Insisting on Persisting: a Rare Defense Mechanism Against

Antibiotics

Malini BasuPine Crest School

Significance• 2013: 23,000 deaths due to chronic

bacterial infections

• Number of hospital visits due to reoccurring bacterial infections has doubled in the last 5 years

Significance• Bacterial infections are a global health

concern because of increasing mortality rates

• Bacterial colonies including persister cells are often found in biofilms • Biofilms are often naturally occurring on indwelling medical devices such as catheters and valve replacements

Background• What are persister cells?•Microbial cells•Dormant in the presence of antibiotics•Multidrug tolerancy•Comparison to sensitive cells• Genetically identical

•Rarity: 1 persister in 1 million normal (sensitive) cells• Persisters rare occurrence makes it hard to

perform research on them•Often found in biofilms

Difference between Persisters and sensitive cells

Antibiotic Resistant Cells

Difference between resistant cells and persisters

http://jmm.sgmjournals.org/content/60/6/699/F2.expansion

Background

• Persister Cells• Function: Survival• Can be created from oxidative

stress• Most common bacteria with

persisters• E coli. and Staphylococcus

• Aminoglycosides• Only current treatment for E

coli• Key difference between resistant

cells and persisters

Antibiotics and persisters

• Persister Cells go into a state of dormancy in the presence of antibiotics

• Antibiotics function via the inhibition of important cellular functions such as translation while the cell is growing

• No growth = no affect of antibiotics

Active cell

DORMANT PERSISTER

AMINOGLYCOSIDES• Amino-modified glycoside (sugar)

• Exhibits protein synthesis inhibiting qualities

• Has been proven effective in E Coli Persister Cell eradication

E. Coli Persisters• hipA gene (High Persistence A)•Regulates the function of hipA proteins which can prevent cells from growing•Mutations in hipA gene have shown increased production of Persisters

• hipB proteins bind to hipA and function as a regulator •Lack of hipB leads to free hipA proteins which lead to a greater production of Persisters

Persister cells and cystic fibrosis

• Incurable airway infections in CF patients have been linked to Persister Cells

• A study in CF patients revealed hipA and hipB mutations in bacterial cells of CF infections

Future Research• Other kinds of treatment options•Biofilms on medial devices are located on commonly used prosthetic limbs and other implants

• What allows persisters to act in the way they do•Regardless of being genetically identical to sensitive cells

References • http://www.nature.com/emi/journal/v3/n1/full/emi20143a.html• http://www.nytimes.com/2013/09/17/health/cdc-report-finds-23000-deaths-a-year-from-antibiotic-resistant-infections

.html?_r=0

• Kenn, G. Et al. 2013 Antibiotics: Killing the survivor. Nature, 503, 347-349• Klein, E. Et al. 2007 Hospitalizations and Deaths Caused by methicillin-Resistant Staphylococcus aureus, United

States, 1999-2005 Emerging Infectious Diseases, Volume 13, (Number 12)• Lewis, K. 2010 “Persister Cells and the Paradox of Chronic Infections” [On-Line],

https://www.microbemagazine.org/index.php?option=com_content&view=article&id=2848:persister-cells-and-the-paradox-of-chronic-infections&catid=664&Itemid=882

• https://www.microbemagazine.org/index.php?option=com_content&view=article&id=2848:persister-cells-and-the-paradox-of-chronic-infections&catid=664&Itemid=882

• http://jb.asm.org/content/192/23/6191.full• Persister cells and tolerance to antimicrobials Iris Keren, Niilo Kaldalu, Amy Spoering, Yipeng Wang, Kim Lewis

Department of Biology, Northeastern University, 360 Huntington Avenue, Mugar 405, Boston, MA 02115, USA Received 29August 2003; received in revised form 31 October 2003; accepted 1 November 2003 First published online 28 November 2003

• http://www.nature.com/nrmicro/journal/v5/n1/abs/nrmicro1557.html• http://www.nature.com/nrmicro/journal/v5/n1/full/nrmicro1557.html• https://

www.microbemagazine.org/index.php?option=com_content&view=article&id=2848:persister-cells-and-the-paradox-of-chronic-infections&catid=664&Itemid=882

• http://www.readcube.com/articles/10.1038/nrmicro1557