Forging New Antibiotic Combinations under Iron-Limiting Conditions

Abstract

Pseudomonas aeruginosa is a multidrug-resistant nosocomial pathogen. We showed previously that thiostrepton (TS), a Gram-positive thiopeptide antibiotic, is imported via pyoverdine receptors and synergizes with iron chelator deferasirox (DSX) to inhibit the growth of P. aeruginosa and Acinetobacter baumannii clinical isolates. A small number of P. aeruginosa and A. baumannii isolates were resistant to the combination, prompting us to search for other compounds that could synergize with TS against those strains. From literature surveys, we selected 14 compounds reported to have iron-chelating activity, plus one iron analogue, and tested them for synergy with TS. Doxycycline (DOXY), ciclopirox olamine (CO), tropolone (TRO), clioquinol (CLI), and gallium nitrate (GN) synergized with TS. Individual compounds were bacteriostatic, but the combinations were bactericidal. Our spectrophotometric data and chrome azurol S agar assay confirmed that the chelators potentiate TS activity through iron sequestration rather than through their innate antimicrobial activities. A triple combination of TS plus DSX plus DOXY had the most potent activity against P. aeruginosa and A. baumannii isolates. One P. aeruginosa clinical isolate was resistant to the triple combination but susceptible to a triple combination containing higher concentrations of CLI, CO, or DOXY. All A. baumannii isolates were susceptible to the triple combinations. Our data reveal a diverse set of compounds with dual activity as antibacterial agents and TS adjuvants, allowing combinations to be tailored for resistant clinical isolates.

Pseudomonas aeruginosa FpvB Is a High-Affinity Transporter for Xenosiderophores Ferrichrome and Ferrioxamine B

“…TS exploits the pyoverdine transporters, FpvA and FpvB, while thiocillin uses the ferrioxamine transporter, FoxA ( Fig. 1 ) ( 13 , 14 , 28 ). Here, we further characterized the interaction of TS with the pyoverdine transporters.…”

Antimicrobial activity of clioquinol and nitroxoline: a scoping review

“…Considering in vitro assays, Chan et al ( 2020 ) evaluated the efficacy of the association of clioquinol with thiostrepton, relying on the heavy metal chelating capacity of the first compound to optimize the antibacterial activity of the second compound. According to the researchers, clioquinol, at a concentration of 1 µg/ml, together with thiostrepton, effectively inhibited the growth of A. baumannii .…”

Biofilm-specific uptake of a 4-pyridone-based iron chelator by Pseudomonas aeruginosa

“…Our current research aims to explore the clinical applicability of CP94 further. Also of interest is to investigate whether CP94 could be used in combination with antibiotics, as several other chelator-antibiotic combinations have shown to have antimicrobial synergy (Chan et al 2020 ; Lambert et al 2004 ; van Asbeck et al 1983b ).…”