A Clinically Selected Staphylococcus aureus
            <i>clpP</i>
            Mutant Survives Daptomycin Treatment by Reducing Binding of the Antibiotic and Adapting a Rod-Shaped Morphology

Xu, Lijuan; Henriksen, Carsten; Mebus, Viktor H; Guérillot, Romain; Petersen, Andreas; Jacques, Nicolas; Jiang, Jhih-Hang; Derks, Rico; Sánchez-López, Elena; Giera, Martin; Leeten, Kirsten; Stinear, Timothy P.; Oury, Cécile; Howden, Benjamin P; Peleg, Anton Y.; Frees, Dorte

doi:10.1128/aac.00328-23

Cited by 7 publications

(3 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a few cases, accumulation of Spx has been experimentally verified in clinical MRSA strains that developed resistance during treatment (50). The clinical relevance of Spx stabilization for S. aureus survival during antibiotic treatment is further supported by the selection of mutations that inactivate the YjbH-ClpXP protease in S. aureus isolates from patients undergoing treatment with β-lactams, daptomycin or vancomycin (42–45, 51). Moreover, a comprehensive genetic study identified the yjbH gene as a hot spot for adaptive mutations during infections supporting that S. aureus may benefit from high Spx levels in clinical settings, but the role of antibiotics in selection was not discussed in this study (28).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations that inactivate the YjbH-ClpXP protease complex responsible for Spx degradation have on several occasions been identified in clinical strains that developed resistance to these antibiotics during treatment (42)(43)(44)(45). This prompted us to investigate if inactivation of yjbH or depletion of Spx would impact growth of S. aureus in the presence of these critical antibiotics.…”

Section: High Spx Broadly Potentiates Resistance To Compounds Targeti...mentioning

confidence: 99%

See 1 more Smart Citation

The Spx stress regulator confers high-level β-lactam resistance and decreases susceptibility to last-line antibiotics in methicillin resistantStaphylococcus aureus

Nielsen,

Petersen,

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Infections caused by methicillin resistantStaphylococcus aureus(MRSA) are a leading cause of mortality worldwide. MRSA have acquired resistance to next generation β-lactam antibiotics through the horizontal acquisition of themecAresistance gene. Development of high resistance is, however, often associated with additional mutations in a set of chromosomal core genes, known as potentiators which through poorly described mechanisms enhance resistance. TheyjbHgene was recently identified as a hot spot for adaptive mutations during severe infections. Here, we show that inactivation ofyjbHincreased β-lactam MICs up to 16-folds and transformed MRSA cells with low level of resistance to being homogenously highly resistant to β-lactams. TheyjbHgene encodes an adaptor protein that targets the transcriptional stress regulator Spx for degradation by the ClpXP protease. Using CRISPRi to knock downspxtranscription, we unambiguously linked hyper-resistance to accumulation of Spx. Spx was previously proposed to be essential, however, our data indicate that Spx is dispensable for growth at 37°C but becomes essential in the presence of antibiotics with various targets. On the other hand, high Spx levels bypassed the role of PBP4 in β-lactam resistance and broadly decreased MRSA susceptibility to compounds targeting the cell wall or the cell membrane including vancomycin, daptomycin, and nisin. Strikingly, Spx potentiated resistance independently of its redox sensing switch. Collectively, our study identifies a general stress pathway that, in addition to promoting the development of high-level, broad-spectrum β-lactam resistance, also decreases MRSA susceptibility to critical antibiotics of last resort.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: High Spx Broadly Potentiates Resistance To Compounds Targeti...mentioning

confidence: 99%

The Spx stress regulator confers high-level β-lactam resistance and decreases susceptibility to last-line antibiotics in methicillin resistantStaphylococcus aureus

Nielsen,

Petersen,

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The blue-shaded cells identify mutations that have been previously observed in laboratory and clinical isolates. [14][15][16][17][18][19][20][21][22][23][24][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] We list the affected genes along the bottom in order of the total number of mutations.…”

Section: Genomic Analysis Reveals Mutations and Pathways In Vancomyci...mentioning

confidence: 99%

The evolution of diverse antimicrobial responses in vancomycin-intermediateStaphylococcus aureusand its therapeutic implications

Crozier,

Gray,

Maltas

et al. 2023

Preprint

View full text Add to dashboard Cite

Staphylococcus aureuscauses serious clinical infections, including bacteremia and endocarditis. When clinicians suspect these diseases, they prescribe broad-spectrum antibiotics like vancomycin and then adjust treatment based on antimicrobial susceptibility test results. However, these results reflect the infection’s state before treatment and do not account for any potential changes in its antibiotic response arising from intervening evolution. Thus, an initial test may indicate that the infection is susceptible to a particular drug, but this recommendation may be tentative. In this study, we aimed to understand how treatment effectiveness changes over time by accounting for evolution. First, we evolved 18 methicillin-susceptibleS. aureus(MSSA) populations under increasing vancomycin concentrations until they reached intermediate resistance levels. We then sequenced their complete genomes to characterize the mutational paths to their evolved vancomycin-intermediate states. Lastly, we subjected these evolved populations to seven antibiotics used to treat MSSA infections and compared drug susceptibilities between the evolved lines and their common ancestor. Mutations in several genes responsible for regulating the cell membrane stress response and cell-wall biosynthesis appeared in parallel among the evolved vancomycin-intermediateS. aureus(VISA) populations, and these lines were repeatedly cross-resistant to daptomycin. These observations align with previous clinical findings, reinforcing the role of these genes in mediating resistance. In contrast, the populations exhibited diverse responses to other antibiotics. Most lines were susceptible to meropenem, gentamicin, and nafcillin, but several replicates were also resistant. We accounted for this diversity by deriving likelihood estimates that express a population’s probability of exhibiting a drug response following vancomycin treatment. Our findings support using antistaphylococcal penicillins (e.g., nafcillin) as a first-line treatment for MSSA, even in light of intermediate vancomycin resistance. They also emphasize the inherent uncertainty and risk that evolution poses to effective therapies, attributes one cannot account for by susceptibility tests alone. Instead, clinicians must consider infections as evolving systems that may take several different paths, with implications on their potential sensitivities to other drugs.

show abstract

Virulence factors in biofilm formation and therapeutic strategies for Staphylococcus aureus: A review

Wang,

Liu

et al. 2024

Animals and Zoonoses

View full text Add to dashboard Cite

A Clinically Selected Staphylococcus aureus clpP Mutant Survives Daptomycin Treatment by Reducing Binding of the Antibiotic and Adapting a Rod-Shaped Morphology

Cited by 7 publications

References 70 publications

The Spx stress regulator confers high-level β-lactam resistance and decreases susceptibility to last-line antibiotics in methicillin resistantStaphylococcus aureus

The Spx stress regulator confers high-level β-lactam resistance and decreases susceptibility to last-line antibiotics in methicillin resistantStaphylococcus aureus

The evolution of diverse antimicrobial responses in vancomycin-intermediateStaphylococcus aureusand its therapeutic implications

Virulence factors in biofilm formation and therapeutic strategies for Staphylococcus aureus: A review

Contact Info

Product

Resources

About