“I will forever persist” – the unsaid words of Persister cells

Persister cells are antibiotic tolerant cells which can be identified in almost all phases of bacterial cellular growth with antibiotic tolerance. It holds many unfold mysteries of in biofilm resistance. They are not mutants, rather phenotypic wild type variants and the reduced metabolic rate makes them distinguishable. The extensive research behind the mechanism has identified many persister genes and the reason behind the non-dividing state of these cells. The article here discuss over why persister cells persist any invasion on them.

Before we look into some researches it is better to provide a brief introduction about how persister cells develop. There are two types of persister cells based on the intracellular and environmental stress.

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Type1 and Type2 persister cells (Credit:Microbe Wiki)

Type 1: These cells develop persistence in stationary phase when nutrients are low enough for numerous cell growths. Bacteria are known to sense these stressful conditions and allow them to push some of their population to be dormant, while rest thrive and risk death. These dormant cells are antibiotic tolerant and starve to live without enough nutrition.

Type 2: These cells believed to be evolved from prolonged antibiotic stress and often some stress imposed by prophages. These cells are not triggered by environment and are slow growing.

Why can’t we stop persister cells?

Dr. Kim Lewis from North-Eastern University unleashes a gene which fakes the action of antibiotics to prevent the growth of biofilm. In year 2004, the research published in Journal of Bacteriology explained about HipA gene which generates a toxin named RelE that allows the persister cells to hibernate. As antibiotics must work on metabolically active growing cells hence outlasting the antibiotic activity then repopulates the infection.

A question does arise about how these persister cells maintain their persistence. The answer was revealed in late 2015, a research published in PNAS about a toxin called HigB that able to recognize and rips up RNA to allow growth inhibition function. Although it does not degrade all RNAs equally under stress, it is exquisitely selective. X-ray crystallography studies reveal the exact mechanism how HigB recognizes mRNA and then interacts with ribosomes. The protein was investigated in the bacterium Proteus vulgaris a potent contender of urinary tract infection.

Efforts were done to further understand and visualize the persister mechanism of cells. A year before, i.e. in 2014 researchers from Imperial College of London publishes a research in journal Science , where they describe the mechanism of forming persisters inside macrophages. They fluorescently labelled protein which is produced inside bacterium Salmonella and found that some group of bacteria form persister cells by rendering their growth while remaining follows normal growth. The phenomenon was observed after macrophages engulfed the bacterium. Thus helping bacterium to survive the antibiotics treated.

Door for success behind impossibility

Researchers were almost confused and tried to open doors of possibility to defeat the hidden troops of bacteria called persisters. It was not impossible but to find out a way was difficult. Yet there are some researches which unwrapped the possibilities.

Researchers from Scripps Research Institute, Howard Huges Medical Institute and Albert Einstein College of Medicine of Yeshiva University came up with promising anti-tuberculosis compound which is able to attack both active and dormant Tuberculosis bacterium. After screening diverse library of compounds they found TCA1 capable to kill 99.9% of the activated replicating TB bacterium. But with combination with Isoniazid or Rifampin is 100% effective in any TB bacterium. Positive shade of the experiment was received after thorough experiment over mice and no adverse side effects were found. The research was published in 2013 in PNAS.

In 2015, Northeastern University researchers described a method called pulse dosing. Their findings were published in the journal Nature where they identify toxin-antitoxin gene pairs which maintain the persister cells. These gene pairs encode proteins called HipA (for toxin) and HipB (for antitoxin) where they can regulate each other to module the functioning of the persister mechanism. It is also found that mutation in gene of HipA allow more persisters to form. Researchers came forward with a mechanism called pulse dosing, where antibiotics are provided at intervals. Post antibiotic treatment initially makes the cells to form persister but as they rise up again another antibiotic treatment is followed.

 

There are lot of strategies which have followed by researchers but still there are certain gaps behind understanding the mechanism of persister cells that remain vague. Bacteria always follow a cell to cell communication which allows them to collect nutrients and also response to danger. The collective evolution of genetic makeup that bacteria posses with environmental stress made them to modify. We can say the result of one such type of modification is persister cells. They do not posses antibiotic resistance gene yet they are resistant to antibiotic treatment. They do not grow yet they are alive. Persister cells research is now a rising calamity among microbiologists to identify cure against this evil. Yet it is magical to understand that these tiny creatures developed themselves strategies to escape their eradication.

Further Reading

  1. Northeastern University. “New Study Discovers Why ‘Persister’ Cells Never Say Die.” ScienceDaily. ScienceDaily, 15 December 2004.
  2. Marc A. Schureck, Jack A. Dunkle, Tatsuya Maehigashi, Stacey J. Miles, Christine M. Dunham.Defining the mRNA recognition signature of a bacterial toxin protein. PNAS, 2015.
  3. Helaine, A. M. Cheverton, K. G. Watson, L. M. Faure, S. A. Matthews, D. W. Holden.Internalization of Salmonella by Macrophages Induces Formation of Nonreplicating PersistersScience, 2014; 343 (6167): 204
  4. Feng Wang, Dhinakaran Sambandan, Rajkumar Halder, Jianing Wang, Sarah M. Batt, Brian Weinrick, Insha Ahmad, Pengyu Yang, Yong Zhang, John Kim, Morad Hassani, Stanislav Huszar, Claudia Trefzer, Zhenkun Ma, Takushi Kaneko, Khisi E. Mdluli, Scott Franzblau, Arnab K. Chatterjee, Kai Johnson, Katarina Mikusova, Gurdyal S. Besra, Klaus Fütterer, William R. Jacobs, Jr., and Peter G. Schultz.Identification of a small molecule with activity against drug-resistant and persistent tuberculosisPNAS, 2013
  5. Maria A. Schumacher, Pooja Balani, Jungki Min, Naga Babu Chinnam, Sonja Hansen, Marin Vulić, Kim Lewis, Richard G. Brennan.HipBA–promoter structures reveal the basis of heritable multidrug tolerance. Nature, 2015.

 

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About Saumyadip

Science Communicator and Biologist. Keep interests in host-pathogen interaction research. Specifically bacterial infection mechanism, host infection evasion and immune susceptibility of host. PhD student at Academia Sinica Molecular and Cell Biology, Taiwan
This entry was posted in Molecular Biology and Genetics, Uncategorized and tagged , , . Bookmark the permalink.

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