Synergy Between Antibiotics and Nonantibiotic Drugs

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Antibiotic resistance is an ever-growing clinical problem. Four years ago, a study found that antibiotics are overprescribed for sinus infections. Compounding the issue is the fact that as bacteria are learning to tolerate and even circumvent existing classes of antibiotics, not enough work is being done to discover new ones. Combinations or cocktails of antibiotics are often used to broaden the antimicrobial spectrum of each and to achieve synergistic effects; this approach has successfully been applied to combat tuberculosis, leprosy, malaria, and famously, HIV. Yet the discovery of effective combinations has usually been almost fortuitous, most often resulting from trial and error rather than a systematic analysis.

In the current study, researchers systematically examined combinations of 1,057 compounds previously approved as drugs to find those that exhibited synergy with the antibiotic minocycline. Their work is reported in the April 24, 2011 issue of the journal Nature Chemical Biology [1]. The compounds were chosen because they have already been approved as drugs, they are known to have activity in vivo and are known to be relatively safe. Many approved drugs are known to have utility for clinical indications other than those for which they initially received approval. Moreover, using pre-approved compounds also reduces the time and cost associated with developing new compounds for therapeutic use.

The compounds were combined with half of the minimal inhibitory concentration of minocycline and then applied to three strains of bacteria: two pathogens resistant to minocycline, Pseudomanas aeruginosa and Staphylococcus aureus, as well as Escheria coli. About half of the compounds that initially synergized with minocycline were other antibiotics, and thus were not interesting to these researchers — they were looking for new types of chemicals, against which bacteria would not know how to fight. After those were eliminated, there were 69 nonantibiotic compounds, never before used clinically to treat bacterial infection, found to synergize with minocycline.

Disulfiram, a drug used to treat alcoholism, had only weak antibiotic activity against S. aureus when used alone, but strongly synergized with minocycline to inhibit growth of S. aureus — even some strains of MRSA (methicillin-resistant staphylococcus aureus). Six compounds synergized with minocycline to inhibit the growth of P. aeruginosa, and they were initially approved for very different uses: (1) loperamide, known more commonly by its trade name, Imodium, is used to treat diarrhea; (2) mitomycin C is a chemotherapeutic agent; (3) vitamin C; (4) benserazide is used to treat Parkinson’s disease; (5) tegaserod is used to treat irritable bowel syndrome; and (6) chloroxine is used to treat dandruff. As with S. aureus, multidrug resistant versions of P. aeruginosa were also susceptible to combinations of these compounds with minocycline.

Loperamide was a particularly interesting case. It also synergized with eight other tetracycline antibiotics, those in the same class as minocycline. These antibiotics work by inhibiting protein synthesis in bacteria. Since loperamide has no antibacterial activity when used alone, the researchers delved into figuring out how the synergy might work. They found that loperamide increased the permeability of the bacteria’s outer membrane, which enhances the bug’s uptake of tetracyclines. When the tetracyclines then inhibit the synthesis of outer membrane proteins, this then enhances loperamide’s effects in what’s called a “positive feedback loop”.

A challenge in finding effective drug concentrations is that the drugs need to be be able to get where they are needed in tandem. Fortunately, loperamide and minocycline can bothe be taken orally. The researchers thus used a mouse model to confirm what they had found when the combination was applied to bacteria growing in petri dishes. Salmonella enterica is a pathogen that resides in the intestine. The combination of loperamide and minocycline decreased the number of bacteria in these mice as much as a million times, but each agent alone had no effect.

The scientists also collected data suggesting that different combinations might be used to specifically target different species of bacteria. This newly found synergy, especially that against multidrug resistant strains of bacteria, will hopefully buy humanity a little more time in our ongoing battle with microbial pathogens.

References

1. Ejim et al. Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol. 2011 Apr 24. [Epub ahead of print]
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