Gentamicin

Gentamicin is a bactericidal aminoglycoside that was discovered and isolated from

Micromonospora purpurea in 1963.7 It is one of the most frequently prescribed aminoglycosides
due to its spectrum of activity, low cost, and availability.5,8 Gentamicin is effective against both
gram-positive and gram-negative organisms but is particularly useful for the treatment of severe
gram-negative infections including those caused by Pseudomonas aeruginosa. There is the added
benefit of synergy when gentamicin is co-administered with other antibacterials such as beta-
lactams. This synergistic activity is not only important for the treatment of complex infections,
but can also contribute to dose optimization and reduced adverse effects.

Although gentamicin is well-established and may be used in a variety of clinical applications, it

is also associated with severe adverse effects including nephrotoxicity and ototoxicity which may
limit its use.

Struktur Gentamicin
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There are 3 key phases of aminoglycoside entry into cells.9 The first “ionic binding phase”
occurs when polycationic aminoglycosides bind electrostatically to negatively charged
components of bacterial cell membranes including with lipopolysaccharides and phospholipids
within the outer membrane of Gram-negative bacteria and to teichoic acids and phospholipids
within the cell membrane of Gram-positive bacteria. This binding results in displacement of
divalent cations and increased membrane permeability, allowing for aminoglycoside entry.9 The
second “energy-dependent phase I” of aminoglycoside entry into the cytoplasm relies on the
proton-motive force and allows a limited amount of aminoglycoside access to its primary
intracellular target - the bacterial 30S ribosome.9 This ultimately results in the mistranslation of
proteins and disruption of the cytoplasmic membrane.[A233320] Finally, in the “energy-
dependent phase II” stage, concentration-dependent bacterial killing is observed.
Aminoglycoside rapidly accumulates in the cell due to the damaged cytoplasmic membrane, and
protein mistranslation and synthesis inhibition is amplified.9 The necessity of oxygen-dependent
active transport explains why aminoglycosides are ineffective against anaerobic bacteria.1
Hence, aminoglycosides have both immediate bactericidal effects through membrane disruption
and delayed bactericidal effects through impaired protein synthesis; observed experimental data
and mathematical modeling support this two-mechanism model.9 Inhibition of protein synthesis
is a key component of aminoglycoside efficacy. Structural and cell biological studies suggest that
aminoglycosides bind to the 16S rRNA in helix 44 (h44), near the A site of the 30S ribosomal
subunit, altering interactions between h44 and h45. This binding also displaces two important
residues, A1492 and A1493, from h44, mimicking normal conformational changes that occur
with successful codon-anticodon pairing in the A site.[A232324, A232329] Overall,
aminoglycoside binding has several negative effects including inhibition of translation, initiation,
elongation, and ribosome recycling.9 Recent evidence suggests that the latter effect is due to a
cryptic second binding site situated in h69 of the 23S rRNA of the 50S ribosomal subunit.
[A232329, A232339] Also, by stabilizing a conformation that mimics correct codon-anticodon
pairing, aminoglycosides promote error-prone translation.[A232344] Mistranslated proteins can
incorporate into the cell membrane, inducing the damage discussed above.9
Drugbank.com