#Bacterial resistance

#Outline the mechanisms of bacterial antibiotic resistance

#Drug modification

Bacteria produce an enzyme that inactivates the antibiotic.

Examples:

• Some bacteria, including some Escherichia coli and Klebsiella pneumoniae, produce beta-lactamases or extended-spectrum beta lactamases (ESBL) which hydrolyse the beta-lactam ring on beta-lactams antibiotics, inactivating them (enzyme inactivation).
• Common resistance patterns to aminoglycosides in Staphylococcus aureus are via the addition of functional groups to the antibiotic (e.g. acetylation), inhibiting its action (enzyme addition).

#Preventing access to the drug target

#Impermeability

Bacteria decrease the permeability of their cell membrane to an antibiotic.

Examples:

• Beta-lactams gain entry to gram negative cells by diffusing through porin channels in the cell membrane. Mutations in porin genes decrease permeability to beta-lactams.
• Aminoglycosides diffuse through the bacterial cell membrane by oxygen-dependent active transport. Anaerobes lack these transport channels which prevents their penetration.

#Antibiotic efflux

A bacteria ejects the antibiotic via an efflux pump.

Example:

• Doxycycline resistance in E. coli is due to the synthesis of cytoplasmic membrane proteins that pump the tetracyclines out of the cell.

#Modification of cell processes

#Alteration of the drug target

Bacteria alter the target site, decreasing or preventing the antibiotic's affinity for it. Many common and important resistance patterns occur by this method.

Examples:

• MRSA produces an alternative penicillin-binding-protein known as PBP2a, encoded by the mecA gene, which has a lower affinity for beta-lactams.
• VRE alters its peptidoglycan wall precursors from D-Ala-D-Ala to D-Ala-D-Lac by acquisition of the vanA gene, preventing the binding of vancomycin.
• E. coli resistance to trimethoprim is via alteration of the genes that synthesise dihydrofolate reductase, which prevents the binding of trimethoprim.

#Alteration of a metabolic pathway

Bacteria alter their metabolic processes so that the antibiotic is ineffective.

Examples:

• Sulfamethoxazole resistance in Staphylococcus aureus is due to an increased production of para-aminobenzoic acid (PABA), which is used to synthesise folic acid via the enzyme dihydropteroate synthase. Sulfamethoxazole is a competitive antagonist of dihydropteroate synthase which is outcompeted by the increased concentration of PABA, allowing folic acid synthesis to continue.
• Some bacteria have evolved mechanisms such that they do not require PABA for folic acid synthesis at all, which also confers resistance to sulfamethoxazole.

By Husna et al. CC-BY published in Biomedicines

#How is bacterial resistance is spread?

#Spontaneous gene mutation

A spontaneous gene mutation may alter protein synthesis, interfering with the action of an antimicrobial in one of the following ways:

• destruction of an antibiotic
• efflux of the antibiotic out of the bacterium
• preventing the antibiotic from diffusing into the cell (non-permeability)
• alteration of the antibiotic target, preventing it from binding or acting
• changing a metabolic function of the bacterium, such that it interferes with the mechanism of action of the antibiotic

#Host-host spread

A host who is infected or colonised by a resistant organism may transfer these organisms to a new host, for example by respiratory droplets.

#Horizontal gene transfer

All mechanisms of resistance are encoded in a bacterium's DNA. This DNA can be transferred between bacteria, conferring resistance, a process known as horizontal gene transfer.

Horizontal gene transfer occurs via one of three ways:

1. Transduction

• a bacteriophage (virus) infects a resistant bacteria and replicates within it, internalising some bacterial DNA fragments during this process
• the bacteriophage then infects other bacteria, carrying DNA fragments with it which are incorporated into the new bacteria's genome

2. Transformation

• a resistant organism lyses and its DNA is released and taken up by nearby bacteria

3. Conjugation

• plasmids are loops of double-stranded DNA which are independent of the bacterial nucleoid
• they acquire resistant genes which can be transferred to a neighbouring bacteria by cell-cell contact and the formation of a bridge between the bacteria