The Story of Zyvox
Steven J. Brickner, Ph.D.
Douglas K. Hutchinson, Ph.D.
Michael R. Barbachyn, Ph.D.
From the hyperbolic – “Superbugs have climbed out of their cage and into hospitals and nursing homes” – to the clinical – “bacteremia caused by MRSA has a poor prognosis,” reports in the late 1990s of the increasing virulence of methicillin-resistant Staphylococcus aureus (MRSA) and the emergence of vancomycin-resistant strains had the public and medical community worried. 1
Make that, very worried. The threat was real, the risks were unimaginable. “This is not the Andromeda strain,” Fred Tenover, Ph.D., of the U.S. Centers for Disease Control and Prevention cautioned, “but it is close to the bug we have been dreading.” 2
New, more powerful antibiotics were still in development, creating a window of opportunity for the bugs to spread and become, aghast, more resistant and lethal. In large city hospitals, MRSA had been on a rampage. From causing 5-10 % of staph infections in the early 1980s, MRSA was responsible for 40 % just a decade later. In other countries as well, prevalence rates had jumped; by the end of the 1990s, Britain reported prevalence rates of 30 %.
The New York Times, nicknamed the Gray Lady for its renowned seriousness, went so far as to predict that “modern medicine might revert to the days before penicillin, when sore throats could become fatal and patients who walked into the hospital for routine surgery might be carried out in coffins.” 3
For millions of people around the world, and their doctors, the discovery of the antibiotic Zyvox® (linezolid) came not a minute too soon. This is no exaggeration, for an estimated two million people, each almost certainly fighting a life- or limb-threatening infection, have been treated with Zyvox since its approval in 2000. In recognition of their contribution to humankind, not to mention their stroke of good timing, Drs. Steven J. Brickner, Michael R. Barbachyn and Douglas K. Hutchinson, the co-inventors of Zyvox, received the 2007 Discoverers Award, the Pharmaceutical Research and Manufacturers of America’s highest scientific honor.
Necessity, the Mother of Zyvox
In reflecting on the discovery of Zyvox, one may be reminded of the old adage, “necessity is the mother of invention.” For its discovery was born out of a determined effort to defeat the superbug MRSA and other pathogenic Gram-positive organisms, as well as provide relief for their vicious infections. It is no coincidence that this year’s winners began their work on Zyvox two decades ago, just after multi-drug resistant infections first emerged as a public health concern.*
The 2007 Discoverers Award winners.
At an international scientific conference held in New York City in 1987, Dr. Steven Brickner, a synthetic organic chemist, listened to a scientist from Dupont describe an extraordinary new class of antibiotics, called oxazolidinones. Wholly synthetic and simple in structure, the two compounds described at the presentation possessed excellent pharmacokinetic properties. Additionally, their unique mechanism of action inhibited Gram-positive bacteria associated with serious infections without demonstrating cross resistance with any known antibiotics; Dupont scientists also were unable to induce resistance in the laboratory.
Brickner was intrigued by the results. He brought to his work a commitment to science and antibiotic research formed by the crucible of personal experience. “When I was in the eighth grade, a serious strep infection turned into Rheumatic Fever, and for one year I was confined to bed,” Brickner said. “Needless to say, I had a lot of time on my hands – during that time I developed a strong interest in chemistry. I learned about it through self-study and soon aspired to become a research scientist.”
Brickner understood the potential of what Dupont had discovered – the antibacterial agents he heard described could be effective against MRSA and other serious bugs – plus the opportunity. Oxazolidinones were an exciting new class of antibiotics, and so far “only one company was trying to bring it to market,” Brickner recalled. “There’s always room for one more.”
Back in Kalamazoo, he set out to find novel oxazolidinone compounds that would be effective. Amazingly enough, this work was done largely on his own time. An Upjohn† policy, unique then as it is now, allowed research scientists to spend 10 % of their time exploring long shots.
|"Physicians are getting an important new weapon in the growing battle against drug-resistant infections: the U.S. government approved a long awaited drug called Zyvox…"
- Health & Medicine Week (2000)
Within months, Brickner and his lab team developed several compounds that were similar in activity to the Dupont compounds. Then they heard through the grapevine that DuPont had terminated their oxazolidinone research program out of frustration with their compounds’ toxicity.
This created a serious dilemma for the Upjohn team: Now they had to produce a compound that was safe. What followed, Brickner said, was “a pivotal point” in the ultimate discovery of Zyvox, as well as an amazing stroke of luck.
A toxicologist at Upjohn named Dr. Richard Piper offered to run 30-day toxicology studies. Like Brickner, Piper would be working on his own time. With DuPont’s experience fresh in his mind and corporate managers looking over his shoulder, Brickner selected what he thought was his best oxazolidinone prospect, called U-82965.
Thirty days later, the results were in – the compound was (relatively) nontoxic!
Even though Dupont soon thereafter acquired a patent on this first lead compound, Brickner’s stroke of luck in 1989 bought him more time – a toxicity result would most likely have ended the project.
More important, he and his lab team had established that a structure toxicity relationship existed for these compounds. This crucial knowledge would help the oxazolidinone team eventually identify 20–25 separate subclasses of oxazolidinones, some of which were found to exhibit good antibacterial activity and encouraging safety profiles.
“Highly unusual” is how Brickner described this phase of the project. “I can’t emphasize enough how many compounds we identified and put through tox studies before any of them were deemed drug candidates.” Then, the Brickner lab made two more crucial findings: first, in an indoline called U-85112, the introduction of a nitrogen atom on the phenyl group, which gave compounds improved safety; and second, the incorporation of a favored side chain, which would later prove useful in the discovery of Upjohn’s first oxazolidinone candidate, eperezolid.
Out of the hundreds of synthesized analogs that possessed promising safety profiles, the team eventually focused on one series, a step which ultimately bore fruit. Ingeniously and fortuitously, the compound that would become known as Zyvox (linezolid) was conceived.
Pioneers of Collaborative Research
A new medicine has been called many things, but rarely a poster drug, one can imagine. But that’s exactly what the Harvard Business Review did last year, when it called Zyvox “the poster drug … for a culture characterized by cross-functional collaboration and speedy execution. Through dialogue, the group created a product that neither the scientists, clinicians, nor marketers acting by themselves could have envisioned or executed.” 4
Integral to that pioneering endeavor were this year’s other winners, Dr. Douglas Hutchinson, whose lab teamed up with Brickner in 1990, and Dr. Michael Barbachyn, whose lab made its entrance a year later. Together, their three labs became the Oxazolidinone Working Group, which was led by Brickner and included a total of nine chemists.
|"An important new weapon in the fight against antibiotic-resistant germs."
- The New York Times (2000)
Their primary mission was to develop a vancomycin equivalent that not only had a different mechanism of action, but also could be taken orally. No oral therapy for MRSA-caused infections or other multi-resistant strains existed, complicating treatment, lengthening hospital stays and increasing risks of re-infection and secondary infections – all of which cost lives and money. As the saying goes, hospitals are no place for sick people.
For Douglas Hutchinson, it can be said with some irony that pharmaceutical research was in his blood.
“My great-grandmother was a strict Christian Scientist and did not believe in medicine at all,” Hutchinson said. “While my grandmother felt the same way, she happened to marry an electrical engineer who had faith in science. She and my grandfather got into quite a row about whether my father would be vaccinated against diphtheria.”
“My grandfather had lost several family members, including a brother, to diphtheria, and he was not going to let my father fall ill when a preventative technology existed.”
“You might say I witnessed the logic of medicine intervening to save members of my family,” Hutchinson explained. “That was a powerful revelation, having grown up around my great-grandmother. She’s probably rolling in her grave, knowing her great-grandson is trying to discover drugs.”
Hutchinson’s role in the discovery of linezolid actually involved a major contribution to the discovery of its precursor, eperezolid. The Hutchinson laboratory’s initial focus was on exploring ways to make structure activity relationship refinements, eventually settling on a piperazine ring. From research on AIDS medicines, Hutchinson was aware of piperazine’s solubility, making it a good candidate for an oral therapy. It was also generally available, so that synthesis and ultimate manufacture was considerably easier.
While his was the third lab in, Michael Barbachyn’s role was no less crucial.
A high school teacher first sparked Barbachyn’s interest in chemistry, and an NSF undergraduate project led him to an interest in pursuing a graduate degree in chemistry and eventually into pharmaceutical research. But what drew him to antibiotic research specifically was its iterative process, which turns scientists into sleuths determined to outfox resistance.
“Bacteria are always developing resistance mechanisms,” Barbachyn said. “It is the constant reinventing, redesigning and readapting of antibacterial agents to address these mechanisms that really intrigues me.”
“Ironically, synthetic organic chemistry is often less science than art. There may be a dozen ways to synthetically make a molecule – that’s where art comes into it. It’s the abstract nature of antibiotic research that was the attraction.”
His most important contribution to the discovery of linezolid, Barbachyn and others agree, was his “realizing the potency, solubility and pharmacokinetic benefits” of incorporating one or two strategically positioned fluorine substituents on the oxazolidinone’s phenyl ring. Fluorination of the phenyl ring is a common structural feature of both eperezolid and linezolid.
In late 1992, the three scientists and their lab teams got together in a room, leaving their egos at the door, and set out to select the compound series with the most promise of becoming a drug candidate. They chose the piperazinyl oxazolidinone series.
“Selected piperazine derivatives exhibited excellent in vitro and in vivo activity while also maintaining an acceptable safety profile, good water solubility, and excellent pharmacokinetic parameters,” Barbachyn and two other colleagues wrote in 2001. “As a bonus the piperazine analogs were also the easiest compounds to synthesize. Because of these and other characteristics the piperazine series became the principal focus of the ongoing chemistry effort.” 5
|"It is a major advance to have this option."
- Dr. George Eliopolous, Beth Israel Medical Center, Boston
Ultimately, this series led to the first Upjohn clinical oxazolidinone, eperezolid.
Hutchinson and his team created a piperazine intermediate that had enormous versatility, creating more chances for the scientists to discover compounds with even more activity, less toxicity and better pharmacokinetic properties.
“There were just a lot of things you could do with the piperazine series,” Hutchinson said. “I guess my process research background came through. I wanted to use some relatively straightforward chemistry and we were ultimately successful. I think that was the most important part of my contribution.”
In a brainstorming session with Brickner and Hutchinson in April 1993, Barbachyn persuaded his colleagues to consider replacing the usual piperazine moiety (found in eperezolid) with a morpholine or thiomorpholine residue. Subsequent testing of these prepared analogs, which included linezolid, confirmed that some of these compounds exhibited activity, solubility, and especially pharmacokinetic performance characteristics meeting many of the team’s criteria. This breakthrough eventually led the team to select the morpholine derivative now known as linezolid for further development. Remarkably, linezolid was synthesized just two days after eperezolid. Two days!
What Zyvox’s Discovery Means
Would Zyvox ever have been discovered in a world without superbugs? Indeed, necessity is the mother of invention, an adage apropos for another reason. Just as the wisdom it conveys has stood the test of time – experts now trace its origin back to Plato’s Republic, the new science, knowledge and medical gains produced by this year’s winners will too stand the test of time.
Of the many important aspects of their achievement, three stand out.
First are the historic dimensions of Zyvox’s discovery. When it was approved in 2000, its active ingredient linezolid was the first member of any entirely new class of antibacterial agents to reach the market in more than 35 years – specifically, the first new antibiotic with a novel mechanism of action since the first quinolone was approved in 1963.
To this day, linezolid remains the only oxazolidinone on the market.
|"The approval of ZYVOX [for pediatric use] is a tremendous advance for the medical community, providing a new, effective and well-tolerated option for infants and children with certain serious infections."
- Sheldon Kaplan, M.D.,
Baylor College of Medicine
Second is its major scientific distinction, namely, its novel mechanism of action. Linezolid works by inhibiting the first step of bacterial protein synthesis, thereby also inhibiting the production of bacterial toxins. Even toxin production in MRSAs that spew up to 40 different toxins is suppressed, Brickner said.
What exactly makes linezolid’s mechanism of action so novel and so effective against multi-resistant bacterial agents?
Antibiotics kill bacteria or prevent their growth by a variety of mechanisms. The most common involve blocking bacterial cell wall synthesis or inhibiting bacterial protein synthesis. … [Being a protein synthesis inhibitor] linezolid binds to the 50S ribosomal subunit, where it blocks the formation of the initiation complex. Without this critical initiation complex, protein synthesis cannot occur, so the bacterial cell cannot carry out essential functions and dies. Most other antibiotics that inhibit protein synthesis act at a much later step … in protein synthesis than does linezolid. This explains why linezolid is unaffected by resistance mechanisms to other protein synthesis inhibitors or bacterial resistance mechanisms in general. 6
In other words, linezolid does not demonstrate cross-resistance with any known antibiotics – including vancomycin; it also has the double benefit of inducing resistance at a very slow rate. (In fact, there have been less than ten cases of MRSA resistance to linezolid.) Specifically, it explains why linezolid is effective against resistant strains of Gram-positive pathogens.
|"Linezolid is the last line of defense against infections by various Gram-positive bacteria…"
- Journal of the American Dental Association (2001)
The Last Line of Defense
When Brickner, Hutchinson, Barbachyn and their teams gave us linezolid, what exactly did we get? In its seventh year on the market, Zyvox has proven to be a major breakthrough in the treatment of some of the most dangerous bacterial infections on the planet. MRSA strains today cause up to 60-70 % of hospital-borne staph infections in the U.S. and Japan, and a more recently emerging superbug, vancomycin-resistant Enterococcus faecium (VRE), is resistant to virtually all known antibiotics.
|"That I was lucky enough to be involved in discovering a drug that has saved so many lives is to this day still a very hard concept to accept."
- Dr. Steven Brickner
In short, it is literally the last line of defense against the superbugs MRSA and VRE. For millions of people, Zyvox has meant the difference between living and dying or keeping a limb and losing one. In measuring any drug’s clinical benefits, it doesn’t get any clearer than this.
There is, though, much more to Zyvox’s place in the antibiotic armamentarium. To be precise, Zyvox is approved for use against serious Gram-positive infections, including those caused by MRSA and VRE. It is used to treat community- and hospital-acquired pneumonia and bloodstream, skin and soft tissue infections, including diabetic foot infections (without concomitant osteomyelitis). Zyvox is the only oral medicine approved for use against hospital-borne infections caused by MRSA and VRE. In fact, its 100 % bioavailability, a rarity in and of itself, simplifies (no dosage adjustment) and hastens the switch from intravenous therapy and lets the patient go home sooner, thereby saving precious healthcare dollars as well as limbs and lives.
|"When I think ‘the drug actually does work,’ it really hits home that Zyvox is helping people. It’s been incredibly rewarding."
- Dr. Michael Barbachyn
Zyvox is also approved for use against Streptococcus pneumoniae. Indeed, it’s the only approved treatment for pneumonia caused by multi-drug resistant S. pneumoniae in the hospital setting.
What Makes Them Winners
Distinguishing this year’s winners is their remarkable dedication – to science, to their research mission and to humankind. When scientists at Dupont were foiled by the toxicity of this new antibiotic, these three scientists sprung into action. Motivating them was the compound series’ promising anti-bacterial activity, as well as their acute awareness of emerging antibiotic resistance.
Undaunted by the odds, they set out to identify the series with the best safety profile. Always the innovators, they employed the then-uncommon strategy of running multiple, early preclinical toxicological evaluations to drive compound selection. Their initial strokes of genius and luck were followed by several years of more hard work in refining the medicinal chemistry insights required to find a potent and well-tolerated antibiotic. Along the way they pioneered what was later to become known as collaborative research.
PhRMA President and CEO Billy Tauzin presents the 2007 Discoverers Award to (from left to right) Douglas K. Hutchinson, Ph.D.; Michael R. Barbachyn, Ph.D.; and Steven J. Brickner, Ph.D.
“Zyvox is truly a unique and important addition to the antibiotic armamentarium,” PhRMA Chairman Kevin Sharer said in March 2007. “Considering the dire and desperate situations in which it’s used, there’s no doubt thousands of lives have been saved, and the suffering of many more relieved.
|"A significant percentage of the 2 million treated with Zyvox have been cured of life-threatening infections. That makes one feel very good at the end of the day."
- Dr. Douglas Hutchinson
“For these reasons alone, this year’s winners deserve our esteem.
“But it’s because of ‘their dedication to improving the quality of life’ – the vision, ingenuity and determination they brought to bear on their research work – that we honor them with the 2007 Discoverers Awards.”
Perhaps Plato was only partly right about the genesis of invention. Surely necessity focuses human endeavors, but desire and brilliance distinguishes inventors from others. Accordingly, the 2007 Discoverers Award honors these indispensable attributes in the inventors of Zyvox.
2007 Clinical Trial Exceptional Service Award
In recognition of the crucial role that clinical research plays in new drug discovery, PhRMA this year established the Clinical Trial Exceptional Service Award, honoring in its first year three individuals who made significant contributions to the development of Zyvox. The recipients – who “were all instrumental in achieving a scientific breakthrough that has literally helped improve the lives of millions of patients worldwide,” PhRMA’s President and CEO Billy Tauzin said – included:
Donald H. Batts, M.D., Professor of Medicine at Michigan State University College of Human Medicine-Kalamazoo Campus, and Sharon Nachman, M.D., Professor of Pediatrics and Division Chief of Pediatric Infectious Diseases, Stony Brook University Medical Center in New York, two researchers who helped make incredible advances in the clinical trials which were critical to Zyvox’s development, and Maryam Imam, an 11-year-old volunteer patient who as an infant participated in compassionate use clinical trials of Zyvox.
PhRMA President and CEO Billy Tauzin presents the 2007 Clinical Trial Exceptional Service Award to (from left to right) Maryam Imam; Sharon Nachman, M.D.; and Donald H. Batts, M.D
The New York Times
To trace the evolution of the new superbugs, experts inevitably look back to the introduction of penicillin in 1943. If ever there was a miracle of modern medicine, it was penicillin, the first drug that could quell a wide range of microbial invaders without harming the body. “It was as if Prometheus had stolen fire from the gods,” Dr. Stuart B. Levy, the Tufts University professor, wrote in his 1992 book The Antiobiotic Paradox.
For its ability to kill bacteria, penicillin was dubbed an “antibiotic.” It was available at first without a prescription, and consumers gobbled it up like candy.
But amid the initial euphoria, penicillin’s discoverer, the British bacteriologist Alexander Fleming, urged caution; in a 1945 interview with The New York Times, Fleming warned that misuse of penicillin could lead to the propagation of mutant forms of bacteria that would resist the new miracle drug. Before long, Levy writes, Fleming’s predictions came true; an estimated 14 percent of the staphylococcus strains isolated from patients in a London hospital had developed resistance to penicillin by 1946, just three years after the miracle drug was introduced.
2 August 1998
* Gram-positive organisms are technically classified as those stained purple when treated with Gram’s stain, in contrast to Gram-negative organisms, which are red stained. A more significant characteristic difference is that Gram-positive bacteria have only one membrane (cytoplasmic), while Gram-negative bacteria have two (a cytoplasmic and an outer) membranes.
† Upjohn was later acquired by Pharmacia, which itself was acquired by Pfizer in 2003.
1Modern Healthcare (16 November 1998); The Lancet (2 August 1997).
2Medical Laboratory Observer (1 January 1998).
3 The New York Times (2 August 1998).
4Ram Charan, “Conquering a Culture of Indecision,” Harvard Business Review (1 January 2006).
5 C.W. Ford, G.E. Zurenko and M.R. Barbachyn, “The Discovery of Linezolid, the First Oxazolidinone Antibacterial Agent,” Infectious Disorders (2001).
6 Chuck Ford, “First of a Kind,” cembytes e-zine (Royal Society of Chemistry, 2001).
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