, at center) protein secondary structure elements such as
alpha-helices in bright green, and the RNA phosphodiester backbone shown in orange (and the ladder of base pairs in dark green and blue) Aminoglycosides display concentration-dependent bactericidal activity against "most gram-negative aerobic and facultative anaerobic bacilli" but not against gram-negative anaerobes and most gram-positive bacteria. These activities are attributed to a primary mode of action as
protein synthesis inhibitors, though additional mechanisms are implicated for some specific agents, and/or thorough mechanistic descriptions are as yet unavailable. (
Spectinomycin, a related but distinct chemical structure class often discussed with aminoglycosides, does not induce mRNA misreading and is generally not bactericidal.) The incorporation of oxidized guanine nucleotides into
DNA could be bactericidal since incomplete repair of closely spaced
8-oxo-2'-deoxyguanosine in the DNA can result in lethal double-strand breaks.
Pharmacokinetics and pharmacodynamics There is a significant variability in the relationship between the dose administered and the resultant plasma level in blood.
Therapeutic drug monitoring (TDM) is necessary to obtain the correct dose. These agents exhibit a
post-antibiotic effect in which there is no or very little drug level detectable in blood, but there still seems to be inhibition of bacterial re-growth. This is due to strong, irreversible binding to the ribosome, and remains intracellular long after plasma levels drop, and allows a prolonged dosage interval. Depending on their concentration, they act as
bacteriostatic or
bactericidal agents.
Indications Aminoglycosides are useful primarily in infections involving
aerobic,
Gram-negative bacteria, such as
Pseudomonas,
Acinetobacter, and
Enterobacter. In addition, some
Mycobacteria, including the bacteria that cause
tuberculosis, are susceptible to aminoglycosides. Streptomycin was the first effective drug in the treatment of tuberculosis, though the role of aminoglycosides such as streptomycin and amikacin has been eclipsed (because of their toxicity and inconvenient route of administration) except for multiple-drug-resistant strains. The most frequent use of aminoglycosides is empiric therapy for serious infections such as
sepsis, complicated intra-abdominal infections, complicated urinary tract infections, and nosocomial respiratory tract infections. Usually, once cultures of the causal organism are grown and their susceptibilities tested, aminoglycosides are discontinued in favor of less toxic antibiotics. As noted, aminoglycosides are mostly ineffective against anaerobic bacteria, fungi, and viruses. The aminoglycoside
gentamicin has been used to treat
cystic fibrosis (CF) cells in the laboratory to induce them to grow full-length proteins. CF is caused by a mutation in the
gene coding for the
cystic fibrosis transmembrane conductance regulator (
CFTR) protein. In approximately 10% of CF cases, the mutation in this gene causes its early termination during
translation, leading to the formation of a truncated and non-functional CFTR protein. It is believed that
gentamicin distorts the structure of the ribosome-RNA complex, leading to a mis-reading of the
termination codon, causing the
ribosome to "skip" over the stop sequence and to continue with the normal elongation and production of the CFTR protein. ==Routes of administration==