The emergence of antibiotic resistance is a major public health threat. With the rise of multidrug-resistant (MDR) bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), it is becoming more difficult to find effective drugs to treat bacterial infections, and thus, increasing fatality of such infections.
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Mechanism of resistance includes the acquisition of resistance genes, mutations in genes, and secretion of enzymes degrading the antibiotic.
How did antibiotics resistance occur?
Antibiotics are drugs that target different metabolic pathways of bacteria to either inhibit growth (bacteriostatic) or kill the bacteria (bactericidal). Different classes of antibiotics target different pathways such as protein synthesis, DNA replication, and cell wall synthesis.
With the overuse of antibiotics in clinical and agricultural settings, bacteria are constantly exposed to antibiotics. This puts selective pressure on bacteria to survive antibiotics.
A fraction of bacteria that can resist the effects of antibiotics would survive and multiply, and thus leading to the spread of antibiotics resistant strains and threatening global health.
Another factor giving rise to antibiotics resistance is the lack of new classes of antibiotics. Although much research is carried out in developing new classes of antibiotics, there has been no new approved antibiotics class since the 1980s.
Resistance by changes within the bacteria
Bacteria adopts various strategies such as altering their genomes and acquiring foreign genetic material via horizontal gene transfer (HGT) to confer genetic resistance.
Firstly, by mutations in target genes. In a susceptible population of bacteria, mutations in genes occur randomly. When a mutation allows the bacteria to survive the antibiotic, the population of bacteria carrying the mutated gene survives. These mutations could be modifying the antibiotics target.
This decreases the drug’s affinity to the target and thus decreasing the effectiveness of the drug to inhibit the bacterial target. For example, resistance to the β-lactam drugs is conferred by alterations in the structure of penicillin-binding proteins (PBP).
PBPs are enzymes responsible for constructing cell walls. Changes in PBP structure makes it harder for β-lactam drugs to bind and inhibit cell wall synthesis.
Another mechanism would be to alter gene expression and upregulate drug efflux pumps. There are 5 major families of efflux pumps. These include the major facilitator superfamily (MFS), the small multidrug resistance family (SMR), the resistance-nodulation-cell-division family (RND), the ATP-binding cassette family (ABC), and the multidrug and toxic compound extrusion family (MATE).
They differ in structure, drug substrate, and are distributed in different types of bacteria. For example, the tet genes in Escherichia coli encodes an efflux pump that specifically extrudes tetracyclines, a group of antibiotics that inhibit protein synthesis.
Horizontal gene transfer refers to the acquisition of foreign genetic material via transformation, transposition, and conjugation. It confers resistance as the acquired genetic material may contain genes that influence the effectiveness of the drug.
The acquisition may be temporary or permanent and plasmid-mediated transfer is the most common. For example, the mobilized colistin resistance (mcr) gene is encoded on a plasmid and confers resistance to colistin, one of the last-resort antibiotics.
Mcr encodes a phosphatidylethanolamine transferase that modifies the lipid A components of the cell membrane of Gram-negative bacteria. The altered membrane has a lower affinity for colistin and related polymyxins class of antibiotics.
Resistance by targeting the drug molecule
The antibiotic molecule can be altered chemically or destroyed by bacterial enzymes. Producing enzymes that introduce chemical changes to the drug molecule is a common strategy of Gram-positive and negative bacteria. Many types of modifications have been described, with acetylation, phosphorylation, and adenylation being most common.
This results in steric hindrance that decreases the drug’s affinity to its bacterial target. An example of this is chloramphenicol acetyltransferases (CAT). Cat genes have been found in both Gram-negative and positive species and they confer resistance by adding acetyl groups to chloramphenicol and prevent its binding to ribosomes.
Another class of enzymes produced by bacteria degrades the antibiotics. The most famous example would be β- lactamases, a group of enzymes that degrades β- lactam class of antibiotics.
This class of antibiotics are characterized by the β- lactam ring, which mimics the substrate for cell wall synthesis. β- lactamases destroy the amide bond of the β- lactam ring, making the antibiotic ineffective.
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