We tend to think of bacteria as engaging in chemical warfare only when they attack us, wreaking havoc on our cells. But the microbiome is a vicious place, with many species hurling toxins at each other, attempting to gain a competitive advantage. A bacterium called Bacillus subtilis goes beyond the pale; it contains a set of genes for a "cannibalism system" that it uses to off its close relatives when facing starvation, enabling it to get enough nutrients to form a spore and ride out the lean times. A study that will appear in PNAS describes how a clever experimental approach let them purify one of the cannibalism factors, which turns out to be a potent antibiotic.
Many bacteria form spores when faced with starvation; the spores have tough shells, and the bacteria inside remain inert, needing neither nutrients nor water. Once conditions improve, the spore opens, allowing the bacteria to resume their normal activities. Some of these spores, which have a specialized base and a stalk that extends from it to ensure the spores spread widely, involve an orderly form of suicide. Cells die in the process of forming a stalk so that their neighbors, who are likely to be their close genetic relatives, can survive in the form of spores.
Bacillus subtilis does nothing of the sort, as a single cell can form a perfectly functional spore. But doing so does require nutrients, and the cells typically sporulate (form spores) only when nutrients are limited. So, they've evolved a system to off their neighbors—again, likely to be their close genetic relatives—in order to free up the nutrients needed.
The cannibalism system has been known about for a while, and a few of its components and resistance factors have been identified using genetic mutations. But the factors that mediate the actual killing have been extremely difficult to pin down since the bacteria only make them in small quantities when growing on solid media, and they exist in a complex mixture of other chemicals and metabolites.
To isolate the molecules in question, the authors performed a technique they call imaging mass spectrometry. This involves using standard microscope imaging to figure out where cells were dead or had stopped growing, and then using a technique called mass spectrometry to identify all the molecules present in that area, but absent elsewhere. This enabled the authors to identify two factors, sporulation killing factor (SKF) and sporulation delaying protein (SDP) that could block the growth of Bacillus subtilis and, in some cases, kill them.
The factors themselves are short proteins, one about 25 amino acids long, the other a bit shorter. Both have some rather unusual chemical modifications; the shorter one, for example, ends up as a circular chain of amino acids, rather than a linear one. With the chemicals identified and isolated, the researchers were able to test them on bacteria, and show that SDP is actually a more effective killer, causing major disruptions in the bacterial membrane. Both the chemicals are hydrophobic in nature, suggesting they may end up inserted into the membranes to produce these effects.
Normally, Bacillus subtilis uses SDP on its neighbors, which tend to be other Bacillus subtilis. But there's no reason to think that these chemicals would necessarily be specific to one type of bacteria, so the authors tried it on a number of others. It turned out to kill a number of pathogenic bacteria, including methicillin-resistant S. aureus, better known as MRSA, the multidrug-resistant bacteria. In fact, it was effective down to concentrations similar to vancomycin, a drug known to be effective against MRSA.
Although developing any of these into a drug would be a long process, the authors suggest the general approach—using this technique to snoop on the chemical warfare that occurs at the microbial level—might be generally effective at identifying other naturally occurring antibiotics. Given the rise of drug resistance and the small number of drugs in development, any potential new leads can only be seen as a good thing.
PNAS, 2010. DOI: 10.1073/pnas.1008368107 (About DOIs).
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