Aminoglycoside antibiotic

What are aminoglycoside antibiotics?

Aminoglycosides are powerful antibiotics that have a wide range of activity and cause their effects by inhibiting the production of proteins. In 1944, streptomycin was originally identified from Streptomyces griseus and put into clinical usage. Since since, this family of antibiotics has been an essential component of antibacterial chemotherapy.

A wide range of bacteria, both Gram-positive and Gram-negative, are susceptible to the action of aminoglycosides. Enterobacteriaceae, which includes Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Enterobacter cloacae, E. aerogenes, Providencia spp., Proteus spp., Morganella spp., and Serratia spp., are especially susceptible to aminoglycosides. Additionally, aminoglycosides inhibit the growth of the tularemia-causing Francisella tularensis and the plague-causing Yersinia pestis. Pseudomonas aeruginosa, Staphylococcus aureus (including strains resistant to methicillin and vancomycin), and, to a lesser degree, Acinetobacter baumannii are all effectively targeted by this family of bacteria. In addition to Mycobacterium avium, Mycobacterium TB, Mycobacterium chelonae, and Mycobacterium fortuitum are all sensitive to aminoglycosides.

Three separate steps form the process of aminoglycoside entrance into bacterial cells. The first stage is responsible for increasing the permeability of the bacterial membrane, while the second and third stages are reliant on energy and energy levels. During the first stage, the polycationic aminoglycoside is electrostatically bound to the negatively charged components of the bacterial membrane. These components include the phospholipids and teichoic acids of Gram-positive organisms, as well as the phospholipids and lipopolysaccharide (LPS) of Gram-negative organisms. Additionally, magnesium ions are displaced during this stage. Through the elimination of these cations, the outer membrane of the bacterial cell is disrupted, improved permeability is achieved, and the process of aminoglycoside absorption is initiated. These cations are responsible for cross-bridging and stabilizing the lipid components of the bacterial membrane. By means of a gradual, energy-dependent, electron-transport-mediated process, this event makes it easier for one to enter the cytoplasm. As soon as aminoglycoside molecules enter the cytoplasm, they begin to inhibit the process of protein synthesis and cause mistranslation of proteins. Subsequent aminoglycoside entrance is facilitated by these mistranslated proteins, which insert themselves into the cytoplasmic membrane and cause damage to the membrane itself. This, in turn, causes an increase in the inhibition of protein synthesis, mistranslation, and hastened cell death. Additionally, it causes the fast absorption of extra aminoglycoside molecules into the cytoplasm.

The Examples of aminoglycosides antibiotics

Several other members of the aminoglycosides antibiotics were introduced over the intervening years including neomycin (1949, S. fradiae), kanamycin (1957, S. kanamyceticus), gentamicin (1963, Micromonospora purpurea), netilmicin (1967, derived from sisomicin), tobramycin (1967, S. tenebrarius), and amikacin (1972, derived from kanamycin).

Streptomycin and paromomycin enhance the frequency of errors during translation by stabilizing the 30S subunit in the ram form, resulting in reduced accuracy in recognizing tRNA at the A site. Hygromycin B hinders the mobility of helix H44, hence impeding the necessary structural alterations for the movement of this helix during translocation. Additionally, the antibiotic seizes the tRNA at the A site. Spectinomycin hinders the translocation of peptidyl-tRNA from the A site to the P site by inhibiting elongation-factor-G. Apramycin primarily inhibits translocation, whereas gentamicin has a multifaceted mechanism of action that includes inducing considerable miscoding, preventing intersubunit rotation, and inhibiting translocation.

The representative aminoglycosides. (Krause K M., et al., 2016)

Aminoglycoside antibiotics at BOC Sciences

Aminoglycoside antibiotics uses

When aminoglycosides were administered systemically in amounts that were ototoxic, negative symptoms and even death were common results. Neomycin at 300 mg/kg/24 h for 15 days caused the most systemic toxicity and 71% death in our experiment. Although all of the therapies were well-tolerated, amikacin had the lowest death rate. About 30% of the subjects died after 15 days of therapy with 600 and 800 mg kanamycin/kg twice daily. Other adverse effects seen in the expermental animals given toxic amounts of aminoglycosides included loss of weight, respiratory failure, and abrupt injection-related mortality. Amikacin injections under the skin often left behind sores.

The effects of various dosages of aminoglycosides were compared after they were delivered subcutaneously, intramuscularly, or intraperitoneally. The HsdOla:MF1 mice had a 50% mortality rate after 15 days of receiving 300 mg/kg of gentamicin intramuscularly. The injections caused very minor changes (0-5 dB SPL) and variable shifts in threshold. The same strain was also used to study tolerance to amikacin and neomycin; the results showed that the lowest death rate (25%), while no significant modifications in auditory thresholds, was caused by subcutaneous treatment of amikacin (500 mg/kg/24 h). Alternatively, neomycin given intraperitoneally at a dose of 300 mg/kg/24 h resulted in very high death rates and an inadequate shift response.

At a dosage of less than 4 μg/ml, sisomicin inhibits almost all species tested, making it the most powerful among the bunch. See figure below for an illustration of kanamycin, the least powerful aminoglycoside (see image below). Not only does kanamycin need larger amounts to prevent bacterial growth, but it also fails to inhibit, at measured quantities, some isolates that are susceptible to other aminoglycosides. Amikacin inhibits most organisms at therapeutically feasible quantities, while it is also generally ineffective at lower concentrations. Even though aminoglycosides only work against 40% of streptococci, they work well against Staphylococci. Less than 2.5 ug/ml of gentamicin, tobramycin, and sisomicin inhibits almost all strains of Staphylococci, according to in vitro experiments.

Aminoglycoside antibiotics moa

Among the conventional antibiotics, aminoglycosides bind to the 30S bacterial ribosome's 16S rRNA component and prevent protein synthesis by causing translation mistakes. Specifically, they attach to the A site of aminoacyl-tRNA and interact with the ribosome decoding site that is responsible for proper codon-anticodon recognition. An extensive network of hydrogen bonds with areas of the 16S rRNA is formed by the hydroxyl and amino substituents on the cyclitol rings.

Aminoglycoside antibiotics structure

In the case of aminoglycosides, the main structure consists of amino sugars that are linked to a dibasic aminocyclitol by glycosidic connections. The dibasic aminocyclitol that is most typically found in aminoglycosides is 2-deoxystreptamine. In general, aminoglycosides can be divided into four subclasses according to the identity of the aminocyclitol moiety. These subclasses are as follows: (1) a mono-substituted deoxystreptamine ring (for example, apramycin); (2) a mono-substituted deoxystreptamine ring (for example, streptomycin); (3) a 4,5-di-substituted deoxystreptamine ring (for example, neomycin and ribostamycin); or (4) a 4,6-di-substituted deoxystreptamine ring (for example, gentamicin, amikacin, tobramycin, and plazomicin). The central structure is embellished with a wide range of amino and hydroxyl substitutions, each of which has a direct impact on the modes of action and sensitivity to the numerous aminoglycoside-modifying enzymes (AMEs) that are connected with each of the aminoglycosides.

Structures of aminoglycosides used in the clinic. (Dozzo P., et al., 2010)

References

1. Krause K M., et al., Aminoglycosides: an overview, Cold Spring Harbor perspectives in medicine, 2016, 6(6): a027029.
2. Murillo-Cuesta S., et al., Comparison of different aminoglycoside antibiotic treatments to refine ototoxicity studies in adult mice, Laboratory animals, 2010, 44(2): 124-131.
3. Burkle W S. Comparative evaluation of the aminoglycoside antibiotics for systemic use[J]. Drug Intelligence & Clinical Pharmacy, 1981, 15(11): 847-862.
4. Dozzo P., et al., New aminoglycoside antibiotics, Expert opinion on therapeutic patents, 2010, 20(10): 1321-1341.