Staphylococcus aureus cell growth and division are regulated by an amidase that trims peptides from uncrosslinked peptidoglycan

Do, Truc; Schaefer, Kaitlin; Santiago, Ace George; Coe, Kathryn A.; Fernandes, Pedro B.; Kahne, Daniel; Pinho, Mariana G.; Walker, Suzanne

doi:10.1038/s41564-019-0632-1

Cited by 55 publications

(86 citation statements)

References 59 publications

(130 reference statements)

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“…Previous work has shown that cell division defects result when S. aureus cells grow larger than normal (6, 42-45). Consistent with these findings, we observed a remarkable correlation between cell size and frequency of cell division defects for the mutants studied here.…”

Section: Discussionmentioning

confidence: 99%

“…The cells were imaged at 30°C as described previously (45). For each field of view, 3 images were taken: 1) phase-contrast, 2) brightfield, and 3) fluorescence.…”

Section: Methodsmentioning

confidence: 99%

“…Image segmentation, cell volume quantification, and cellular phenotype classification were performed as described previously (45). Cell volumes were calculated from cells lacking visible septa.…”

Section: Methodsmentioning

confidence: 99%

“…Multiple independent cultures were used to increase the diversity of mutants. Whole-genome sequencing of select mutants was performed with an Illumina MiSeq as described previously (45).…”

Section: Methodsmentioning

confidence: 99%

“…UgtP evidently does not act to increase cell size in S. aureus because Δ ugtP mutant cells are larger, rather than smaller, than those of the wild type (32). Like other S. aureus cells that grow too large (6, 42-45), the mutant cells have cell division defects such as multiple and misplaced septa (32). While these defects may result directly from the loss of the ugtP gene product, the Δ ugtP deletion is pleiotropic and causes multiple effects, including the absence of the disaccharide anchor Glc 2 DAG and an abnormal lengthening of LTA polymers (Fig.…”

Section: Introductionmentioning

confidence: 99%

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The length of lipoteichoic acid polymers controlsStaphylococcus aureuscell size and envelope integrity

Hesser¹,

Matano²,

Vickery³

et al. 2020

Preprint

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24The opportunistic pathogen Staphylococcus aureus is protected by a cell envelope 25 that is crucial for viability. In addition to peptidoglycan, lipoteichoic acid (LTA) is an 26 especially important component of the S. aureus cell envelope. LTA is an anionic polymer 27 anchored to a glycolipid in the outer leaflet of the cell membrane. It was known that 28 deleting the gene for UgtP, the enzyme that makes this glycolipid anchor, causes cell 29 growth and division defects. In Bacillus subtilis, growth abnormalities from the loss of ugtP 30 have been attributed to the absence of the encoded protein, not to loss of its enzymatic 31 activity. Here, we show that growth defects in S. aureus ugtP deletion mutants are due to 32 the long, abnormal LTA polymer that is produced when the glycolipid anchor is missing 33 from the outer leaflet of the membrane. Dysregulated cell growth leads to defective cell 34 division, and these phenotypes are corrected by mutations in the LTA polymerase, ltaS, 35 that reduce polymer length. We also show that S. aureus mutants with long LTA are 36 sensitized to cell wall hydrolases, beta-lactam antibiotics, and compounds that target 37 other cell envelope pathways. We conclude that control of LTA polymer length is 38 important for S. aureus physiology and promotes survival under stressful conditions, 39including antibiotic stress. 40 41 IMPORTANCE 42Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of 43 community-and hospital-acquired infections and is responsible for a large fraction of 44 deaths caused by antibiotic-resistant bacteria. S. aureus is surrounded by a complex cell 45 envelope that protects it from antimicrobial compounds and other stresses. Here we show 46 3 that controlling the length of an essential cell envelope polymer, lipoteichoic acid, is critical 47 for controlling S. aureus cell size and cell envelope integrity. We also show that genes 48 involved in LTA length regulation are required for resistance to beta-lactam antibiotics in 49MRSA. The proteins encoded by these genes may be targets for combination therapy 50 with an appropriate beta-lactam. 51 52 129 RESULTS 130 ugtP and ltaA mutants are larger than wild type cells and have cell division 131 defects 132A previous study in S. aureus reported that ugtP cells are larger than wild type 133 cells and have other morphological defects (32), but ltaA mutant cells have not been 134 examined in detail. We compared the morphology of otherwise isogenic wild type, ltaA, 135 and ugtP strains by transmission electron microscopy (TEM) and quantified cell size 136 using brightfield and epifluorescence microscopy after staining with a membrane dye. 137 8. Weidenmaier C, Peschel A, Kempf VA, Lucindo N, Yeaman MR, Bayer AS. 2005. DltABCD-and 595 MprF-mediated cell envelope modifications of Staphylococcus aureus confer resistance to 596 platelet microbicidal proteins and contribute to virulence in a rabbit endocarditis model. Infect 597 Immun 73:8033-8.598 9.

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Section: Discussionmentioning

confidence: 99%

“…The cells were imaged at 30°C as described previously (45). For each field of view, 3 images were taken: 1) phase-contrast, 2) brightfield, and 3) fluorescence.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Multiple independent cultures were used to increase the diversity of mutants. Whole-genome sequencing of select mutants was performed with an Illumina MiSeq as described previously (45).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The length of lipoteichoic acid polymers controlsStaphylococcus aureuscell size and envelope integrity

Hesser¹,

Matano²,

Vickery³

et al. 2020

Preprint

Self Cite

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Reducing Peptidoglycan Crosslinking by Chemical Modulator Reverts β‐lactam Resistance in Methicillin‐Resistant Staphylococcus aureus

Kim,

Lee,

Kim

et al. 2024

Advanced Science

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Small molecule can be utilized to restore the effectiveness of existing major classes of antibiotics against antibiotic‐resistant bacteria. In this study, it is demonstrated that celastrol, a natural compound, can modify the bacterial cell wall and subsequently render bacteria more suceptible to β‐lactam antibiotics. It is shown that celastrol leads to incomplete cell wall crosslinking by modulating levels of c‐di‐AMP, a secondary messenger, in methicillin‐resistant Staphylococcus aureus (MRSA). This mechanism enables celastrol to act as a potentiator, effectively rendering MRSA susceptible to a range of penicillins and cephalosporins. Restoration of in vivo susceptibility of MRSA to methicillin is also demonstrated using a sepsis animal model by co‐administering methicillin along with celastrol at a much lower amount than that of methicillin. The results suggest a novel approach for developing potentiators for major classes of antibiotics by exploring molecules that re‐program metabolic pathways to reverse β‐lactam‐resistant strains to susceptible strains.

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Mechanistic Insights into the Activities of Major Families of Enzymes in Bacterial Peptidoglycan Assembly and Breakdown

Kwan

Qiao

2023

ChemBioChem

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Staphylococcus aureus cell growth and division are regulated by an amidase that trims peptides from uncrosslinked peptidoglycan

Cited by 55 publications

References 59 publications

The length of lipoteichoic acid polymers controlsStaphylococcus aureuscell size and envelope integrity

The length of lipoteichoic acid polymers controlsStaphylococcus aureuscell size and envelope integrity

Reducing Peptidoglycan Crosslinking by Chemical Modulator Reverts β‐lactam Resistance in Methicillin‐Resistant Staphylococcus aureus

Mechanistic Insights into the Activities of Major Families of Enzymes in Bacterial Peptidoglycan Assembly and Breakdown

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