Aminoglycoside Resistance

There are three mechanisms of aminoglycoside resistance: reduced uptake or decreased cell permeability, alterations at the ribosomal binding sites, or production of aminoglycoside modifying enzymes.

Reduced uptake or decreased cell permeability

Some strains of Pseudomonas aeruginosa and other gram-negative bacilli exhibit aminoglycoside resistance due to a transport defect or membrane impermeabilization.^{1, 4}  This mechanism is likely chromosomally mediated and results in cross-reactivity to all aminoglycosides.^1,4  The level of resistance that is seen is moderate (i.e. intermediate susceptibility).¹

Altered Ribosome Binding Sites

Mutations at the site of aminoglycoside attachment may interfere with ribosomal binding.  Resistance to streptomycin can occur by this mechanism since this agent binds to a single site on the 30S subunit of the ribosome.  Resistance to the other aminoglycosides by this mechanism is uncommon since they bind to multiple sites on both ribosomal subunits and high-level resistance cannot be selected by a single step.⁴

Enzymatic Modification

      Enzymatic modification is the most common type of aminoglycoside resistance. Over 50 different enzymes have been identified.⁵  Enzymatic modification results in high-level resistance.⁴  The genes encoding for aminoglycoside modifying enzymes are usually found on plasmids and transposons.  Most enzyme-mediated resistance in gram-negative bacilli is due to multiple genes.  It is hypothesized that the enzymes are derived from organisms that make the aminoglycoside or from the mutation of genes that encode the enzymes involved in cellular respiration.²

      There are three types of aminoglycoside modifying enzymes: ⁵

1.      N-Acetyltransferases (AAC) – catalyzes acetyl CoA-dependent acetylation of an amino group

2.      O-Adenyltransferases (ANT) – catalyzes ATP-dependent adenylation of hydroxyl group

3.      O-Phosphotransferases (APH) – catalyzes ATP-dependent phosphorylation of a hydroxyl group

REFS:

1. Mingeot-Leclercq MP, Glupczynski Y, and Tulkens PM. Aminoglycosides: Activity and Resistance. Antimicrobial Agents and Chemotherapy 1999;43:727-37.

2. Gilbert D. Aminoglycosides. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5^th ed. Philadelphia: Churchill Livingstone, 2000:307-336.

3. Opal S, Mayer K, and Medeiros A.  Mechanisms of Bacterial Antibiotic Resistance. In:   Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 5^th ed. Philadelphia: Churchill Livingstone, 2000:236-252.

4. Kucers A, Crowe S, Grayson ML, and Hoy J, eds.   The Use of Antibiotics: A Clinical Review of Antibacterial, Antifungal, and Antiviral Drugs. 5^th ed. Oxford: Butterworth Heinemann, 1997:452-457.

5. Davies J and Wright G. Bacterial Resistance to Aminoglycoside Antibiotics. Trends in Microbiology 1997;5:234-39.