Aminoglycosides are a class of antibiotics used for decades to treat bacterial infections. Understanding their chemical architecture is fundamental to comprehending their therapeutic actions and how bacteria develop resistance.
Basic Structural Features
Aminoglycosides are complex molecules characterized by multiple amino sugar units interconnected by glycosidic bonds. The amino groups within their structure are particularly noteworthy, as they carry a positive charge at physiological pH, a feature central to their biological activity.
Many aminoglycosides feature a central aminocyclitol ring, such as streptamine or 2-deoxystreptamine (2-DOS), to which various amino sugar moieties are attached. Streptomycin, an early discovered aminoglycoside, uniquely possesses a streptidine ring instead of the more common 2-deoxystreptamine.
Key Structural Variations
Despite sharing a common foundational structure, different aminoglycosides exhibit distinct variations in their chemical makeup. These differences often involve the number, type, and specific arrangement of the amino sugar rings linked to the central aminocyclitol core. The positions of amino and hydroxyl groups can also vary, influencing the drug’s overall shape and reactivity.
Examples include gentamicin, tobramycin, amikacin, and streptomycin, each possessing unique properties. For instance, gentamicin’s structure includes a 2-deoxystreptamine backbone with purpurosamine and garosamine amino sugars attached at specific carbon positions. Such variations contribute to differences in their spectrum of activity against various bacteria and their susceptibility to bacterial resistance mechanisms.
How Structure Dictates Function
The antibacterial action of aminoglycosides is linked to their chemical structure, particularly the positively charged amino groups. These positively charged groups are drawn to the negatively charged backbone of bacterial ribosomal RNA (rRNA), specifically interacting with the 16S rRNA within the 30S ribosomal subunit. This electrostatic attraction drives their binding to the bacterial ribosome.
Once bound, aminoglycosides interfere with the process of protein synthesis in bacteria. Their binding to the A-site of the 16S rRNA causes a conformational change, leading to misreading of the messenger RNA (mRNA) code. This misreading results in the incorporation of incorrect amino acids into growing protein chains and can also lead to premature termination of translation. The disruption of bacterial protein synthesis impairs cellular function and leads to bacterial cell death.
Structural Basis of Resistance and Modification
Bacteria have evolved sophisticated mechanisms to resist the effects of aminoglycosides, by modifying the antibiotic’s structure. A major mechanism involves aminoglycoside-modifying enzymes (AMEs), which chemically alter the drug. These enzymes include acetyltransferases (AACs), nucleotidyltransferases (ANTs, also known as adenylyltransferases), and phosphotransferases (APHs).
These AMEs add chemical groups, such as acetyl, adenylyl, or phosphoryl moieties, to specific amino or hydroxyl groups on the aminoglycoside molecule. These structural modifications prevent the aminoglycoside from binding effectively to its ribosomal target, rendering the antibiotic inactive and allowing the bacteria to continue protein synthesis unimpeded. Understanding these enzymatic modifications has guided the development of semi-synthetic aminoglycosides, such as amikacin, which are designed with altered structures to evade inactivation by some common AMEs, thereby retaining their antibacterial potency against resistant strains.