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Antibiotic Drug Resistance
JosĂ©-Luis Capelo-MartĂnez, Gilberto Igrejas, JosĂ©-Luis Capelo-MartĂnez, Gilberto Igrejas
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eBook - ePub
Antibiotic Drug Resistance
JosĂ©-Luis Capelo-MartĂnez, Gilberto Igrejas, JosĂ©-Luis Capelo-MartĂnez, Gilberto Igrejas
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Ă propos de ce livre
This book presents a thorough and authoritative overview of the multifaceted field of antibiotic science â offering guidance to translate research into tools for prevention, diagnosis, and treatment of infectious diseases.
- Provides readers with knowledge about the broad field of drug resistance
- Offers guidance to translate research into tools for prevention, diagnosis, and treatment of infectious diseases
- Links strategies to analyze microbes to the development of new drugs, socioeconomic impacts to therapeutic strategies, and public policies to antibiotic-resistance-prevention strategies
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Informations
Part I
Current Antibiotics and Their Mechanism of Action
1
Resistance to Aminoglycosides: Glycomics and the Link to the Human Gut Microbiome
Viviana G. Correia Benedita A. Pinheiro Ana LuĂsa Carvalho, and Angelina S. Palma
UCIBIOâREQUIMTE, Departamento de QuĂmica, Faculdade de CiĂȘncias e Tecnologia, Universidade NOVA de Lisboa, Caparica, Portugal
1.1 Aminoglycosides as Antimicrobial Drugs
The exponential appearance of antibioticâresistant infections, in particular those caused by Gramânegative pathogens, is a major public health concern. The observed decrease in the emergence of new effective antimicrobial drugs is an inevitable consequence of the use of antibiotics, and new approaches to fight infection are a matter in need of attention from the scientific community (Magiorakos et al. 2012). In response to this challenge, the optimization of existing drugs with known mechanisms of action and resistance, such as aminoglycosides, is an attractive approach for the development of new antimicrobials.
Aminoglycosides or aminoglycoside antibiotics (AGAs) are secondary metabolites of bacteria used in the warfare against other microorganisms, which were repurposed in medicine as broadâspectrum antibiotics in both humans and animals. This class of antibiotics has activity against Gramânegative and Gramâpositive bacteria by targeting ribosomal RNA (rRNA), leading to protein misfolding. AGAs have predictable pharmacokinetics and often act in synergy with other antibiotics, such as betaâlactams, making them powerful antiâinfective drugs (Hanberger et al. 2013). Despite their potential renal toxicity and ototoxicity and known bacterial resistance, diverse molecules of this family of antibiotics have been used in clinical practice for several decades (Thamban Chandrika and GarneauâTsodikova 2018).
AGAs are constituted by a carbohydrate residue moiety and possess several amino and hydroxyl group functionalities, determinants for the interaction with target sequences on the rRNA and for impairing normal ribosomal function. Although natural AGAs share the same myoâinositolâbased core (Figure 1.1), these molecules exhibit significant structural differences depending on the bacterial origin, which result in different biological activities. Importantly, the bacterial origin is also the driving force behind bacterial resistance, as it enables bacteria to alter the structure of AGAs by modifying their amino and hydroxyl groups.
Streptomycin was the first identified and characterized AGA and the first useful antibiotic obtained from a bacterial source (1944). This AGA was isolated from the soilâdwelling bacterial species Streptomyces and Micromonospora and successfully introduced into clinical practice in 1940 to treat tuberculosis. After the initial discovery of streptomycin and its streptamineâbased relatives (Figure 1.1a), several others followed, and the development of bacterial resistance was largely overcome by introduction of AGAs derived from 2âdeoxystreptamine (DOS) (Figure 1.1c), reviewed in (Davies 2007). These included neomycin (1949), kanamycin (1957), gentamycin (1963), tobramycin (1967), and sisomicin (1970). The acquisition of bacterial resistance for the DOS aminoglycosides prompted the development of novel and potent semisynthetic AGAs. These secondâgeneration AGAs resulted from the insertion of a 4âhydroxyâ2âaminobutyric acid (HABA) substituent of the Câ1 amine group on the DOS ring of kanamycin and gentamycinâderived compounds. Examples are dibekacin (1971), amikacin (1972), arbekacin (1973), isepamicin (1975), and netilmicin (1976). However, because of their clinical usage, bacteria also developed resistance mechanisms against these semisynthetic antibiotics, almost leading to the abandon of AGAs.
Recently, the interest in AGAs research has resurged as consequence of the increasing number of strains resistant to other classes of antibiotics, such as the Gramânegative bacteria Enterococcus faecium responsible for serious invasive nosocomial infections (Buelow et al. 2017). New approaches have been used for developing semisynthetic AGAs using combined structureâactivity relationship (SAR), in search for less toxic but effective AGAs (Thamban Chandrika and GarneauâTsodikova 2018). The AGA plazomicin developed by Achaogen Inc. (ACHNâ490) (Aggen et al. 2010), currently in phase III clinical trials, is an evidence of the renewed interest. Table 1.1 summarizes described AGAs and their distinctive features.
Table 1.1 Overview of major aminoglycoside antibiotics (AGAs) and their distinctive features and effect on the human gut microbiome.
Source: Adapted from Piepersberg et al. (2007) and Becker and Cooper (2013).
AGA | Coreâderived structure | Common use | Effect on human gut microbiome | Related pathology or disease | Microbiomeârelated studies |
Naturally occurring | |||||
Apramycin (APR) | 4âMonosubstituted 2âDOS | Veterinary | NA | NA | NA |
Butirosin (BTR) | 4,5âDisubstituted 2âDOS | Biochemical reagent | NA | NA | NA |
Fortimicin (... |