Mechanism of Antimicrobial Resistance

There are various different mechanisms of resistance to common antimicrobials. Genes for such mechanisms can be grouped into four main categories.

The four main categories of antimicrobial resistance in bacteria

Antibiotic-Degrading Enzymes

Resistance via antibiotic-degrading enzymes refers to mechanisms that result in the inactivation of the antimicrobial drug of choice. For example, bacteria may produce enzymes that alter or inactivate an antibiotic. A common enzyme produced is β-lactamase. β-lactamase can be produced by most Staphylococcus aureus strains and in an increasing number of Gram-negative bacteria. Different β-lactamases affect different antibiotics:

• Common β-lactamases inactivate all penicillins and most early-generation cephalosporins
• Extended-spectrum beta-lactamase (ESBL) can degrade all penicillins and 1st-3rd-generation cephalosporins
• Carbapenemases can degrade carbapenems

Inhibitors of β-lactamase/ β-lactams have been shown to help with resistance, though they do not overcome all resistance.

Production of Efflux Pumps

Efflux pumps aid resistance by pumping antimicrobial agents out of the bacterial cell. Removing the antimicrobial decreases its effectivity as it is less likely to reach its binding site(s), and therefore less likely to cause bactericidal or bacteriostatic effects.

Bacteria such as Pseudomonas aeruginosa and Stenotrophomonas maltophilia have been noted as being able to have more than one efflux system overexpressed simultaneously, increasing resistance to multiple antimicrobials.

Resistance to tetracycline by P. aeruginosa is mediated by largely by efflux pumps situated in the cell membrane – through tetracycline can enter the cell, it is rapidly pumped back out.

Modification of Antibiotic Binding Targets

Antibiotics have specific mechanisms of action and therefore often target one particular part of the bacterial cell. Bacteria may change the target site for the antibiotic, making the bacteria resistant against that antibiotic.

An example is seen in enterococci vancomycin resistance against Linezolids – which primarily target stages within bacterial protein synthesis. Mutations have been identified in the 23S rRNA which decreases Linezolid binding affinity. Similar mutations in 23S rRNA against Linezolids have also been shown in Escherichia coli.

Rifampicin is often used to treat TB, though resistance is reducing its use as a mono-therapeutic drug. The drug targets the β-subunit of RNA polymerase which is encoded by the gene rpoB. In Mycobacterium tuberculosis, the rpoB gene has a very high mutation frequency, resulting in increased Rifampicin resistance.

Reduced Drug Uptake

Reduced uptake (influx) of antimicrobials into the bacterial cell can be caused by mutations in porin molecules (i.e. the sites of entry into the bacteria). In Mycobacterium species antibiotic influx is restricted by the lipid-rich cell wall and the lipid-bilayer which creates a large barrier to antimicrobial entry into the bacterial cell.