Multidrug tolerance

Not to be confused with multidrug resistance.

Multidrug tolerance or antibiotic tolerance is the ability of a disease-causing microorganism to resist killing by antibiotics or other antimicrobials. It is mechanistically distinct from multidrug resistance: It is not caused by mutant microbes, but rather by microbial cells that exist in a transient, dormant, non-dividing state. Microorganisms that display multidrug tolerance can be bacteria, fungi or parasites.

Relevance to chronic infections

Multidrug tolerance is caused by a small subpopulation of microbial cells termed persisters. Persisters are not mutants, but rather are dormant cells that can survive the antimicrobial treatments that kill the majority of their genetically identical siblings. Persister cells have entered a non- or extremely slow-growing physiological state which makes them insensitive (refractory or tolerant) to the action of antimicrobial drugs. When such persisting microbial cells cannot be eliminated by the immune system, they become a reservoir from which recurrence of infection will develop. Indeed, it appears that persister cells are the main cause for relapsing and chronic infections. Chronic infections can affect people of any age, health, or immune status.

Medical importance

Bacterial multidrug or antibiotic tolerance poses medically important challenges. It is largely responsible for the inability to eradicate bacterial infections with antibiotic treatment. Persister cells are highly enriched in biofilms, and it has been suggested that this is the reason that makes biofilm-related diseases so hard to treat. Examples are chronic infections of implanted medical devices such as catheters and artificial joints, urinary tract infections, middle ear infections and fatal lung disease .

Distinction from multidrug resistance

Unlike resistance, multidrug tolerance is a transient, non-heritable phenotype. Multidrug tolerant persister cells are not antibiotic resistant mutants. Resistance is caused by newly acquired genetic traits (by mutation or horizontal gene transfer) that are heritable and confer the ability to grow at elevated concentrations of antimicrobial drugs. In contrast, multidrug tolerance is caused by a reversible physiological state in a small subpopulation of genetically identical cells, similar to a differentiated cell type. It enables this small subpopulation of microbes to survive the antibiotic killing of their surrounding siblings. Persisting cells resume growth when the antimicrobial agent is removed, and their progeny is sensitive to antimicrobial agents.

Molecular mechanisms

The molecular mechanisms that underlie persister cell formation and multidrug tolerance are largely unknown. Persister cells are thought to arise spontaneously in a growing microbial population by a stochastic genetic switch, although inducible mechanisms of persister cell formation have been described. Owing to their transient nature and relatively low abundance, it is hard to isolate persister cells in sufficient numbers for experimental characterization, and only a few relevant genes have been identified to date. The best-understood persistence factor is the E. coli high persistence gene, commonly abbreviated as hipA.

Potential treatment

In May 2011, it was reported by Nature.com that the addition of certain metabolites can help suppress multidrug tolerance in numerous species of bacteria, including E. coli and S. aureus, by "the generation of a proton-motive force which facilitates aminoglycoside uptake".

See also

• Antibiotic resistance
• Antibiotic sensitivity
• Bacteria
• Biofilm
• Chronic wound
• Dormancy
• Infection
• Infectious Disease
• Multidrug resistance
• Pathogen
• Relapse

External links

• Persister cells and mode of action of HipA