^{Resistance Mechanisms
for Specific Antimicrobials}

 

Aminoglycosides

• Enzymatic modification of the antimicrobial by aminoglycoside-modifying enzymes (AMEs) which prevents them
binding to their target (these enzymes are broad spectrum and encoded on mobile genetic elements)⁵⁵

• Target modification by mutation or enzymatic modification⁵⁵

• Efflux pumps but these are rare⁵⁵

 

Beta-lactam agents

Gram-positive bacteria:

• Expression of low affinity penicillin-binding proteins (PBPs)
encoded on mobile chromosomal elements⁵⁴

Gram-negative bacteria:

• Production of beta-lactamases^54,74

• Production of low affinity PBPs⁷⁴

• Reducing entry of antimicrobial into the cell by mutations in porins⁷⁴

• Multidrug efflux pumps to remove the antimicrobial agent from the cell^54,74

 

Fluoroquinolones

Mechanisms in Gram-negative bacteria:

• Chromosomal mutations in quinolone resistance determining regions (QRDRs) of target genes encoding DNA gyrase and topoismerase IV^51,53

• Altered expression of porins resulting in decreased antimicrobial penetration of the bacterial cell⁵¹

• Chromosomally mediated increased efflux from the cell via multidrug efflux pumps⁵¹

• Plasmid encoded protein QnrA which binds to DNA gyrase and prevents the antimicrobial binding to DNA⁵³

 

Macrolides and Lincosamides

Resistance mechanisms in Gram-positive organisms include:

• Target site modification by methylation or mutation which prevents binding of a broad spectrum of antimicrobials in these classes⁵²

• Plasmid encoded efflux pumps which are usually more specific⁵²

• Drug inactivation but this is less clinically important⁵²

 

Tetracyclines

Resistance to tetracyclines is usually acquired and genes are usually associated with plasmids or transposons⁵⁶

• Energy dependent efflux of antimicrobial by a membrane associated protein^56,75

• Protection of the ribosomal binding site of the antimicrobial through binding of specific proteins^56,75

These mechanisms are found in both Gram-positive and Gram-negative bacteria⁵⁶

 

Trimethoprim/Sulphonamide (TMPS)

Plasmid encoded production of insensitive enzymes by bacteria:⁷⁶

• Single or multiple amino acid substitutions in dihydrofolate reductase (target for trimethoprim)⁵⁸

• Insertions of one or two amino acids in dihydropteroate synthetase (target for sulphonamides)⁵⁸