Mechanisms of resistance

Bacteria can resist antibiotics in multiple ways. Understanding mechanisms of resistance is key to making the best use of existing antibiotics, and designing the next generation of drugs so that resistance evolves less frequently.

Broadly, bacteria resist antibiotics because they can either avoid or destroy them. Avoiding the antibiotic could mean pumping it out of the cell, not taking it up in the first place, or preventing it from reaching its target (through altering or overproducing the target, or making a functional alternative to the target). Destroying the antibiotic means making a specific enzyme that either breaks it down, or modifies it so it is no longer active. The different mechanisms are summarised below.

Summary of AMR mechanisms in bacteria (Click image to enlarge) © Francesca Short 2018

Intrinsic resistance

Resistance to specific antibiotics is a natural characteristic of some bacteria. This is known as intrinsic resistance. Bacteria in nature often produce antibiotics (many of which are the same as the ones used in the clinic) to compete with nearby bacteria – obviously, this is only a good competitive strategy if a bacterium is resistant to the antibiotics it produces! Intrinsic resistance can work in two ways: either the bacterium already has resistance genes in its genome, or it lacks the target of the antibiotic. Intrinsic resistance is one reason why improved diagnostic tests would be so useful – Klebsiella pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosa are responsible for a large proportion of hospital-acquired infections, but each of these species is intrinsically resistant to some antibiotics, making it very difficult to choose the right one.

Missing drug target: Polymyxin and the bacterial outer membrane

All bacterial cells are surrounded by a membrane, that acts as a barrier between the outside of the cell and the inside. Gram-positive bacteria (named after their result in a Gram stain test) have a single cell membrane inside a thick cell wall. Gram-negative bacteria instead have an inner and an outer cell membrane, with a thin cell wall in between them. Polymyxin is an antibiotic that targets both membranes of a Gram-negative bacterium and makes them unstable and leaky, resulting in death of the cell. In Gram-positive bacteria the thick cell wall prevents polymyxin from reaching the cell membrane (and there is no outer membrane), so bacterial species in this category, such as S. aureus are intrinsically resistant to polymyxin.

Efflux pumps

Bacterial efflux pumps are membrane protein complexes which transport molecules from the inside of the cell to the outside. Some of these pumps can transport antibiotics, including those that have entered the cell from the outside. Bacteria with efflux pumps specific to a class of antibiotic will expel these drugs, and therefore be resistant. For example, the bacterium Pseudomonas aeruginosa, which causes chronic infections in cystic fibrosis patients, has high intrinsic resistance to aminoglycoside class antibiotics because it produces two efflux pumps active against this class of drug.

Detoxifying enzymes

Many bacteria produce enzymes that degrade or inactivate specific antibiotics. For example, many bacteria produce beta-lactamase enzymes that break down penicillin-family antibiotics (which contain a beta-lactam ring). Similarly, aminoglycoside antibiotics can be inactivated by enzymes that modify them and prevent them binding to their target.

Intrinsic resistance or acquired resistance?

Efflux pumps, beta-lactamases and aminoglycoside-modifying enzymes can also be acquired by gene transfer from other bacteria (discussed in step 3.10). So, how do we know if resistance to a drug is intrinsic or acquired, when the mechanism of resistance can be the same? Intrinsic resistance normally describes a characteristic that is shared across a whole species or lineage of bacterial strains, and where the relevant genes are stably carried rather than being found on mobile DNA elements such as plasmids. Genomic analysis can give a high resolution picture of the spread and origins of AMR in groups of bacteria.