A new study describes how bacteria use a previously unknown means to defeat
an antibiotic. The researchers found that the bacteria have modified a common “housekeeping” enzyme in a way that enables the enzyme to recognize and disarm
the antibiotic.
The study appears in the Proceedings
of the National Academy of Sciences.
Bacteria often engage in chemical warfare with one another, and many
antibiotics used in medicine are modeled on the weapons they produce. But
microbes also must protect themselves from their own toxins. The defenses they
employ for protection can be acquired by other species, leading to antibiotic
resistance.
The researchers focused on an enzyme, known as MccF, that they knew could
disable a potent “Trojan horse” antibiotic that sneaks into cells disguised as
a tasty protein meal. The bacterial antibiotic, called microcin C7 (McC7) is
similar to a class of drugs used to treat bacterial infections of the skin.
“How Trojan horse antibiotics work is that the antibiotic portion is
coupled to something that’s fairly innocuous—in this case it’s a peptide,”
said University
of Illinois biochemistry
professor Satish Nair, who led the study. “So susceptible bacteria see this
peptide, think of it as food and internalize it.”
The meal comes at a price, however: Once the bacterial enzymes chew up the
amino acid disguise, the liberated antibiotic is free to attack a key component
of protein synthesis in the bacterium, Nair said.
“That is why the organisms that make this thing have to protect
themselves,” he said.
In previous studies, researchers had found the genes that protect some
bacteria from this class of antibiotic toxins, but they didn’t know how they
worked. These genes code for peptidases, which normally chew up proteins
(polypeptides) and lack the ability to recognize anything else.
Before the new study, “it wasn’t clear how a peptidase could destroy an
antibiotic,” Nair said.
To get a fuller picture of the structure of the peptidase, Illinois graduate
student Vinayak Agarwal crystallized MccF while it was bound to other
molecules, including the antibiotic. An analysis of the structure and its
interaction with the antibiotic revealed that MccF looked a lot like other
enzymes in its family, but with a twist—or, rather, a loop. Somehow MccF has
picked up an additional loop of amino acids that it uses to recognize the
antibiotic, rendering it ineffective.
“Now we know that specific amino acid residues in this loop are responsible
for making this from a normal housekeeping gene into something that’s capable
of degrading this class of antibiotics,” Nair said.
With this information, researchers—and eventually, doctors, and other
clinicians—will be able to scan the genomes of disease-causing bacteria to find
out which ones have genes with the antibiotic-resistance loop in them, Nair
said. “If we know what type of bacteria are causing an infection we know what
kind of antibiotic to give and what kind not to give,” he said.
