This was, as Zasloff put it later, his “eureka” moment, for even as he asked himself the question, he intuited the answer: the surviving frogs must have generated some substance that afforded them natural antibiotic protection. (Zasloff never did figure out why the dead frogs hadn’t done the same, but he suspected that their immune systems had been too compromised to help save them.) No likely suspects appeared under a microscope, so Zasloff began grinding samples of frog skin and isolating its elements. After two months, he still couldn’t see what he was after. He could identify it, however, by its activity. He was dealing with two kinds of short amino acid chains called peptides—like proteins, but smaller. Scientists knew that peptides participated in many metabolic functions of living organisms, either as hormones or other compounds. They didn’t know what Zasloff had just realized: that some peptides in frogs worked as antibiotics. Zasloff named them magainins—the Hebrew word for “shields”—and theorized that they might lead to a whole new class of human-use antibiotics. So promising was Zasloff’s finding that when it was published a year later, the New York Times devoted an editorial to it, comparing Zasloff to Alexander Fleming, the British discoverer of the antibiotic properties of a fungus called Pencillium. “If only part of their laboratory promise is fulfilled,” the Times opined of his peptides, “Dr. Zasloff will have produced a fine successor to penicillin.”
Like Fleming, Zasloff had made his discovery through serendipity. It was a means about to become quaint. Soon genomics would begin to transform drug discovery into a high-speed, systematic search with state-of-the-art tools that analyzed bacterial DNA—the very antithesis of serendipity. But targeting individual genes, by definition, would yield narrow-spectrum drugs. No doctor wanted to rely exclusively on narrow-spectrum drugs, especially in the hours before a patient’s culture was analyzed at the lab. Besides, a drug designed to hit one bacterial gene might soon provoke a target-changing mutation. Whole new kinds of broad-spectrum antibiotics were needed, too, and the best of those seemed less likely to be found by genomics than by eureka moments like Fleming’s and Zasloff’s, when a different approach presented itself as suddenly and clearly as a door opening into a new room. To date, virtually all antibiotics with any basis in nature had been found in soil bacteria or fungi. The prospect of human antibiotics from an animal substance suggested a very large room indeed.
The world had changed a lot since Fleming had published his observation about a Penicillium fungus, then basically forgot about it for more than a decade. Now biotech venture capitalists scanned the medical journals for finds that might be the next billion-dollar molecule. Zasloff would find himself swept from his NIH lab into the chairmanship of a new public company with Wall Street money and Wall Street expectations, his magainins hyped as the Next New Thing. Nearly $100 million later, he would also be the tragic hero of a cautionary tale about the challenges a maverick faced in bringing new antibiotics to market.
As he monitored their action, Zasloff discovered that the peptides he called magainins act not by targeting a bacterial protein, as nearly all modern antibiotics do, but by punching their way through the bacterial cell’s membrane and forming ion channels that let water and other substances flow in. These, in turn, burst the bacterium. This bursting or lysing occurred because the magainins were positively charged and the bacteria had negatively charged elements called phospholipids on their membrane walls. The positively charged peptides homed in on the negatively charged cell membrane as if piercing an armored shell.
The wall-punching mechanism suggested that peptides might be especially useful against resistant bacteria. The proteins targeted by nearly all existing antibiotics could be changed or replaced. For a bacterium to change its whole membrane would be orders of magnitude more difficult. It seemed impossible. And as far as Zasloff could see, peptides were drawn only to bacterial cell walls—never, in vitro at least, to the membranes of normal human cells. Which made them a perfect antibiotic.