Multidrug tolerance

Multidrug tolerance

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:[1] 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.

Contents

Relevance to chronic infections

Multidrug tolerance is caused by a small subpopulation of microbial cells termed persisters.[2] 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.[3] Indeed, it appears that persister cells are the main cause for relapsing and chronic infections.[1] Chronic infections can affect people of any age, health, or immune status.

Medical importance

Bacterial multidrug or antibiotic tolerance poses medically important challenges.[1] 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.[1] Examples are chronic infections of implanted medical devices such as catheters and artificial joints, urinary tract infections, middle ear infections and fatal lung disease (cystic fibrosis).

Distinction from multidrug resistance

Unlike resistance, multidrug tolerance is a transient, non-heritable phenotype.[1][2][3] 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,[1][2][3] similar to a differentiated cell type.[4] 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.[1][2][3]

Molecular mechanisms

The molecular mechanisms that underlie persister cell formation and multidrug tolerance are largely unknown.[1][3] Persister cells are thought to arise spontaneously in a growing microbial population by a stochastic genetic switch,[3][5] although inducible mechanisms of persister cell formation have been described.[3][6] 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.[1][3] The best-understood persistence factor is the E. coli high persistence gene, commonly abbreviated as HipA.[7][8]

Potential treatment

In May 2011, it was reported by Nature.com that aminoglycosides 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".[9]

See also

References

  1. ^ a b c d e f g h i Lewis K (2007). "Persister cells, dormancy and infectious disease". Nat Rev Microbiol. 5 (1): 48–56. doi:10.1038/nrmicro1557. PMID 17143318. http://www.nature.com/nrmicro/journal/v5/n1/abs/nrmicro1557.html. 
  2. ^ a b c d Bigger JW (14 October 1944). "Treatment of staphylococcal infections with penicllin by intermittent sterilization". Lancet 244 (6320): 497–500. doi:10.1016/S0140-6736(00)74210-3. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2800%2974210-3/fulltext. 
  3. ^ a b c d e f g h Gefen O, Balaban NQ (July 2009). "The importance of being persistent: heterogeneity of bacterial populations under antibiotic stress". FEMS Microbiol. Rev. 33 (4): 704–17. doi:10.1111/j.1574-6976.2008.00156.x. PMID 19207742. http://www.phys.huji.ac.il/bio_physics/nathalie/GefenFEMS2009.pdf. 
  4. ^ Lopez D, Vlamakis H, Kolter R (January 2009). "Generation of multiple cell types in Bacillus subtilis". FEMS Microbiol Rev 33 (1): 152–63. doi:10.1111/j.1574-6976.2008.00148.x. PMID 19054118. http://www3.interscience.wiley.com/journal/121529639/abstract. 
  5. ^ Jayaraman R (2008). "Bacterial persistence: some new insights into an old phenomenon". J Biosci. 33 (5): 795–805. doi:10.1007/s12038-008-0099-3. PMID 19179767. http://www.ias.ac.in/jbiosci/dec2008/795.pdf. 
  6. ^ Dörr T, Lewis K, Vulic M (2009). Rosenberg, Susan M.. ed. "SOS Response Induces Persistence to Fluoroquinolones in Escherichia coli". PLoS Genet. 5 (12): e1000760. doi:10.1371/journal.pgen.1000760. PMC 2780357. PMID 20011100. http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000760. 
  7. ^ Moyed HS, Bertrand KP (1983). "hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis". J Bacteriol. 155 (2): 768–75. PMC 217749. PMID 6348026. http://jb.asm.org/cgi/reprint/155/2/768. 
  8. ^ Schumacher MA, Piro KM, Xu W, Hansen S, Lewis K, Brennan RG (2009). "Molecular Mechanisms of HipA Mediated Multidrug Tolerance and its Neutralization by HipB". Science 323 (5912): 396–401. doi:10.1126/science.1163806. PMC 2764309. PMID 19150849. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2764309. 
  9. ^ "Metabolite-enabled eradication of bacterial persisters by aminoglycosides". Nature.com. Retrieved May 16, 2011.

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