Antibiotic Drug Resistance

José-Luis Capelo-Martínez, Gilberto Igrejas, José-Luis Capelo-Martínez, Gilberto Igrejas

• Publisher: Wiley
• Year: 2019
• ISBN:
  9781119282556
• Edition: 1
• Topic: Medicina
• Subtopic: Farmacología

This book presents a thorough and authoritative overview of the multifaceted field of antibiotic science – 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

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 Luísa Carvalho, and Angelina S. Palma

UCIBIO‐REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, Portugal

1.1 Aminoglycosides as Antimicrobial Drugs

The exponential appearance of antibiotic‐resistant infections, in particular those caused by Gram‐negative 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 broad‐spectrum antibiotics in both humans and animals. This class of antibiotics has activity against Gram‐negative and Gram‐positive bacteria by targeting ribosomal RNA (rRNA), leading to protein misfolding. AGAs have predictable pharmacokinetics and often act in synergy with other antibiotics, such as beta‐lactams, making them powerful anti‐infective 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 Garneau‐Tsodikova 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 myo‐inositol‐based 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.

Figure 1.1 Core structural elements of the aminoglycosides and examples of clinically relevant AGA families. Each family has a primary structure with different substitutions (Rn) at hydroxyl and amino groups. The rings (I–III) of the neomycins' representative structure are numbered as usually observed in the literature for disubstituted 2‐DOS AGAs. In panel (e), the pseudodisaccharide core structure paromamine, also termed as neamine, is demarked.

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 soil‐dwelling bacterial species Streptomyces and Micromonospora and successfully introduced into clinical practice in 1940 to treat tuberculosis. After the initial discovery of streptomycin and its streptamine‐based relatives (Figure 1.1a), several others followed, and the development of bacterial resistance was largely overcome by introduction of AGAs derived from 2‐deoxystreptamine (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 second‐generation AGAs resulted from the insertion of a 4‐hydroxy‐2‐aminobutyric acid (HABA) substituent of the C‐1 amine group on the DOS ring of kanamycin and gentamycin‐derived 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 Gram‐negative bacteria Enterococcus faecium responsible for serious invasive nosocomial infections (Buelow et al. 2017). New approaches have been used for developing semisynthetic AGAs using combined structure–activity relationship (SAR), in search for less toxic but effective AGAs (Thamban Chandrika and Garneau‐Tsodikova 2018). The AGA plazomicin developed by Achaogen Inc. (ACHN‐490) (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	Core‐derived structure	Common use	Effect on human gut microbiome	Related pathology or disease	Microbiome‐related studies
Naturally occurring
Apramycin (APR)	4‐Monosubstituted 2‐DOS	Veterinary	NA	NA	NA
Butirosin (BTR)	4,5‐Disubstituted 2‐DOS	Biochemical reagent	NA	NA	NA
Fortimicin (...