Abstract
Background: Persisters are important reasons for persistent infections, and they can lead to antibiotic treatment failure in patients and consequently chronic infection. Staphylococcus aureus small colony variants (SCVs) have been shown to be related to persistent infection. Mutations in the genes of the heme biosynthesis pathway lead to the formation of SCVs. However, the relationship between heme production genes and persister has not been tested.Methods:HemA and hemB were knocked out by allelic replacement from S. aureus strain USA500 separately, and then, the heme deficiency was complemented by overexpression of related genes and the addition of hemin. The stress-related persister assay was conducted. RNA-sequencing was performed to find genes and pathways involved in heme-related persister formation, and relative genes and operons were further knocked out and overexpressed to confirm their role in each process.Results: We found that heme biosynthesis deficiency can lead to decreased persister. After complementing the corresponding genes or hemin, the persister levels could be restored. RNA-seq on knockout strains showed that various metabolic pathways were influenced, such as energy metabolism, amino acid metabolism, carbohydrate metabolism, and membrane transport. Overexpression of epiF and operon asp23 could restore USA500∆hemA persister formation under acid stress. Knocking out operon arc in USA500∆hemA could further reduce USA500∆hemA persister formation under acid and oxidative stress.Conclusion: Heme synthesis has a role in S. aureus persister formation.
Highlights
Persisters, which were first described in Staphylococcus aureus in 1944 (Bigger, 1944), are of major clinical concern worldwide
We found that heme biosynthesis deficiency can lead to decreased persister
Heme synthesis has a role in S. aureus persister formation
Summary
Persisters, which were first described in Staphylococcus aureus in 1944 (Bigger, 1944), are of major clinical concern worldwide. Staphylococcus aureus, as a commensal pathogen, can cause multiple infections in humans, including cellulitis, endocarditis, osteomyelitis, bacteremia, and septic shock (Harms et al, 2016; Michiels et al, 2016). A reduction in the ATP level induces persister formation, and in the stationary phase, persister formation is associated with a low membrane potential (Wang et al, 2018). These findings provide a link between persisters and respiratory-deficient small colony variants (SCVs). The relationship between heme production genes and persister has not been tested
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
