Sugar and iron: Toward understanding the antibacterial effect of ciclopirox in Escherichia coli

Abstract

New antibiotics are needed against antibiotic-resistant gram-negative bacteria. The repurposed antifungal drug, ciclopirox, equally blocks antibiotic-susceptible or multidrug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates, indicating that it is not affected by existing resistance mechanisms. Toward understanding how ciclopirox blocks growth, we screened E. coli mutant strains and found that disruption of genes encoding products involved in galactose salvage, enterobacterial common antigen synthesis, and transport of the iron binding siderophore, enterobactin, lowered the minimum inhibitory concentration of ciclopirox needed to block growth of the mutant compared to the isogenic parent strain. We found that ciclopirox induced enterobactin production and that this effect is strongly affected by the deletion of the galactose salvage genes encoding UDP-galactose 4-epimerase, galE, or galactose-1-phosphate uridylyltransferase, galT. As disruption of ECA synthesis activates the regulation of capsular synthesis (Rcs) phosphorelay, which inhibits bacterial swarming and promotes biofilm development, we test whether ciclopirox prevents activation of the Rcs pathway. Sub-inhibitory concentrations of ciclopirox increased swarming of the E. coli laboratory K12 strain BW25113 but had widely varying effects on swarming or surface motility of clinical isolate E. coli, A. baumannii, and K. pneumoniae. There was no effect of ciclopirox on biofilm production, suggesting it does not target Rcs. Altogether, our data suggest ciclopirox-mediated alteration of lipopolysaccharides stimulates enterobactin production and affects bacterial swarming.

Structure-based analyses ofSalmonellaRcsB variants unravel new features of the Rcs regulon

“…Moreover, EMSA experiments detected direct binding between phosphorylated RcsB and the promoter or Intra-CDS regions of some differently expressed genes including the fepE gene which is located within a cluster of genes responsible for enterobactin synthesis and transport. This fact has suggested that fepE may possess a potential biological role regulating co-ordinately O antigen chain polymerization and iron transport ( 57 ), indeed, alteration of LPS has shown to stimulate enterobactin production ( 63 ). Interestingly, the Rcs system is involved in production of colanic acid capsule, thus, an interrelation between O antigen polymerization in LPS and colanic acid in the stress response is plausible as denotes the fact that bacteria without O antigen in LPS overproduces colanic acid ( 64 ).…”

Giving Drugs A Second Chance: Antibacterial and Antibiofilm Effects of Ciclopirox and Ribavirin Against Cystic Fibrosis <em>Pseudomonas Aeruginosa</em> Strains

“…Ciclopirox is an off-patent, broad-spectrum antifungal agent used, as an olamine salt, in various formulations to treat superficial fungal infections [17]. It has recently been found to have considerable potential to act against both Gram-positive and Gram-negative bacterial pathogens [18,19]. The synthetic fluorinated pyrimidine 5-fluorocytosine is used as an antimycotic drug with the brand name Ancobon.…”

Associations between sensitivity to antibiotics, disinfectants and heavy metals in natural, clinical and laboratory isolates of Escherichia coli

“…FetA (ybbL), the ATP binding subunit of a putative ABC family iron transporter, was associated with decreased cefotaxime and ciprofloxacin susceptibility (fetA-cefotaxime association by PGLS: beta = 3.487, t 4.814,90 = 4.169, corrected p < 0.05; fetAciprofloxacin association by PGLS: beta = 5.204, t 4.546,90 = 7.285, corrected p < 0.001). It has been previously reported that fetA and fetB, the second component of the iron transport system, play a role in resistance to oxidative stress (Nicolaou et al, 2013) and antibiotics (Conley et al, 2019).…”