Connecting iron acquisition and biofilm formation in the ESKAPE pathogens as a strategy for combatting antibiotic resistance

Abstract

Biofilms are linked to resistance development in the ESKAPE pathogens. This perspective summarizes several strategies for affecting iron homeostasis that have been implicated in biofilm inhibition.

Small Molecule Inhibitors of the Bacterioferritin (BfrB)–Ferredoxin (Bfd) Complex Kill Biofilm-Embedded Pseudomonas aeruginosa Cells

“…The field has centered on four major avenues: ( i ) The development of siderophore-antibiotic conjugates aims at capitalizing on siderophore uptake receptors to enhance antibiotic cell penetration. 72 , 73 ( ii ) The sequestration of iron with the aid of chelators is also directed at depleting intracellular iron, and whereas iron chelation has been shown to lead to biofilm dispersion or to prevent biofilm maturation in vitro, 35 , 37 , 48 , 68 , 74 a potential concern is the probability of secondary infections fueled by the chelated iron. 75 , 76 ( iii ) The perturbation of heme uptake or heme degradation aims at denying pathogens from using heme, a rich iron source during infection.…”

“…These studies also showed that the irreversible accumulation of iron in BfrB is accompanied by depletion of free iron in the cytosol. 23 Given that P. aeruginosa requires sufficient environmental and intracellular iron reserves to establish mature biofilms, 34 − 37 we reasoned that the iron deficiency that ensues in the cytosol of the Δ bfd cells might adversely affect biofilm formation. Studies conducted to pursue this idea showed that the Δ bfd cells form poorly developed biofilms and that the biofilm-embedded cells experience cytosolic iron deficiency, even in iron-sufficient culture media.…”

Iron-withdrawing anti-infectives for new host-directed therapies based on iron dependence, the Achilles’ heel of antibiotic-resistant microbes

“…A very important aspect in considering the use of iron withdrawal chelators as alternatives to antibiotics is that these, if Ciprofloxacin and other fluoroquinolone efflux in P. aeruginosa (Lubelski et al 2007;Amaral et al 2014) Yes, iron withdrawal can affect energy production by iron-dependent enzymes and iron insufficiency causes membrane instability (Prasad et al 2006) Physical resistance to antibiotic delivery into microbes Biofilm growth physically protecting microbes within biofilm P. aeruginosa biofilm displays resistance (Gupta et al 2016) Yes, iron withdrawal can suppress biofilm formation and also disrupt established biofilm growth (Post et al 2019) Metabolic mutation; persister cells Slower growth and reduced electron transport reduces antibiotic sensitivity S. aureus small colony variants-hemin/menadione and thymidine auxotrophs display multiple resistance (Proctor et al 1998(Proctor et al , 2014) Yes, deferiprone-Gallium active against S. aureus SCVs, particularly hemin auxotrophs (Richter et al 2017) Fig. 4 Iron chelators suppress infection from both Gram-positive and Gram-negative antibiotic-resistant bacteria.…”

Mobilization of Iron Stored in Bacterioferritin Is Required for Metabolic Homeostasis in Pseudomonas aeruginosa

“…To combat the threat posed by multidrug-resistant organisms, there is an urgent need to discover novel antibiotics and validate new targets in antibacterial research [5][6][7]. A new approach to combat infection currently under investigation is to capitalize on the iron requirement of pathogens for establishing infections [8][9][10][11][12][13][14]. Iron is essential because of its requirements of enzymes mediating respiration, DNA synthesis, amino acid synthesis and many other key metabolic processes [15].…”