Loss of a pyoverdine secondary receptor in Pseudomonas aeruginosa results in a fitter strain suitable for population invasion

Abstract

The rapid emergence of antibiotic resistant bacterial pathogens constitutes a critical problem in healthcare and requires the development of novel treatments. Potential strategies include the exploitation of microbial social interactions based on public goods, which are produced at a fitness cost by cooperative microorganisms, but can be exploited by cheaters that do not produce these goods. Cheater invasion has been proposed as a 'Trojan horse' approach to infiltrate pathogen populations with strains deploying built-in weaknesses (e.g. sensitiveness to antibiotics). However, previous attempts have been often unsuccessful because population invasion by cheaters was prevented by various mechanisms including the presence of spatial structure (e.g. growth in biofilms), which limits the diffusion and exploitation of public goods.Here we followed an alternative approach and examined whether the manipulation of public good uptake and not its production could result in potential 'Trojan horses' suitable for population invasion. We focused on the siderophore pyoverdine produced by the human pathogen Pseudomonas aeruginosa MPAO1 and manipulated its uptake by deleting and/or overexpressing the pyoverdine primary (FpvA) and secondary (FpvB) receptors. We found that receptor synthesis feeds back on pyoverdine production and uptake rates, which led to strains with altered pyoverdine-associated costs and benefits. Moreover, we found that the receptor FpvB was advantageous under iron-limited conditions but revealed hidden costs in the presence of an antibiotic stressor (gentamicin). As a consequence, FpvB mutants became the fittest strain under gentamicin exposure, displacing the wildtype in liquid cultures, and in biofilms and during infections of the wax moth larvae Galleria mellonella, which both represent structured environments. Our findings reveal that an evolutionary trade-off associated with the costs and benefits of a versatile pyoverdine uptake strategy can be harnessed for devising a Trojan horse candidate for medical interventions.

Local adaptation, geographical distance and phylogenetic relatedness: Assessing the drivers of siderophore‐mediated social interactions in natural bacterial communities

“…Our interpretations are supported by molecular studies on the laboratory strains P. aeruginosa PAO1 (González et al, 2021) and P. protegens Pf-5 (Sexton et al, 2017), which revealed that cognate receptors are preferred over noncognate receptors and that noncognate receptors are conditionally expressed upon sensing of a heterologous pyoverdine. How this sensing exactly works is unclear, but it comes with a time delay (Sexton et al, 2017), probably further reducing the iron-uptake efficiency of noncognate relative to cognate receptors.…”

“…Our interpretations are supported by molecular studies on the laboratory strains P . aeruginosa PAO1 (González et al., 2021 ) and P . protegens Pf‐5 (Sexton et al., 2017 ), which revealed that cognate receptors are preferred over noncognate receptors and that noncognate receptors are conditionally expressed upon sensing of a heterologous pyoverdine.…”

Pseudomonas aeruginosa FpvB is a high-affinity transporter for xenosiderophores ferrichrome and ferrioxamine B

“…Supporting this finding, we previously identified a TS-resistant but thiocillin-sensitive clinical isolate, C0379, missing ~800 bp from the 5' region of fpvB, suggesting that it may have once produced functional FpvB (Ranieri et al, 2019). ∆fpvB mutants are also fitter than WT cells when treated with the antibiotic gentamicin (González et al, 2021). Its absence may reduce the metabolic burden on cells living in stressful environments whether due to nutrient limitation or antibiotic stress.…”

Novel Insights on Pyoverdine: From Biosynthesis to Biotechnological Application

“…A different type of “Trojan horse” approach is represented by the “cheater invasion”, in which MDR pathogen populations were infiltrated by strains with built-in weaknesses ( Figure 2 ). For example, recently, antibiotic-resistant P. aeruginosa strains were replaced by the antibiotic-sensitive P. aeruginosa PAO1; this result was achieved by deleting its FpvB PVD receptor, which gives them a selective advantage [ 133 ].…”