he story begins with a problem - a virulent strain of a drug-resistant bacteria that was imported with the wounded from Afghanistan and spread through the United States. In cancer wards and other places where people with impaired immune systems were treated, this infection caused by the gram-negative bacterium, Acinetobacter baumannii, was particularly dangerous and it evaded the wiles of most known antibiotics. Infections caused by such gram-negative pathogens (Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are major examples) are a major problem in clinics today.
A friend working with cancer patients asked Dr. Lynn Zechiedrich, professor of molecular virology and microbiology at Baylor College of Medicine, and a recognized expert in understanding drug-resistance, to help find a solution. Zechiedrich, over the years, had amassed a huge collection of drug-resistant bacterial specimens. At the same time, Dr. Yongcheng Song, assistant professor in the department of pharmacology at BCM, had developed a new antibiotic with much promise.
Dr. Kimberly M. Carlson-Banning, then a graduate student in Zechiedrich’s laboratory, and with support of colleagues in the lab, merged the collection and the compounds.
Topical antifungal agent
"We have representatives of every antibiotic resistance phenotype we know," said Zechiedrich. When they tested the new compound against these bacteria, it killed them all. However, developing a new antibiotic could take years. Instead, Zechiedrich, Song, and Carlson-Banning came up with a new tactic. Was there an existing drug that resembled Song’s new one? Song looked through the libraries of existing drugs and spotted ciclopirox, an old drug used as a topical antifungal agent.
Carlson-Banning found that ciclopirox indeed inhibited growth of even multidrug-resistant gram-negative bacteria - Acinetobacter baumannii, Escherichia coli and Klebsiella pneumoniae. A report on the research appears online in the journal PLOS ONE. To find out how the drug worked, Carlson-Banning screened its effect in E. coli, a well understood laboratory model bacteria.
Target sugar metabolism
She found that it affected metabolism of a sugar called galactose and the synthesis of lipopolysaccharides, large molecules found in the outer membrane of gram-negative bacteria. This membrane triggers the immediate innate immune response. This mechanism had never been found before, which may explain why, in more than 20 years of clinical use as an antifungal, no resistance developed. New drugs can now be designed to target sugar metabolism.
"What is most exciting is that clinicians can potentially use the drug right now in its topical form," Carlson-Banning said. "There are safety studies done for other formulations,” she said. “However, there are not yet oral or I.V. formulations. I hope our paper will stimulate someone to formulate ciclopirox for internal use."
Others who took part in this work include Drs. Andrew Chou, Zhen Liu and Richard Hamill, all of BCM.
Funding for this work came from the National Institutes of Health Grants R21AI088123, R01AI054830 and T32AI55413). This project was supported in part by facilities and resources of the Michael E. DeBakey VA Medical Center.
Zechiedrich holds the Kyle and Josephine Morrow Chair in Molecular Virology and Microbiology at BCM.