Microcosm_ E. Coli and the New Science of Life - Carl Zimmer [56]
When E. coli first encountered antibiotics, its pumps probably did a poor job of getting rid of them. But on rare occasion the genes for the pumps mutated. A mutant microbe might pump out antibiotics a little faster than others. Before modern medicine, such mutants wouldn’t have been any better at reproducing than other bacteria. Their mutations might even have been downright harmful. But once they began to face antibiotics on a regular basis, the mutants had an evolutionary edge.
That edge may have been razor thin at first. Only a few of the resistant mutants might have survived a dose of antibiotics, but that was better than getting exterminated. Over time, resistant mutants became more common in populations of E. coli. Their descendants acquired new mutations that made them even more resistant. In 1986, scientists discovered strains of E. coli that made an enzyme able to destroy a group of antibiotics called aminoglycosides. In 2003, another team discovered E. coli carrying a new version of the gene. It had two new mutations that made it resistant not just to aminoglycosides but also to a completely different antibiotic, called ciprofloxacin.
Even within a single person, E. coli can evolve to dangerous extremes. In August 1990, a nineteen-month-old girl was admitted to an Atlanta hospital with a fever. Doctors discovered that E. coli had infected her blood, probably through an ulcer in her intestines. Tests on the bacteria revealed that they were already resistant to two common antibiotics, ampicillin and cephalosporin. Her doctors gave her other antibiotics, each more potent than the last. Instead of wiping out her E. coli, however, they made it stronger. It acquired new resistance genes, and the ones it already had continued to evolve. After five months and ten different antibiotics, the child died.
Terrifying failures like this one leave scientists hoping that someday they will find new antibiotics that are immune to the evolution of resistance. Like Fleming before them, they find promising new candidates in unexpected places. One particularly promising group of molecules was discovered in 1987 in the skin of a frog.
Michael Zasloff, then a research scientist at the National Institutes of Health, noticed that the frogs he was studying were remarkably resistant to infection. At the time, Zasloff was using frogs’ eggs to study how cells use genes to make proteins. He would cut open African clawed frogs, remove their eggs, stitch them back up, and put them in a tank. Sometimes the water in the tank became murky and putrid, yet his frogs—even with their fresh wounds—did not become infected.
Zasloff suspected the frogs were making some kind of antibiotic. He ground up frog skin for months until he isolated a strange bacteria-killing molecule. It was a short chain of amino acids known as a peptide. He and other researchers discovered that it is fundamentally different from all previously discovered antibiotics. It has a negative charge, which attracts it to the positively charged membranes of bacteria but not to the cells of eukaryotes such as humans. Once the peptide makes contact with the bacteria, it punches a hole in their membranes, allowing their innards to burst out.
Zasloff realized he had stumbled across a huge natural pharmacy. Antimicrobial peptides, it turned out, are made by animals ranging from insects to sharks to humans, and each species may make many kinds. We produce antimicrobial peptides on our skin and in the lining of our guts and lungs. If we lose the ability to make them, we become dangerously vulnerable. Cystic fibrosis may be due in part to mutations that disable genes for antimicrobial peptides produced in the lungs. The lungs become loaded with bacteria and swell with fluid.
Having discovered antimicrobial peptides, Zasloff now tried to turn them into drugs. They might be able to wipe out bacteria that had evolved resistance