Treatments for Multidrug-Resistant Infections May Be Found in Other FDA-Approved Drugs

Multidrug-resistant pathogens represent a considerable health burden worldwide, leading to thousands of deaths each year. The widespread overuse of antibiotics has contributed to this issue which is compounded by the fact that discovery of novel antibiotics has slowed considerably in recent years. The traditional drug discovery process is not only costly, but also inefficient, and new approaches are needed to identify new antimicrobial compounds. An example of such an approach is to repurpose drugs that are already approved by the Food and Drug Administration (FDA) in new ways.

To this end, a group of investigators led by principal investigator, Ashok Chopra, Csc, PhD, previously identified 3 FDA-approved drugs—doxapram, a breathing stimulant, amoxapine, an anti-depressant, and trifluoperazine, an anti-psychotic—that may be used in other ways. In a study published in Antimicrobial Agents and Chemotherapy, Professor Chopra and his colleagues sought to evaluate the efficacy of these 3 drugs as potential therapeutics against bacterial pathogens. Specifically, the authors used a delayed treatment approach in mouse models of pneumonic as well as bubonic plague, and mice infected with Clostridium difficile spores. In addition, the authors tested the effectiveness of the drugs in combination with antibiotics that are typically used to treat these infections according to current clinical guidelines.

The authors had previously shown that when these drugs are administered following a Yersinia pestis infection in mice, they yielded 40% to 60% protection against pneumonic plague when administered 1-3 days post infection. In the current study, the authors showed that for pneumonic plague, all 3 drugs were effective when administered within 48 hours of infection. The therapeutic window for pneumonic plague is narrow, which hinders treatment leading to significant mortality. Professor Chopra and his colleagues found that the therapeutic window could be extended by using a combination of either trifluoperazine or doxapram with levofloxacin, which has been FDA-approved for the treatment of plague based on animal studies. The results showed that the combination of drugs offered up to 100% protection against pneumonic or bubonic challenge. This finding has the potential to change the way plague is treated.

In addition, the investigators found that the combination of drugs offered protection against other pathogens. For example, the authors write, “all 3 drugs provided 80% to 100% protection from fatal oral Clostridium difficile infection in mice when administered 24 hours post infection. Furthermore, amoxapine provided 40% to 60% protection against respiratory infection with Klebsiella pneumoniae when administered at the time of infection or 24 hours post infection,”

Overall, this work shows that in an animal model, these 3 previously FDA-approved drugs can be repurposed to treat multidrug-resistant infections, either alone or in combination with available antibiotics. This approach could significantly cut down on the cost and time needed to develop new antibiotics, which is critical considering the current antibiotic landscape. However, studies are still needed to assess the effectiveness and safety of these drugs on human subjects, especially since the effect of combining these drugs with antibiotics is unknown.

Samar Mahmoud graduated from Drew University in 2011 with a BA in Biochemistry and Molecular Biology. After two years of working in the industry as a Quality Control Technician for a blood bank, she went back to school and graduated from Montclair State University in 2016 with an MS in Pharmaceutical Biochemistry. She is currently pursuing a PhD in Molecular and Cellular Biology at the University of Massachusetts at Amherst.