Antimicrobial tolerance and its role in the development of resistance: Lessons from enterococci

Darnell, Rachel L.; Paxie, Olivia; Rose, Francesca O. Todd; Morris, Sali M; Krause, Alexandra L.; Monk, Ian R.; Smith, Matigan J.B.; Stinear, Timothy P.; Cook, Gregory M.; Gebhard, Susanne

doi:10.1016/bs.ampbs.2022.06.004

Cited by 7 publications

(4 citation statements)

References 155 publications

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“…Autolysins play an essential role in normal cell wall turnover and their absence has been associated with increased penicillin tolerance in enterococci (44–46). In the RNA-Seq analyses above, we found that CroRS upregulated expression of teichoic acids, a known target of TXB and regulator of cell wall autolytic activity (47, 48). Therefore, it is tempting to speculate that in the absence of CroRS, teichoic acids are depleted and autolytic activity is dysregulated as a consequence.…”

Section: Resultsmentioning

confidence: 89%

The two-component system CroRS regulates isoprenoid flux to mediate antimicrobial tolerance in the bacterial pathogenEnterococcus faecalis

Rose

Darnell

Morris

et al. 2022

Preprint

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Antimicrobial tolerance is the ability of a microbial population to survive, but not proliferate, during antimicrobial exposure. Significantly, it has been shown to precede the development of bona fide antimicrobial resistance. We have previously identified the two-component system CroRS as a critical regulator of tolerance to antimicrobials like teixobactin in the bacterial pathogenEnterococcus faecalis.To understand the molecular mechanism of this tolerance, we carried out RNA-seq analyses in theE. faecaliswild-type and isogeniccroRSmutant to determine the teixobactin-induced CroRS regulon. We identified a 132 gene CroRS regulon and show CroRS upregulates expression of all major components of the enterococcal cell envelope in response to teixobactin challenge. To gain further insight into the function of this regulon we isolated and characterized croRS mutants recovered for wild-type growth and tolerance. We show introduction of a single stop codon in a heptaprenyl diphosphate synthase (hppS), a key enzyme in the synthesis of the quinone electron carrier demethylmenaquinone (DMK), is sufficient to rescue loss of cell envelope integrity in thecroRSdeletion strain. Based on these findings, we propose a model where CroRS acts as a gate-keeper of isoprenoid biosynthesis, mediating flux of isoprenoids needed for cell wall synthesis (undecaprenyl pyrophosphate; UPP) and respiration (DMK) to maintain cell wall homeostasis upon antimicrobial challenge. Dysregulation of this flux in the absence ofcroRSleads to a loss of tolerance, which is rescued by loss of function mutations in HppS, allowing an increase in isoprenoid flow to UPP and subsequently cell wall synthesis.

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Section: Resultsmentioning

confidence: 89%

The two-component system CroRS regulates isoprenoid flux to mediate antimicrobial tolerance in the bacterial pathogenEnterococcus faecalis

Rose

Darnell

Morris

et al. 2022

Preprint

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“…Autolysins play an essential role in normal cell wall turnover, and their absence has been associated with increased tolerance to the

β

‐lactam antimicrobials penicillin and amoxicillin in enterococci (Bravetti et al, 2009; Dubée et al, 2011; Hodges et al, 1992; Tomasz et al, 1970). In the RNA‐seq analyses above, we found that CroRS upregulates the expression of teichoic acid biosynthesis genes, a known target of TXB and regulator of cell wall autolytic activity in response to antimicrobial stress (Darnell et al, 2022; Fabretti et al, 2006). Therefore, it is tempting to speculate that in the absence of CroRS, teichoic acids are depleted and autolytic activity is dysregulated as a consequence.…”

Section: Resultsmentioning

confidence: 99%

The two‐component system CroRS acts as a master regulator of cell envelope homeostasis to confer antimicrobial tolerance in the bacterial pathogen Enterococcus faecalis

Rose

Darnell

Morris

et al. 2023

Molecular Microbiology

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Antimicrobial tolerance is the ability of a microbial population to survive, but not proliferate, during antimicrobial exposure. Significantly, it has been shown to precede the development of bona fide antimicrobial resistance. We have previously identified the two‐component system CroRS as a critical regulator of tolerance to antimicrobials like teixobactin in the bacterial pathogen Enterococcus faecalis. To understand the molecular mechanism of this tolerance, we have carried out RNA‐seq analyses in the E. faecalis wild‐type and isogenic croRS mutant to determine the teixobactin‐induced CroRS regulon. We identified a 132 gene CroRS regulon and demonstrate that CroRS upregulates biosynthesis of all major components of the enterococcal cell envelope in response to teixobactin. This suggests a coordinating role of this regulatory system in maintaining integrity of the multiple layers of the enterococcal envelope during antimicrobial stress, likely contributing to bacterial survival. Using experimental evolution, we observed that truncation of HppS, a key enzyme in the synthesis of the quinone electron carrier demethylmenaquinone, was sufficient to rescue tolerance in the croRS deletion strain. This highlights a key role for isoprenoid biosynthesis in antimicrobial tolerance in E. faecalis. Here, we propose a model of CroRS acting as a master regulator of cell envelope biogenesis and a gate‐keeper between isoprenoid biosynthesis and respiration to ensure tolerance against antimicrobial challenge.

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“…For bacteria, some certain kinds are easily cultured and resistant to drugs, leading a strong pathogenicity 19 , 26 . They “escape” from surveillance of antibiotics in many ways, such as cell stress responses, biofilm formation, and genetic material changes 22 , 24 , 27 . For the host, BPH usually happens in older men with poor self-care abilities and the weakened immune system.…”

Section: Discussionmentioning

confidence: 99%

Pathogen species are the risk factors for postoperative infection of patients with transurethral resection of the prostate: a retrospective study

Lin,

Yang,

et al. 2023

Sci Rep

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This study aimed to analyze the infection risk factors for transurethral resection of the prostate (TURP) and establish predictive models to help make personalized treatment plans. Our study was designed one-center and retrospectively enrolled 1169 benign prostatic hyperplasia (BPH) patients. Risk factors were explored for postoperative infection. A TURP-postoperative infection (TURP-PI) model with infection prediction values was created. The improved-TURP-PI (I-TURP-PI) model, including extra new factors (pathogens species), was also built to see whether it could optimize the prediction abilities. At last, we developed a nomogram for better clinical application. Operation time, preoperative indwelling urinary catheter (PIUC), and positive preoperative urine culture were independent risk factors (all P < 0.05). Interestingly, pathogens species in pre-surgery urine (PEnterococcus faecium = 0.014, PPseudomonas aeruginosa = 0.086) were also independent risk factors. Patients with positive Enterococcus faecium (37.50%) were most likely to have postoperative infection. We built two models with AUCTURP-PI = 0.709 (95% CI 0.656–0.763) and AUCI-TURP-PI = 0.705 (95% CI 0.650–0.760). The nomogram could help improve the prediction ability. To our knowledge, our study is the first to use pathogen species in urine before surgery as risk factors for infection prediction after TURP. TURP-PI and I-TURP-PI models have essential roles in predicting patients' postoperative infections and in better postoperative antibiotic decision-making.

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Antimicrobial tolerance and its role in the development of resistance: Lessons from enterococci

Cited by 7 publications

References 155 publications

The two-component system CroRS regulates isoprenoid flux to mediate antimicrobial tolerance in the bacterial pathogenEnterococcus faecalis

The two-component system CroRS regulates isoprenoid flux to mediate antimicrobial tolerance in the bacterial pathogenEnterococcus faecalis

The two‐component system CroRS acts as a master regulator of cell envelope homeostasis to confer antimicrobial tolerance in the bacterial pathogen Enterococcus faecalis

Pathogen species are the risk factors for postoperative infection of patients with transurethral resection of the prostate: a retrospective study

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