Antimycotic Ciclopirox Olamine in the Diabetic Environment Promotes Angiogenesis and Enhances Wound Healing

Ko, Sae Hee; Morrison, Shane D.; Zhou, Hongyan; Zimmermann, Andrew; Gurtner, Geoffrey C.; Ding, Sheng; Longaker, Michael T.

doi:10.1371/journal.pone.0027844

Cited by 26 publications

(24 citation statements)

References 34 publications

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“…Current topical formulations of ciclopirox olamine used to treat fungal skin infections and vaginal candidiasis penetrate deep into the skin and mucosal membranes without causing adverse systemic reactions [10]. It has already been shown that ciclopirox olamine applied topically to wounds induces angiogenesis and promotes faster wound healing [13]. Thus the excellent tolerability of ciclopirox and its unique mode(s) of action make it an attractive antibiotic to treat gram-negative pathogens, including those resistant to current antibiotic therapies.…”

Section: Discussionmentioning

confidence: 99%

“…No fungal resistance has been identified in over twenty years of clinical use [10]. Indeed, others have suggested repurposing ciclopirox as an anti-human immunodeficiency virus drug [11], an agent to protect against mitochondrial damaged cells [12], and a way to enhance diabetic wound healing [13]. Additionally, ciclopirox is currently in a Phase I clinical trial for treatment of multiple myeloma [14], [15].…”

Section: Introductionmentioning

confidence: 99%

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Toward Repurposing Ciclopirox as an Antibiotic against Drug-Resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae

et al. 2013

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Toward Repurposing Ciclopirox as an Antibiotic against Drug-Resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae

et al. 2013

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“…Therefore, ciclopirox may be repurposed as an anti-human immunodeficiency virus drug, 8 a protective agent against mitochondrial cell damage, 9 or a promoter of diabetic wound healing. 10 Very recently, ciclopirox was also suggested as a repurposed bacteriostatic antibiotic for gram-negative bacteria. 11 Ciclopirox affects galactose metabolism and alters the composition of lipopolysaccharide (LPS), 11 a target of polymyxin B.…”

mentioning

confidence: 99%

In vitro evaluation of ciclopirox as an adjuvant for polymyxin B against gram-negative bacteria

Kim

Pan

2015

J Antibiot

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“…This increase in collagen deposition was unexpected, as the prolyl hydroxylase inhibitor CPX is known to cross‐inhibit collagen prolyl hydroxylases, which would predict reduced collagen secretion and deposition . In fact, granulation tissue increase had not been reported upon treatment of diabetic murine wounds with high dose 50 mM of CPX as the sole drug …”

Section: Discussionmentioning

confidence: 99%

Combination of ciclopirox olamine and sphingosine‐1‐phosphate as granulation enhancer in diabetic wounds

Lim

Sham

Chee

et al. 2016

Wound Repair Regeneration

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Granulation tissue formation requires a robust angiogenic response. As granulation tissue develops, collagen fibers are deposited and compacted. Forces generated in the wake of this process drive wound contraction to reduce the wound area. In diabetics, both angiogenesis and wound contraction are diminished leading to impaired wound healing. To emulate this pathology and to address it pharmacologically, we developed a wound healing model in the diabetic Zucker fatty rat and tested a topical proangiogenic strategy combining antifungal agent ciclopirox olamine (CPX) and lysophospholipid sphingosine-1-phosphate (S1P) to promote diabetic wound closure. In vitro, we demonstrated that CPX + S1P up-regulates a crucial driver of angiogenesis, hypoxia-inducible factor-1, in endothelial cells. Injection of CPX + S1P into subcutaneously implanted sponges in experimental rats showed, in an additive manner, a fivefold increased endothelial infiltration and lectin-perfused vessel length. We developed a splinted diabetic rodent model to achieve low wound contraction rates that are characteristic for the healing mode of diabetic ulcers in humans. We discovered specific dorsal sites that allowed for incremental full-thickness excisional wound depths from 1 mm (superficial) to 3 mm (deep). This enabled us to bring down wound contraction from 51% in superficial wounds to 8% in deep wounds. While the effects of topical gel treatment of CPX + S1P were masked by the rodent-characteristic dominant contraction in superficial wounds, they became clearly evident in deep diabetic wounds. Here, a fivefold increase of functional large vessels resulted in accelerated granulation tissue formulation, accompanied by a 40% increase of compacted thick collagen fibers. This was associated with substantially reduced matrix metalloproteinase-3 and -13 expression. These findings translated into a fivefold increase in granulation-driven contraction, promoting diabetic wound closure. With CPX and S1P analogues already in clinical use, their combination presents itself as an attractive proangiogenic treatment to be repurposed for diabetic wound healing.

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Antimycotic Ciclopirox Olamine in the Diabetic Environment Promotes Angiogenesis and Enhances Wound Healing

Cited by 26 publications

References 34 publications

Toward Repurposing Ciclopirox as an Antibiotic against Drug-Resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae

Toward Repurposing Ciclopirox as an Antibiotic against Drug-Resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae

In vitro evaluation of ciclopirox as an adjuvant for polymyxin B against gram-negative bacteria

Combination of ciclopirox olamine and sphingosine‐1‐phosphate as granulation enhancer in diabetic wounds

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