New research by a team of European scientists reveals that combining certain antibiotics, and pairing others with non-antibiotics and even food additives, can make them more effective against gram-negative bacteria.
In study published yesterday in Nature, scientists with the European Molecular Biology Laboratory profiled nearly 3,000 combinations of antibiotics, human-targeted drugs, and food additives in six strains of three gram-negative pathogens—Escherichia coli, Salmonella enterica serovar Typhimurium, and Pseudomonas aeruginosa. They were looking to identify potentially synergistic combinations—in which the effect of an antibiotic was enhanced by pairing it with another drug—that could be further explored in clinical settings. They also wanted to get a better understanding of the underlying principles of drug-drug interactions.
What they found was that, overall, a majority of the interactions were antagonistic, resulting in decreased antibiotic effectiveness against the pathogens. But more than 500 of the combinations were synergistic, and further testing of a handful of these combinations showed that they improved antibiotic effectiveness against clinical samples of multidrug-resistant (MDR) bacteria.
Synergistic pairings are species specific
Most of the synergistic pairings were combinations of antibiotics from the same family, such as different beta-lactam antibiotics, or drugs that targeted the same cellular process. They were also highly species specific, with many of the pairings working synergistically in one of the tested pathogens but not the others. Antagonistic pairings also tended to be species specific.
The authors of the study suggest this discovery has two potential benefits. One is that narrow-spectrum therapies that target specific pathogens, and leave others alone, could be created by pairing synergistic antibiotics. But it also raises the possibility of antagonistic pairings that could help minimize the impact of an antibiotic on the beneficial bacteria in the gut. This side-effect of wide-spectrum antibiotic therapy is a common cause of gastrointestinal problems, including Clostridium difficile infection, in hospital patients.
One of the strongest synergies the scientists discovered was between the last-resort antibiotic colistin and macrolide antibiotics, such as clarithromycin. When tested in vitro against clinical isolates of MDR Klebsiella pneumoniae that was also resistant to colistin, the combination appeared to make the pathogen more sensitive to colistin. A similar effect was seen when the colistin-clarithromycin combination was tested in larvae of the greater wax moth Galleria mellonella infected with MDR K pneumoniae and E coli.
A strong synergy was also observed when the compound vanillin, the primary component of vanilla extract and one of four food additives tested, was combined with aminoglycoside antibiotic spectinomycin, which was developed in 1961 to treat gonorrhea but is now rarely used. Although the researchers found that vanillin antagonized other antibiotics, it enhanced the activity of spectinomycin against MDR E coli, both in vitro and in the wax moth larvae infection model.
"This synergy underlines the importance of exploring the role of food additives in combinatorial therapies," the authors write.
While the synergistic combinations will need to be further tested in mice and in humans, the researchers say many more drug pairs are still to be discovered within their dataset. In addition, they believe the findings indicate that more food additives, along with human-targeted drugs, could be profiled for their potential as antibiotic adjuvants.
Jul 4 Nature abstract