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.
Highlights
It is estimated that 23,000 people a year die from infections of antibiotic-resistant bacteria [1]
In our previous work we found that overexpression of galE rescues E. coli growth in the presence of otherwise inhibitory concentrations of ciclopirox and that the deletion of any one of a number of additional genes in the galactose salvage pathway lowers ciclopirox minimum inhibitory concentrations (MICs) [27]
Because GalE is not the direct ciclopirox target [27], we inferred that ciclopirox affects LPS [27] to render bacteria more vulnerable to the availability of sugar monomers provided by the galactose salvage pathway
Summary
It is estimated that 23,000 people a year die from infections of antibiotic-resistant bacteria [1]. According to the Centers for Disease Control and Prevention, Enterobacteriaceae are among. How ciclopirox affects E. coli grant P30AI1036211, respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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