Forging new antibiotic combinations under iron-limiting conditions

Abstract

ABSTRACTPseudomonas aeruginosais a multidrug-resistant nosocomial pathogen. We showed previously that thiostrepton (TS), a gram-positive thiopeptide antibiotic, was imported via pyoverdine receptors and synergized with iron chelator deferasirox (DSX) to inhibit the growth ofP. aeruginosaandAcinetobacter baumanniiclinical isolates. A small number ofP. aeruginosaandA. baumanniiisolates 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 potentate TS activity through iron sequestration rather than through their innate antimicrobial activities. A triple combination of TS + DSX + DOXY had the most potent activity againstP. aeruginosaandA. baumanniiisolates. OneP. aeruginosaclinical isolate was resistant to the triple combination, but susceptible to a triple combination containing higher concentrations of CLI, CO, or DOXY. AllA. baumanniiisolates 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.