Since Alexander Fleming discovered penicillin in 1940, countless lives have been saved by antibiotics. But their effectiveness is severely compromised by the emergence of antibiotic resistant strains of bacteria, accelerated by the over-prescription of antibiotics and their widespread use as growth promoters in livestock farming.
With the failure of these drugs, routine procedures that depend on antibiotics – like hip replacements, cesareans, and organ transplants – may one day become too risky to perform.
The problem of antibiotic resistance and how research may help keep drugs effective was the topic of this year’s Byers Award Lecture in Basic Science, given by Danica Galonić Fujimori, PhD. Her Jan. 31 talk was titled “Unlocking the Mystery of Antibiotic Resistance.”
The Byers Award in Basic Science is awarded annually to recognize and support the outstanding research of a mid-career faculty member. Fujimori is an associate professor of cellular and molecular pharmacology and leads a group studying how bacteria acquire antibiotic resistance.
The Antibiotic Crisis
An estimated 2 million drug-resistant infections occur a year in the U.S., resulting in 23,000 deaths annually, according to the Centers for Disease Control and Prevention. Nearly as quickly as new antibiotics are introduced these days, resistant strains of bacteria emerge.
Antibiotics work by targeting some essential function of bacteria, such as the building of cell walls, synthesis of DNA or synthesis of proteins.
Fujimori’s work has focused on antibiotics that target the bacterial ribosome, an essential protein synthesis machine. These drugs destroy bacteria by binding to sites on their ribosomes, such as the peptidyl transferase center, to block protein biosynthesis.
Linezolid is one antibiotic that works this way. It is a “reserve antibiotic” used against superbugs when other treatments fail. But within a year of Linezolid’s introduction in 2000, resistant strains were already documented.
Goldilocks Zone of Methylation
In the arms race between bacteria and antibiotics, bacteria have evolved ways to modify the ribosome to prevent binding by the antibiotic. A common form of modification is changing the methylation of the binding site. Fujimori’s group has found that many antibiotics work only in a “Goldilocks zone” where the methylation is “just right,” and bacteria that increase or decrease methylation can gain resistance.
For instance, an enzyme called Cfr is known to introduce hypermethylation, adding methyl groups that protrude into the binding site and prevent access by antibiotics. Bacteria with Cfr resistance are immune to even reserve antibiotics like linezolid.
Other bacteria may develop resistance by stripping down ribosome methylation. A loss-of-function mutation in the RlmN enzyme leads to a complete lack of methylation that also prevents antibiotics from binding effectively.
Solutions from Basic Science
The understanding of how too much and too little methylation confers antibiotic resistance might help researchers design better antibiotics in the future. One option, suggested Fujimori, would be to develop an inhibitor against the Cfr enzyme that can be given alongside antibiotics.
“Basic science is what allows us to unlock the basic underpinnings of life itself,” said Sam Hawgood, MBBS, UCSF chancellor and the Arthur and Toni Rembe Rock Distinguished Professor, in his opening remarks. “And it’s also the platform on which we build our attack on the biggest health challenges of our time.”
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