Penicillin, the wonder drug discovered in 1928, works in ways that remain mysterious nearly a century later. One of the more widely used antibiotics, penicillin attacks enzymes that build the bacterial cell wall, a mesh that surrounds the bacterial membrane and gives the cell its integrity and shape. Once those walls are breached, bacteria die—giving our bodies the opportunity to recover from infection.
That would be the end of the story if resistance to penicillin and other antibiotics hadn’t become a serious threat to human health in recent decades. Now, Thomas Bernhardt, an HMS associate professor of microbiology and immunobiology, and his colleagues have added another chapter to the story.
Their findings, published December 4, 2014, in Cell, reveal that penicillin deals bacteria a fatal blow by causing the cells’ wall-building machinery to malfunction. This malfunction dooms the cell to a futile cycle of building and then immediately destroying that wall. This death spiral depletes cells of the resources they need to survive.
There are two parts to the wall-assembly process: synthesizing strands of linked sugars and then linking them into an expanding matrix. Penicillin and other beta-lactam drugs block enzymes that build cross-links, weakening the wall to the degree that the bacterial cell bursts. The researchers wanted to know what happens after blockage of the cross-linking process to promote the death of the bacterial cell.
To answer this, Bernhardt’s team used a derivative of penicillin that targets only one enzyme in cell-wall assembly, and then genetically manipulated a bacterium to make that enzyme nonessential to the cell. To their surprise, the scientists found that targeting the nonessential enzyme with the penicillin still killed the cell. Thus, the enzyme could be removed from a cell without harming it, yet when it was present and bound by the drug, the cell would die.
The investigators found that the drug not only inhibited the enzyme, it also caused it to malfunction. The bacteria made new cell-wall strands, but because linking was blocked, the walls were immediately degraded.
The findings suggest that while a cell has many molecular machines building its wall, antibiotics need to hit some of them to drain resources from the rest.
Image: Nancy Nehring