Curbing fatty acid production in bacteria lowers antibiotic resistance

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

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

Eric Brown at 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, a last-resort antibiotic that binds to fatty acids in cell membranes in order to infiltrate and kill bacteria.

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

After 18 hours, they measured the efficacy of the treatment by analysing how much the drug pair prevented bacterial growth compared with 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 bacteria resistant to colistin, whereas it was 0.5 or greater for all non-resistant bacteria. This indicates that preventing biotin production increases susceptibility to antibiotics, but only in bacteria resistant to the drugs.

“Biotin, it turns out, is essential in bacteria for one reason, and that’s to serve as a co-factor in fatty acid synthesis,” says Brown.

Genetic analysis revealed that colistin-resistant bacteria have alterations in genes related to fatty acid production. These changes prevent colistin from adhering to cell membranes. As such, impairing 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 prevents fatty acid synthesis or both. Blood samples collected 7 hours later showed mice given both drugs had more than 99.9 per cent fewer bacteria than those in the other groups, indicating the drug pairing overcomes antibiotic resistance.

However, drugs inhibiting fatty acids aren’t currently available for humans. “Certainly, the biggest limitation is that no one can act on this information straight away,” says Brown.

Even so, the findings still offer a new treatment target for antibiotic resistance, and provide clues into how colistin works. “The more we learn about how drugs like colistin work, the better we will be at developing completely new classes of [antibiotics],” says Andrew Edwards at Imperial College London.

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