicrob. Chemother., 1994, 33, 685–706. 60 Mitscher LA, Devasthale PV, Zavod RM. Structure–activity relationships of fluoro-4-Quinolones. In: The 4-Quino- lones: Antibacterial Agents in Vitro. Crumplin GC (Ed.). Springer: London, Berlin, Heidelberg, New York, Paris, Tokyo, Hong Kong, 1990, pp. 115–146. 61 Mitscher LA, Devasthale P, Zavod R. Structure–activity relationships. In: Qui- nolone Antimicrobials Agents, 2nd edn. Hooper DC, Wolfson JS (Eds.) Ameri- can Society for Microbiology: Washing- ton, 1993, pp. 3–51. 62 Rádl S. Structure–activity relationships in DNA gyrase inhibitors. Pharmacol. Ther ., 1990, 48, 1–17. 63 Rosen T. The fluoroquinolone antibac- terial agents. In: Progress in Medicinal Chemistry , Vol. 27. Ellis GP, West GB (Eds.).

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  Concepts, Compounds and the Alternatives of Antibacterials

  • Varaprasad Bobbarala(Author)
  • 2015(Publication Date)
  • IntechOpen

    (Publisher)

  The discovery of fluoroQuinolones after 1980 represented a decisive step forward for chemical anti-infectious therapy. A large number of fluoroQuinolones are used today in medical practices and some of them are deemed by leading pharmacologists to be of vital importance to anti-infectious therapy. 2. Tendencies and strategies in the field of Quinolones The basic structure of Quinolones (Figure 1) [9], is a bicyclic structure that contains a ring type A 4-pyridinone combined with an aromatic or heteroaromatic ring B. According to the nature of atoms symbolized by X, Y, Z, they can be defined as four subfamilies: naphthyridine 1-8, cinnoline, pyrido-2,3-pyrimidines, and quinolone. Z Y X N O R CO 2 H A B 1 2 3 4 5 6 7 8 naphthyridines : X=Z=H; Y=N cinnolin: X=N; Y=Z=H pyrido-2,3-pyrimidine: X=H; Y=Z=N Quinolones : X=Y=Z= H Figure 1. Basic structure of Quinolones. The structural modifications of the core of the quinolone influence the antimicrobial activity 2.1. Position 1 Research has been oriented in several directions: Concepts, Compounds and the Alternatives of Antibacterials 46 • Introducing an unsubstituted or substituted alkyl: R 1 = methyl [32], ethyl [32, 28], iso propyl [28, 48, 1], tert-butyl [48, 14], fluoroethyl [28], hydroxyethyl [38], chloroethyl [38]; • Introduction of a vinyl, allyl [38, 32]; • Introduction of alkylamino groups [65]; • Introduction of a cyclpopropyl [38, 56, 57, 49] or cyclobutyl [49, 1]; • Introducing mono or disubstituted phenyl [38, 7, 46, 49]; • Introduction of a five-membered aromatic heterocycles: pyrrolyl, [34]. Usually, the most active compounds contain the ethyl substituent in position 1.

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  Catalytic and Biocatalytic Methods for the Efficient Synthesis of Biologically Relevant Non-Proteinogenic Amino Acids

  • (Author)
  • 2014(Publication Date)
  • Cuvillier Verlag

    (Publisher)

  2 Literature Review 2.1 Clinically Established Antibiotic Classes and Their Targets In order to understand the mode of action of certain antimicrobial substances and antibiotic classes, the classical antibiotic targets will be explained: interference with bacterial cell wall synthesis (a), DNA- and RNA-replication (b), bacterial protein synthesis (c) and folic acid metabolism (d) (Figure 2.1). [4] Figure 2.1 : The four classical targets of established antibiotics (adapted from: K. Lewis et al., Nat. Rev. Drug Discov. 2013 , 12 , 371). [16] In contrast to mammalian cells, folic acid biosynthesis is essential for bacterial survival. By acting as alternative substrates, structural analogues like sulfonamides inhibit the key enzyme dihydropteroate synthase. Another antibiotic targeting folate metabolism is trimethoprim, a 2,4-diaminopyrimidine, with the ability of selective inhibition of dihydrofolate reductase, which catalyzes the reduction of dihydrofolate to the crucial cofactor tetrahydrofolate. [39] As distinct binding sides of the ribosomal RNA subunits 50S and 30S provide the potential to block multiple steps in protein biosynthesis, numerous antimicrobial compounds, such as aminoglycosides, macrolides, tetracyclines, chloramphenicol, and clindamycin, were developed using this mode of action. [39-42] Quinolones, a well-established class of antibiotics (e.g. ciprofloxacin), inhibit DNA gyrase, 'LHVHV :HUN LVW FRSULJKWJHVFKW]W XQG GDUI LQ NHLQHU )RUP YHUYLHOIlOWLJW ZHUGHQ QRFK DQ 'ULWWH ZHLWHUJHJHEHQ ZHUGHQ (V JLOW QXU IU GHQ SHUV|QOLFKHQ *HEUDXFK 8 2 Literature Review which controls the topology of DNA. While promising DNA supercoiling inhibitors with new modes of action (e.g. coumarines) are still in the pipeline, [43] the DNA-dependent RNA polymerase, a major enzyme in the regulation of prokaryotic gene expression, remains quite underexploited in contrast, as it is only targeted by one class of clinically used antibiotics, the rifamycines (e.g. rifampicin).

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