Abstract
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.
Highlights
The World Health Organization lists antibiotic-resistant bacterial infections as an important public health problem [1]
Whereas ciclopirox previously was known to block growth of select gram-negative bacteria, its efficacy had not been tested against antibiotic-resistant bacteria [10,20]
We measured ciclopirox minimum inhibitory concentrations (MICs) for thirty non-clonal E. coli isolated from different patients and that represented the antibiotic resistance phenotypes in the collection
Summary
The World Health Organization lists antibiotic-resistant bacterial infections as an important public health problem [1]. Antibiotic-resistant gram-negative infections will continue to cause serious health problems because few of the antibiotics presently in development are effective against them [4,5]. Most new antibiotics are derivatives of existing drugs and, have bacterial targets already under strong selection to develop resistance. The recent outbreak of carbapenem-resistant Klebsiella pneumoniae at the U.S National Institutes of Health Clinical Center that caused six patient deaths illustrates how quickly these outbreaks spread and that vigilant precautions are needed for containment [6]. Identification of new antimicrobial agents, those that affect novel targets, is needed to provide effective treatment options. Repurposing already approved therapies for alternative uses saves both time and money [7] Already such a strategy was used to find off-patent drugs to repurpose against antibiotic-resistant Acinetobacter baumannii [8]
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