Aminoglycosides represent a class of antibiotics used to combat bacterial infections. These medications are often prescribed for conditions including pneumonia, sepsis, and complicated urinary tract infections. Common examples of these drugs include gentamicin and tobramycin, which have been widely used in clinical settings for decades. Their effectiveness stems from an ability to target and eliminate harmful bacteria within the body.
Entry Into the Bacterial Cell
For aminoglycosides to exert their effects, they must first gain entry into the bacterial cell. This process occurs in two stages. Initially, positively charged aminoglycoside molecules passively diffuse across the outer membrane of Gram-negative bacteria through porin channels, reaching the periplasmic space.
The second step involves active, energy-dependent transport across the inner cytoplasmic membrane. This relies on the bacterial cell’s electron transport chain and requires oxygen. Consequently, aminoglycosides are effective against aerobic bacteria and show limited activity against anaerobic bacteria. Once inside the cytoplasm, the drug accesses its cellular targets.
Targeting the Bacterial Ribosome
Upon entering the bacterial cell, aminoglycosides target the bacterial ribosome. Ribosomes are the cell’s “protein factories,” reading genetic instructions from messenger RNA (mRNA) to construct proteins. Bacterial ribosomes are composed of two main subunits, the 30S and 50S, forming the 70S ribosome.
Aminoglycosides bind with high affinity to the 16S ribosomal RNA within the 30S ribosomal subunit. This binding alters the conformation of the A-site on the 16S ribosomal RNA, a region involved in decoding genetic information. The precise binding site and effects can vary among different aminoglycoside types.
Disruption of Protein Synthesis
Once bound to the 30S ribosomal subunit, aminoglycosides disrupt the bacterial cell’s ability to synthesize functional proteins. They prevent the proper initiation of protein synthesis by interfering with the ribosome’s assembly at the mRNA start codon.
Aminoglycosides also cause misreading of the mRNA code. By distorting the shape of the 30S subunit, the drug leads to the incorporation of incorrect amino acids, producing faulty, nonfunctional proteins.
These antibiotics can also induce premature termination of protein synthesis. The ribosome may prematurely detach from the mRNA template, creating incomplete protein fragments that contribute to cellular dysfunction.
The Bactericidal Outcome
The production of abnormal and nonfunctional proteins, a direct consequence of aminoglycoside action, leads to the bacterial cell’s demise. Many of these misfolded or incomplete proteins are inserted into the bacterial cytoplasmic membrane. This compromises the membrane’s structural integrity, creating “leaks” or pores.
The damaged membrane can no longer maintain its selective barrier, causing essential cellular components to leak out. This uncontrolled leakage disrupts the bacterium’s internal environment and metabolism, making it unable to sustain its functions. These disruptions ultimately kill the bacterium, classifying aminoglycosides as bactericidal antibiotics.
Selective Toxicity
A characteristic of aminoglycosides is their selective toxicity, meaning they primarily harm bacterial cells while leaving human cells unharmed. This selectivity is due to structural differences between bacterial and human ribosomes. Bacterial ribosomes are 70S, composed of 30S and 50S subunits.
Human (eukaryotic) ribosomes are larger 80S ribosomes, consisting of 40S and 60S subunits. Aminoglycosides exhibit high binding affinity specifically for the bacterial 30S ribosomal subunit. Their affinity for the human 40S subunit is much lower. This ensures the drug preferentially interferes with bacterial protein synthesis.