Dataset Information

Targeting Mobilization of Ferrous Iron in Pseudomonas aeruginosa Infection with an Iron(II)-Caged LpxC Inhibitor.

ABSTRACT: Iron is essential to all life, and competition for this vital nutrient is central to host-pathogen interactions during infection. The opportunistic Gram-negative pathogen Pseudomonas aeruginosa utilizes a diverse array of iron-acquisition strategies, including those enabling import of extracellular ferrous iron. We hypothesize that soluble and redox-active ferrous iron can be employed to activate caged antibiotics at sites of infection in vivo. Here we describe new chemistry that expands the application of our laboratory's Fe2+-activated-prodrug chemistry to cage hydroxamic acids, a class of drugs that present manifold development challenges. We synthesize the caged form of a known LpxC inhibitor and show that it is efficacious in an acute P. aeruginosa mouse-lung infection model, despite showing little activity in cell-culture experiments. Overall, our results are consistent with the Fe2+-promoted uncaging of an antibacterial payload at sites of infection in an animal and lend support to recent reports indicating that extracellular pools of ferrous iron can be utilized by bacterial pathogens like P. aeruginosa during infection.

SUBMITTER: Blank BR

PROVIDER: S-EPMC6880962 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Targeting Mobilization of Ferrous Iron in <i>Pseudomonas aeruginosa</i> Infection with an Iron(II)-Caged LpxC Inhibitor.

Blank Brian R BR Talukder Poulami P Muir Ryan K RK Green Erin R ER Skaar Eric P EP Renslo Adam R AR

ACS infectious diseases 20190611 8

Iron is essential to all life, and competition for this vital nutrient is central to host-pathogen interactions during infection. The opportunistic Gram-negative pathogen <i>Pseudomonas aeruginosa</i> utilizes a diverse array of iron-acquisition strategies, including those enabling import of extracellular ferrous iron. We hypothesize that soluble and redox-active ferrous iron can be employed to activate caged antibiotics at sites of infection in vivo. Here we describe new chemistry that expands ...[more]

PMID: 31140267

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Project description:Lay summaryWe probed the evolutionary robustness of two antivirulence drugs, gallium and flucytosine, targeting the iron-scavenging pyoverdine in the opportunistic pathogen Pseudomonas aeruginosa. Using an experimental evolution approach in human serum, we showed that antivirulence treatments are not evolutionarily robust per se, but vary in their propensity to select for resistance.Background and objectivesTreatments that inhibit the expression or functioning of bacterial virulence factors hold great promise to be both effective and exert weaker selection for resistance than conventional antibiotics. However, the evolutionary robustness argument, based on the idea that antivirulence treatments disarm rather than kill pathogens, is controversial. Here, we probe the evolutionary robustness of two repurposed drugs, gallium and flucytosine, targeting the iron-scavenging pyoverdine of the opportunistic human pathogen Pseudomonas aeruginosa.MethodologyWe subjected replicated cultures of bacteria to two concentrations of each drug for 20 consecutive days in human serum as an ex vivo infection model. We screened evolved populations and clones for resistance phenotypes, including the restoration of growth and pyoverdine production, and the evolution of iron uptake by-passing mechanisms. We whole-genome sequenced evolved clones to identify the genetic basis of resistance.ResultsWe found that mutants resistant against antivirulence treatments readily arose, but their selective spreading varied between treatments. Flucytosine resistance quickly spread in all populations due to disruptive mutations in upp, a gene encoding an enzyme required for flucytosine activation. Conversely, resistance against gallium arose only sporadically, and was based on mutations in transcriptional regulators, upregulating pyocyanin production, a redox-active molecule promoting siderophore-independent iron acquisition. The spread of gallium resistance was presumably hampered because pyocyanin-mediated iron delivery benefits resistant and susceptible cells alike.Conclusions and implicationsOur work highlights that antivirulence treatments are not evolutionarily robust per se. Instead, evolutionary robustness is a relative measure, with specific treatments occupying different positions on a continuous scale.

Dataset Information

Targeting Mobilization of Ferrous Iron in Pseudomonas aeruginosa Infection with an Iron(II)-Caged LpxC Inhibitor.

Publications

Targeting Mobilization of Ferrous Iron in <i>Pseudomonas aeruginosa</i> Infection with an Iron(II)-Caged LpxC Inhibitor.

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