Unlocking the genetics of antibiotic resistance

In September of 1928 Alexander Fleming made a momentous discovery. Having left a stack of Petri dishes containing Staphylococcus cultures sitting on a bench while he vacationed for a month, the microbiologist returned to find a fungus growing in one of them that was killing the bacteria. Curious, he extracted the substance the fungus was producing, calling it “mold juice,” and found that it killed a number of other pathogenic bacteria as well.

Fleming published his findings in the British Journal of Experimental Pathology, but his attempts to use the substance as an antiseptic proved unsuccessful, and by 1940 he had abandoned the project. But Howard Florey and Ernst Chain, a pair of researchers at Oxford, had read Fleming’s paper. They succeeded in determining the chemical composition of his “mold juice,” isolated it, and scaled up its production.

Fleming, Florey, and Chain had discovered penicillin. In 1945 they shared the Nobel Prize in Medicine for their efforts. The discovery revolutionized modern medicine: many infections that were once almost a certain death sentence were now treatable.

But the widespread use of penicillin inevitably led to the evolution of bacteria that were resistant to it. Fleming himself predicted the likelihood of the rise of antibiotic-resistant organisms soon after winning the Nobel Prize:

“The thoughtless person playing with penicillin treatment is morally responsible for the death of the man who succumbs to infection with the penicillin-resistant organism.” – Arthur Fleming

The resistance to penicillin was countered with the development of new antibiotics, including ampicillin, methicillin, quinolone, and tetracyclines, but bacteria rapidly became resistant to these as well. By 2002, 60% of Staph aureus infections in hospitals were methicillin-resistant. Within a decade, multidrug-resistant strains were proliferating. It seemed the golden age of antibiotics might soon be over.

Now, however, researchers at the University of Birmingham have uncovered clues to the genetic mechanisms that confer multidrug resistance to bacteria. The discovery identified how E. coli uses certain DNA transcription factors to protect itself from some of our most potent antibiotic weapons. The transcription factors are widespread across a large family of organisms called the Enterobacteria, and this discovery may be significant step toward combating multidrug resistance in them.

“By identifying the systems that bacteria use to combat antibiotics we can begin to develop drugs that might inhibit these defense systems,” said David Grainger, the study’s lead author. “Such approaches may extend the useful lifetime of current drugs or allow drugs that are presently useless to become useful.”

In a novel approach, Grainger’s team applied whole genome sequencing to E. coli to determine how the mar (multiple antibiotic resistance) gene works. They were surprised to find two mechanisms of operation.

The gene modulates efflux pump and porin expression via two transcription factors. One of them, MarA, activates the expression of genes that are required for DNA repair and lipid trafficking. In doing so, it confers resistance to two kinds of antibiotics: quinolones and doxycycline. Quinolones interfere with bacterial DNA topology, and doxycycline works by inhibiting bacterial protein synthesis. The mar gene in E. coli reduces damage done to DNA by quinolones and interferes with the ability of doxycycline to pass through the bacteria’s outer membrane.

The mar gene is shared by many other Enterobacteria, and the discovery could provide a blueprint for better understanding antibiotic resistance in similar systems across the Enterobacteria.

I asked Dr. Grainger whether the discovery puts us on the cusp of solving the problem of multidrug resistance.

“I don’t think the issue of antibiotic resistance can ever be ‘solved,'” he said. “Bacteria have a remarkable ability to circumvent any drug that we throw at them; all we can do is hold back the tide. However, with respect to the current antibiotic crisis, I think approaching the problem from many angles is the best option.”

Fleming discovered penicillin in 1928, and quinolones were not invented until the 1960s.  Yet pathogenic bacteria, which had existed for billions of years before the advent of these antibiotics, rapidly evolved to resist them. Why would a gene that conferred resistance to multiple synthetic antibiotics have existed in the wild in the first place?

“Certainly, antibiotics are not a new invention,” said Dr. Grainger. “Many different organisms produce antimicrobial compounds and bacteria have had to defend themselves against these for millennia.”

“Indeed, Alexander Fleming’s famous discovery was the identification of a process that microbes have been using to kill each other long before the human concept of antibiotics,” he said. “It’s another illustration that the microbes have always been one step ahead.”

 


Featured photo credit: Janice Haney Carr, Centers for Disease Control and Prevention, 2006. Escherichia coli bacteria of the strain O157:H7. Link

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