Preventing fatty acid production in bacteria reduces antibiotic resistance

Pairing antibiotics with drugs that block bacteria from making fatty acids may help combat antibiotic resistance. The drug combination was more effective at treating bacterial pneumonia in mice than either antibiotic alone.

Bacteria have been developing resistance to antibiotics since the drugs were developed nearly a century ago. Now, only a small subset of these drugs can treat certain pathogens, and even these are losing their efficacy.

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

In the presence of the drug, colistin-resistant bacteria overproduce a vitamin called biotin. Therefore, the researchers applied both colistin and a compound that inhibits biotin production to the bacteria.

After 18 hours, they measured the efficacy of the treatment by analyzing how much the drug pair inhibited bacterial growth compared to either drug alone. This metric, called the fractional inhibitory concentration (FIC) index, ranges from 0 to 1, with smaller numbers indicating greater efficacy.

The FIC index value was below 0.3 for all five strains of colistin-resistant bacteria, while it was 0.5 or higher for all non-resistant bacteria. This indicates that inhibiting biotin production increases susceptibility to antibiotics, but only in bacteria resistant to the drugs.

“Biotin, it turns out, is essential in bacteria for a reason, and it works as a co-factor in fatty acid synthesis,” says Brown.

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

To test this, the researchers infected 18 mice with colistin-resistant Klebsiella pneumoniae, a bacterium that causes pneumonia. Equal numbers of mice received either colistin, a drug that inhibits fatty acid synthesis, or both. Blood samples collected 7 hours later showed that mice given both drugs had 99.9 percent fewer bacteria than the other groups, indicating that the drug pair overcomes antibiotic resistance.

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

Nevertheless, the findings still provide a new treatment target for antibiotic resistance, and provide clues about how colistin works. “The more we learn about how drugs like colistin work, the better we’ll be able to develop entirely new classes of [antibiotics],” They say Andrew Edwards at Imperial College London.