A Potential Treatment For CRE?

In my opinion, the greatest infectious disease threat in the U.S. is CRE–Carbapenem Resistant Enterobacteriaceae. These are bacteria, including E. coli and its relatives (such as Klebsiella and Enterobacter), that are resistant to essentially all drugs (colistin can cause massive side effects and resistance evolves rapidly within a patient; tigecycline isn’t that effective against bloodstream infections). It is the proverbial superbug.

Some potentially good news, however, is that a fungicide might also be able to kill these organisms (boldface mine):

Antibiotic-resistant infections caused by gram-negative bacteria are a major healthcare concern. Repurposing drugs circumvents the time and money limitations associated with developing new antimicrobial agents needed to combat these antibiotic-resistant infections. Here we identified the off-patent antifungal agent, ciclopirox, as a candidate to repurpose for antibiotic use. To test the efficacy of ciclopirox against antibiotic-resistant pathogens, we used a curated collection of Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates that are representative of known antibiotic resistance phenotypes. We found that ciclopirox, at 5–15 µg/ml concentrations, inhibited bacterial growth regardless of the antibiotic resistance status. At these same concentrations, ciclopirox reduced growth of Pseudomonas aeruginosa clinical isolates, but some of these pathogens required higher ciclopirox concentrations to completely block growth. To determine how ciclopirox inhibits bacterial growth, we performed an overexpression screen in E. coli. This screen revealed that galE, which encodes UDP-glucose 4-epimerase, rescued bacterial growth at otherwise restrictive ciclopirox concentrations. We found that ciclopirox does not inhibit epimerization of UDP-galactose by purified E. coli GalE; however, ΔgalU, ΔgalE, ΔrfaI, or ΔrfaB mutant strains all have lower ciclopirox minimum inhibitory concentrations than the parent strain. The galU, galE, rfaI, and rfaB genes all encode enzymes that use UDP-galactose or UDP-glucose for galactose metabolism and lipopolysaccharide (LPS) biosynthesis. Indeed, we found that ciclopirox altered LPS composition of an E. coli clinical isolate. Taken together, our data demonstrate that ciclopirox affects galactose metabolism and LPS biosynthesis, two pathways important for bacterial growth and virulence. The lack of any reported fungal resistance to ciclopirox in over twenty years of use in the clinic, its excellent safety profiles, novel target(s), and efficacy, make ciclopirox a promising potential antimicrobial agent to use against multidrug-resistant problematic gram-negative pathogens.

This seems very promising, though we’ll have to see how it does in clinical practice. By the way, it’s a PLoSOne article. Maybe some people shouldn’t be so snooty about that journal? Just saying.

Cited article: Carlson-Banning KM, Chou A, Liu Z, Hamill RJ, Song Y, et al. (2013) Toward Repurposing Ciclopirox as an Antibiotic against Drug-Resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae. PLoS ONE 8(7): e69646. doi:10.1371/journal.pone.0069646

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One Response to A Potential Treatment For CRE?

  1. Pingback: Resist the resistance: A primer on antibiotics and antibiotic resistance | You've Got Some Science On You

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