These events took place sometime around the turn of the century – this century that is. I was working at Wyeth (now part of Pfizer) as their head of anti-infectives. I was and remain passionate about finding solutions to antimicrobial resistance. But back then, the problems were not quite as complicated as they are today.
Wyeth marketed one of the best-selling antibiotics in history, piperacillin-tazobactam. It is a combination of a penicillin derivative with an inhibitor of the major mechanism by which bacteria become resistant to penicillins, an enzyme family called beta-lactamase. The inhibitor protects the penicillin from destruction by these enzymes. As always, bacterial pathogens had their ways of becoming resistant to this combination. They developed enzymes that were unaffected by tazobactam. We at Wyeth wanted to be able to market a successor to piperacillin-tazobactam that would be effective against bacteria carrying tazobactam-resistant enzymes.
The story started with a perusal of the scientific literature and patents. We discovered a compound that had been synthesized by GlaxoSmithKline (GSK) that would fit the bill. It had problems as a drug that we thought we might be able to fix. So our first step was to speak with GSK to see if they would sell us the rights to their compound. With these rights, we could work to improve their compound without having to skirt around all the chemistry they had patented. This would have made our task much more straightforward. Alas, they were dismissive of our idea. First, of course, we were their competitors in the industry. Second, they didn’t think we would be able to improve on their chemistry (let’s call it arrogance).
Not being one to take no for an answer, I huddled with our chemists. That was our first roadblock. Our chemists were just not familiar with these kinds of structures (penems).
At that time, Wyeth had an affiliate in Japan, Wyeth-Lederle Japan. I was obligated to visit them about twice a year. From these visits, I knew that their chemists had extensive knowledge and experience with penem chemistry. I suggested that we ask them if they could come up with a plan to explore the chemistry we needed to start this project.
Next roadblock. Wyeth was planning to close the affiliate in Japan. All those chemists would lose their jobs. I proposed to Wyeth's top management that we keep these chemists (ten of them) employed for one year. That would be enough time for us to know whether we had a successful project or not. To my surprise, they agreed.
The chemists at Wyeth in Pearl River, New York (where I was based) and our Japanese colleagues worked furiously and quickly to develop a plan of attack to improve key properties of the GSK compound without infringing their multiple patents. This resulted in a large number of compounds for testing within the first few months of work. In Pearl River, our scientists tested them against key enzymes that hydrolyze tazobactam. Those that worked were combined with various penicillin-like antibiotics and tested against bacterial pathogens harboring these enzymes. Within less than a year, we had a number of very active compounds in vitro. That is, they worked on enzymes and bacteria in test tubes.
Would these compounds work against infections in living beings? To answer this, we embarked on a testing scheme using mouse models. These models are an excellent way of predicting the activity of antibiotics in people. They also provide an initial view of drug safety in animals. These tests showed that we had four or five compounds that had all the properties we wanted in terms of activity and safety, at least in a preliminary way.
The next step was to convince Wyeth management that we should invest additional funding to scale up synthesis of our two best-performing compounds (one would be a backup just in case) and to proceed with formal safety testing that would allow us to begin clinical trials in human subjects. We arrived at this step in less than one year – a formidable accomplishment that would not have been possible without our Japanese colleagues. Wyeth management understood the potential of this series of compounds to provide a follow-on to their highly successful piperacillin-tazobactam franchise. They quickly agreed to the additional funding we requested.
Producing medicinal chemicals in large quantities involves more than just replicating the methods used to produce a few milligrams for lab testing. It almost always requires new chemical processes. As you might expect, this is another specialty area of medicinal chemistry. And once again, we relied heavily on the expertise of our Japanese chemistry colleagues. They quickly showed that they were up to the task. By our one-year goal line, we had enough of each of our two top compounds to begin the safety testing that would lead to clinical trials in humans.
As is true of most research projects in the pharmaceutical industry, we were unable to proceed further. Our primary compound showed evidence of kidney toxicity in our safety studies and our backup compound was no better. At that point I was unable to convince myself that further efforts by the chemists would be likely to succeed, and our management was certainly not convinced.
On discontinuing our project, most of our Japanese chemist colleagues lost their positions and after another year or so Wyeth Lederle Japan closed its doors. Wyeth in the US abandoned anti-infectives research altogether. The company was later purchased by Pfizer.
For me, this was a bittersweet experience. I am awed by the scientific acumen of researchers in industry. Industry research requires a different approach in many ways than academic research. But the scientists who carry out this work are in no way inferior to their academic counterparts. I will never forget our Japanese colleagues some of whom did not even speak English. Looking back on this story I realize more than ever that the language of science is global and that some of the world’s greatest scientists are not Americans.
