Reducing fatty acid production in bacteria reduces antibiotic resistance

Combining antibiotics with drugs that stop bacteria from producing fatty acids can help fight antibiotic resistance. The drug combination was more effective at treating bacterial pneumonia in mice than antibiotics alone.

Bacteria have developed resistance to antibiotics since drugs were developed about a century ago. Today, only a small subset of these drugs can treat certain pathogens, and even these lose their effectiveness.

Eric Brown of McMaster University in Canada and his colleagues tested a combination of drugs on two different strains of five bacteria. One strain was resistant to colistin, an antibiotic of last resort that binds to fatty acids in cell membranes to infiltrate and kill bacteria.

In the presence of the drug, bacteria resistant to colistin produce more of a vitamin called biotin. So the researchers applied both colistin and a compound that prevents bacteria from producing biotin.

After 6 p.m., they measured the effectiveness of the treatment by analyzing how well the drug pair inhibited bacterial growth compared to either drug alone. This measure, called the fractional inhibitory concentration (FIC) index, ranges from 0 to 1, with smaller numbers indicating greater efficacy.

The value of the FIC index was less than 0.3 for the five strains of bacteria resistant to colistin, whereas it was 0.5 or more for all the non-resistant bacteria. This indicates that preventing biotin production increases antibiotic sensitivity, but only in drug-resistant bacteria.

“It turns out that biotin is essential in bacteria for a reason, and that’s to serve as a cofactor in fatty acid synthesis,” Brown says.

Genetic analysis revealed that bacteria resistant to colistin exhibit alterations in genes related to fatty acid production. These changes prevent colistin from adhering to cell membranes. As such, the impairment of fatty acid production should increase the susceptibility of antibiotic-resistant bacteria to colistin.

To test this, the researchers infected 18 mice with resistant colistin. Klebsiella pneumoniae, a bacterium that causes pneumonia. An equal number of mice received either colistin, a drug that prevents fatty acid synthesis, or both. Blood samples taken 7 hours later showed that the mice given the two drugs had more than 99.9% fewer bacteria than those in the other groups, indicating that the combination of drugs overcomes antibiotic resistance. .

However, fatty acid inhibiting drugs are not currently available for humans. “Certainly the biggest limitation is that no one can immediately act on this information,” Brown says.

Even so, the findings still offer a new treatment target for antibiotic resistance and provide clues to how colistin works. “The more we learn about how drugs like colistin work, the better we can develop entirely new classes of drugs. [antibiotics]says Andrew Edwards of Imperial College London.