Navigation Links
Scientists discover new, noncommittal mechanism of drug resistance

DURHAM, N.C. -- Microorganisms like bacteria and fungi can evade treatment by acquiring mutations in the genes targeted by antibiotics or antifungal drugs. These permanent mutations were once thought to be the only way for drug-resistant strains to evolve. Now a new study has shown that microorganisms can use a temporary silencing of drug targets -- known as epimutations -- to gain the benefits of drug resistance without the commitment.

Though the new mechanism was discovered in a fungus called Mucor circinelloides, it is likely to be employed by other fungi as well as bacteria, viruses and other organisms to withstand treatment with various drugs. The finding appears July 27, 2014, in Nature.

"This mechanism gives the organism more flexibility," said Joseph Heitman, M.D., Ph.D., senior study author and professor and chair of molecular genetics and microbiology at Duke University School of Medicine. "A classic, Mendelian mutation is a more permanent binding decision, like a traditional marriage. These epimutations are reversible, more akin to moving in together. If conditions change, it is easier to revert to the way things were."

The epimutations are so transient, in fact, that the researchers almost disregarded them. Cecelia Wall, a graduate student in Drs. Heitman and Maria Cardenas' labs, had been looking for mutations that would make the human fungal pathogen M. circinelloides resistant to the antifungal drug FK506 (also known as tacrolimus). This pathogen causes the rare but lethal fungal infection mucormycosis, an emerging infectious disease that predominantly affects individuals with weakened immune systems.

As is typical for most drug resistance experiments, Wall first grew the pathogen in Petri dishes containing the antifungal drug. She found that the few organisms that survived treatment looked different, being smaller and less diffuse than their parent fungi. Wall then isolated those fungi and sequenced the gene FKBP12 -- the target of FK506 -- to look for mutations that would confer drug resistance.

However, she couldn't detect any mutations in about a third of the isolates. What's more, Wall found that many of the mutants kept "disappearing," looking less like mutants and more like their parents after she took the drug away.

"This is an example of something you might find in the laboratory and just throw away," said Silvia Calo, Ph.D., lead study author and postdoctoral fellow in the Heitman and Cardenas labs. "You look for mutants in one gene and when you don't find a mutation in some of the isolates, you decide not to work on those anymore and instead focus on others. But we wanted to know what was going on."

The researchers began to wonder whether a phenomenon known as RNA interference or RNAi could be the cause of this unstable drug resistance. RNAi uses bits of RNA -- the chemical cousin of DNA -- to silence specific genes. Though RNAi doesn't exist in every organism, the researchers knew it was active in M. circinelloides because of the pioneering work of their collaborators Rosa Ruiz-Vazquez and Santiago Torres-Martinez, with whom Calo trained at the University of Murcia, Spain.

So Calo looked for the presence of small RNAs -- a signature of RNAi -- in the drug resistant isolates. She didn't find small RNAs in the isolates that contained mutations in FKBP12, but she did find them in those lacking mutations. Importantly, Calo found that these small RNAs only silenced the FKBP12 gene and not any other loci in the genome. The results demonstrate that M. circinelloides can develop drug resistance two different ways, either stably through permanent mutations or transiently through reversible epimutations.

"This plasticity enables an organism to reverse epigenetic mutations when selective pressures are relaxed," said Calo. "Otherwise, silencing a gene when it doesn't need to be silenced would be a waste of energy."

The researchers think these epimutations could be employed in a variety of situations, enabling an organism to adapt to an unfavorable environment and then adapt again when conditions improve. Though they have only shown epimutations in two species of M. circinelloides, they have already been approached by a number of other researchers who are interested in investigating similar unstable behavior in other organisms like Aspergillus and Neurospora.

"It could be like the discovery of other molecular phenomena like introns or microRNAs, where it all began with just one example," said Heitman. "We think this discovery may turn out to be generalized fairly quickly."


Contact: David Jarmul
Duke University

Related biology news :

1. New tools help neuroscientists analyze big data
2. NIH scientists find 6 new genetic risk factors for Parkinsons
3. NYSCF scientists one step closer to cell therapy for multiple sclerosis patients
4. NYSCF scientists 1 step closer to cell therapy for multiple sclerosis patients
5. NUS scientists use low cost technique to improve properties and functions of nanomaterials
6. Mount Sinai scientists and international team shed new light on schizophrenia
7. Scientists successfully generate human platelets using next-generation bioreactor
8. Scientists map one of most important proteins in life -- and cancer
9. Speedy computation enables scientists to reconstruct an animals development cell by cell
10. Singapore scientists discover genetic cause of common breast tumours in women
11. Scientists enlist big data to guide conservation efforts
Post Your Comments:
Related Image:
Scientists discover new, noncommittal mechanism of drug resistance
(Date:11/12/2015)... 11, 2015   Growing need for low-cost, ... has been paving the way for use of ... discrete analytes in clinical, agricultural, environmental, food and ... used in medical applications, however, their adoption is ... to continuous emphasis on improving product quality and ...
(Date:11/10/2015)... 2015 About signature verification ... to identify and verify the identity of an ... the secure and accurate method of authentication and ... individual because each individual,s signature is highly unique. ... dynamic signature of an individual is compared and ...
(Date:11/4/2015)... 2015 --> ... by Transparency Market Research "Home Security Solutions Market - Global ... - 2022", the global home security solutions market is expected to ... The market is estimated to expand at a CAGR ... 2022. Rising security needs among customers at homes, the ...
Breaking Biology News(10 mins):
(Date:11/24/2015)... ... November 24, 2015 , ... Creation Technologies ... being named to Deloitte's 2015 Technology Fast 500 list of the fastest growing ... a FDA-cleared, Class II medical device that speeds up orthodontic tooth movement by ...
(Date:11/24/2015)... , Nov. 24, 2015 Capricor ... company focused on the discovery, development and commercialization of ... Ph.D., Chief Executive Officer, is scheduled to present at ... 2015 at 10:50 a.m. EST, at The Lotte New ... . . --> ...
(Date:11/24/2015)... -- PDL BioPharma, Inc. (PDL) (NASDAQ: PDLI ) today announced ... chief executive officer, will present at the 27 th ... New York City . The presentation will be webcast ... 9:30 a.m. EST. and go to ... 15 minutes prior to the presentation to allow for any ...
(Date:11/24/2015)... ... ... Laboratories is pleased to announce that it has completed construction on a new ... 61, USP 62 and USP 51 testing specific to raw materials and will enable ... by one supplier. Management has formally announced that the facility will be ...
Breaking Biology Technology: