Naturally occurring polymorphisms in the virulence regulator Rsp modulate Staphylococcus aureus survival in blood and antibiotic susceptibility

Krishna, Aishwarya; Holden, Matthew T. G.; Peacock, Sharon J.; Edwards, Andrew M.; Wigneshweraraj, Sivaramesh

doi:10.1099/mic.0.000695

Cited by 10 publications

(12 citation statements)

References 49 publications

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“…We exposed ~10 8 c.f.u. ml −1 S. aureus from early stationary phase cultures (when σB is maximally active) to antibiotics at a concentration that was 10× the MIC of the wild-type, and measured survival over time as described previously [52,53].…”

Section: Accessmentioning

confidence: 99%

“…We then proceeded to assess the impact of σB on antibiotic susceptibility by measuring the MIC of various classes of clinically relevant antibiotics for the wild-type, mutant and complemented strains as described previously [51][52][53]. For gentamicin, ciprofloxacin, vancomycin, clindamycin and oxacillin, MIC values were the same for all strains, regardless of whether they expressed σB or not (Table 1).…”

Section: Accessmentioning

confidence: 99%

“…Next, we assessed the impact of σB on antibiotic tolerance by measuring the susceptibility of S. aureus to the bactericidal activity of the antibiotic panel over time [52,53]. We exposed ~10 8 c.f.u.…”

Section: Accessmentioning

confidence: 99%

“…In addition to antibiotics, the other key threat to the survival of pathogens is the host immune system. Therefore, we next examined the role of σB in the survival of S. aureus in whole human blood, which contains a high concentration of neutrophils that are crucial in the defence against S. aureus [16,17,53,56]. Previous work from our group and others using similar models have shown that >95 % of S. aureus cells are phagocytosed within 5 min by neutrophils and targeted by the oxidative burst [16,56].…”

Section: Accessmentioning

confidence: 99%

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The general stress response of Staphylococcus aureus promotes tolerance of antibiotics and survival in whole human blood

2020

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Staphylococcus aureus is a frequent cause of invasive human infections such as bacteraemia and infective endocarditis. These infections frequently relapse or become chronic, suggesting that the pathogen has mechanisms to tolerate the twin threats of therapeutic antibiotics and host immunity. The general stress response of S. aureus is regulated by the alternative sigma factor B (σB) and provides protection from multiple stresses including oxidative, acidic and heat. σB also contributes to virulence, intracellular persistence and chronic infection. However, the protective effect of σB on bacterial survival during exposure to antibiotics or host immune defences is poorly characterized. We found that σB promotes the survival of S. aureus exposed to the antibiotics gentamicin, ciprofloxacin, vancomycin and daptomycin, but not oxacillin or clindamycin. We also found that σB promoted staphylococcal survival in whole human blood, most likely via its contribution to oxidative stress resistance. Therefore, we conclude that the general stress response of S. aureus may contribute to the development of chronic infection by conferring tolerance to both antibiotics and host immune defences.

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Section: Accessmentioning

confidence: 99%

Section: Accessmentioning

confidence: 99%

Section: Accessmentioning

confidence: 99%

Section: Accessmentioning

confidence: 99%

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The general stress response of Staphylococcus aureus promotes tolerance of antibiotics and survival in whole human blood

2020

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“…39 These mutations were associated with attenuated mortality in a mouse model of disease, but preserved the ability to disseminate and form abscesses, 40 and have been shown to alter survival in blood and antibiotic tolerance. 41 A comprehensive survey of within-host evolution of S. aureus infection demonstrated evidence of bacterial genomic adaption, with protein altering variation in regulatory genes, and the cell surface proteins under control of key regulators. 43 Similar signals of adaptation were found in the genetic changes associated with prolonged bacteraemia.…”

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confidence: 99%

Antimicrobial resistance determinants are associated with Staphylococcus aureus bacteraemia and adaptation to the hospital environment: a bacterial genome-wide association study

Young

Charlesworth

Earle

et al. 2021

Preprint

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BackgroundStaphylococcus aureus is a major bacterial pathogen in humans, and a dominant cause of severe bloodstream infections. Globally, antimicrobial resistance (AMR) in S. aureus remains challenging. While human risk factors for infection have been defined, contradictory evidence exists for the role of bacterial genomic variation in S. aureus disease.MethodsTo investigate the contribution of bacterial lineage and genomic variation to the development of bloodstream infection, we undertook a genome-wide association study comparing bacteria from 1017 individuals with bacteraemia to 984 adults with asymptomatic S. aureus nasal carriage. Within 984 carriage isolates, we also compared healthcare-associated (HA) carriage with community-associated (CA) carriage.ResultsAll major global lineages were represented in both bacteraemia and carriage, with no evidence for different attack rates. However, kmers tagging trimethoprim resistance-conferring mutation F99Y in dfrB were significantly associated with bacteraemia-vs-carriage (p=10−8.9-10−9.3). Pooling variation within genes, bacteraemia-vs-carriage was associated with the presence of mecA (HMP=10−5.3) as well as the presence of SCCmec (HMP=10−4.4).Among S. aureus carriers, no lineages were associated with HA-vs-CA carriage. However, we found a novel signal of HA-vs-CA carriage in the foldase protein prsA, where kmers representing conserved sequence allele were associated with CA carriage (p=10−7.1-10−19.4), while in gyrA, a ciprofloxacin resistance-conferring mutation, L84S, was associated with HA carriage (p=10−7.2).ConclusionsIn an extensive study of S. aureus bacteraemia and nasal carriage in the UK, we found strong evidence that all S. aureus lineages are equally capable of causing bloodstream infection, and of being carried in the healthcare environment.Genomic variation in the foldase protein prsA is a novel genomic marker of healthcare origin in S. aureus but was not associated with bacteraemia. AMR determinants were associated with both bacteraemia and hospital-associated carriage, suggesting that AMR increases the propensity not only to survive in hospital environments, but also to cause invasive disease.

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Commensal Staphylococcus epidermidis Defends against Staphylococcus aureus through SaeRS Two-Component System

Nurxat,

Wang,

Wang

et al. 2023

ACS Omega

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Staphylococcus aureus is a high-virulent Gram-positive pathogen that is responsible for a serious of diseases. The emergence of antibiotic-resistant S. aureus poses a significant challenge in terms of treatment. The recent research on the human microbiome suggested that the application of commensal bacteria is a new strategy for combating pathogenic infections. Staphylococcus epidermidis, one of the most abundant species in the nasal microbiome, is able to inhibit the colonization of S. aureus. However, during bacterial competition, S. aureus undergoes evolutionary changes to adapt to the diverse environment. Our study has demonstrated that the nasal colonized S. epidermidis possesses the ability to inhibit the hemolytic activity of S. aureus. Moreover, we deciphered another layer of mechanism to inhibit S. aureus colonization by S. epidermidis. The active component present in the cell-free culture of S. epidermidis was found to significantly reduce the hemolytic activity of S. aureus in SaeRS- and Agr-dependent manner. Specifically, the hemolytic inhibition on the S. aureus Agr-I type by S. epidermidis is primarily dependent on the SaeRS two-component system. The active component is characterized as a small molecule that is heat sensitive and protease resistant. Critically, S. epidermidis significantly inhibit the virulence of S. aureus in a mouse skin abscess model, suggesting that the active compound could potentially be used as a therapeutic agent for managing S. aureus infections.

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Naturally occurring polymorphisms in the virulence regulator Rsp modulate Staphylococcus aureus survival in blood and antibiotic susceptibility

Cited by 10 publications

References 49 publications

The general stress response of Staphylococcus aureus promotes tolerance of antibiotics and survival in whole human blood

The general stress response of Staphylococcus aureus promotes tolerance of antibiotics and survival in whole human blood

Antimicrobial resistance determinants are associated with Staphylococcus aureus bacteraemia and adaptation to the hospital environment: a bacterial genome-wide association study

Commensal Staphylococcus epidermidis Defends against Staphylococcus aureus through SaeRS Two-Component System

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