The Serratia marcescens Siderophore Serratiochelin Is Necessary for Full Virulence during Bloodstream Infection

Abstract

Serratia marcescens is a bacterium frequently found in the environment, but over the last several decades it has evolved into a concerning clinical pathogen, causing fatal bacteremia. To establish such infections, pathogens require specific nutrients; one very limited but essential nutrient is iron. We sought to characterize the iron acquisition systems in S. marcescens isolate UMH9, which was recovered from a clinical bloodstream infection. Using RNA sequencing (RNA-seq), we identified two predicted siderophore gene clusters (cbs and sch) that were regulated by iron. Mutants were constructed to delete each iron acquisition locus individually and in conjunction, generating both single and double mutants for the putative siderophore systems. Mutants lacking the sch gene cluster lost their iron-chelating ability as quantified by the chrome azurol S (CAS) assay, whereas the cbs mutant retained wild-type activity. Mass spectrometry-based analysis identified the chelating siderophore to be serratiochelin, a siderophore previously identified in Serratia plymuthica. Serratiochelin-producing mutants also displayed a decreased growth rate under iron-limited conditions created by dipyridyl added to LB medium. Additionally, mutants lacking serratiochelin were significantly outcompeted during cochallenge with wild-type UMH9 in the kidneys and spleen after inoculation via the tail vein in a bacteremia mouse model. This result was further confirmed by an independent challenge, suggesting that serratiochelin is required for full S. marcescens pathogenesis in the bloodstream. Nine other clinical isolates have at least 90% protein identity to the UMH9 serratiochelin system; therefore, our results are broadly applicable to emerging clinical isolates of S. marcescens causing bacteremia.

Transporter genes in biosynthetic gene clusters predict metabolite characteristics and siderophore activity

“…Siderophores are both considered critical pathogenicity factors for many humanassociated microbes (Weakland et al 2020) and are also known to facilitate interactions with other microbes and the innate immune system in the human gut microbiome (Behnsen and Raffatellu 2016;Holden et al 2016;Zhu et al 2020;Lam et al 2018). Therefore, being able to annotate genes for the production of siderophores across diverse bacterial species may be critical for understanding the distribution of virulence factors, yet it is difficult to do using traditional annotation pipelines alone.…”

TonB‐dependent transporters in the Bacteroidetes: Unique domain structures and potential functions

“…As homologous transporters have been characterized across Gram‐negative bacteria, it has become clear that these transporters play a large role in transporting many different macromolecules across the outer membrane that are too large to diffuse via porins. Because of this key role in nutrient uptake, TBDTs are often essential for sensing and adapting to environmental signals and are associated with pathogenicity in bacteria such as E. coli, Pseudomonas aeruginosa, and Serratia marcescens , among others (Takase et al., 2000; Torres et al., 2001; Weakland et al., 2020).…”

Prevalence and Characterization of Serratia marcescens Isolated from Clinical Bovine Mastitis Cases in Ningxia Hui Autonomous Region of China

“…The iutA gene encoding the ferric aerobactin receptor involves typical ATP binding cassette (ABC)-type transporters. 54 The ferric uptake transporter encoded by kfu mainly mediates the uptake of ferric iron. 19 Previous study found that the highly virulent strains were more likely to carry the ferric ion carriers.…”