Increased Overall Antibiotic Susceptibility in
            <i>Staphylococcus aureus femAB</i>
            Null Mutants

Ling, Baodong; Berger‐Bächi, Brigitte

doi:10.1128/aac.42.4.936

Cited by 35 publications

(42 citation statements)

References 12 publications

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“…LytM is a glycyl-glycyl endopeptidase, cleaving the pentaglycine interpeptide crossbridges of the S. aureus cell wall [29], [30], [38]. Cross-bridges stabilize the S. aureus cell wall and are essential since mutants impaired in their biosynthesis ( fmhB , femA, femB ) are non- or barely viable [39]–[41]. Furthermore, the pentaglycine interpeptide bridges are involved in exposure of cell surface proteins that are covalently anchored to them by sortase-dependent cross-linking [42].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the pentaglycine interpeptide bridges are involved in exposure of cell surface proteins that are covalently anchored to them by sortase-dependent cross-linking [42]. Several studies have established a link between the degree of crosslinking of peptidoglycan and methicillin resistance in a PBP2′-independent manner, as well as resistance to other unrelated classes of antibiotics such as glycopeptides [39], . Pentaglycine cross-bridges thus play key roles in bacterial fitness, antibiotic resistance and in virulence, through the control of surface protein display, so it is not surprising that their biosynthesis genes are essential.…”

Section: Discussionmentioning

confidence: 99%

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Peptidoglycan Crosslinking Relaxation Plays an Important Role in Staphylococcus aureus WalKR-Dependent Cell Viability

et al. 2011

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The WalKR two-component system is essential for viability of Staphylococcus aureus, a major pathogen. We have shown that WalKR acts as the master controller of peptidoglycan metabolism, yet none of the identified regulon genes explain its requirement for cell viability. Transmission electron micrographs revealed cell wall thickening and aberrant division septa in the absence of WalKR, suggesting its requirement may be linked to its role in coordinating cell wall metabolism and cell division. We therefore tested whether uncoupling autolysin gene expression from WalKR-dependent regulation could compensate for its essential nature. Uncoupled expression of genes encoding lytic transglycosylases or amidases did not restore growth to a WalKR-depleted strain. We identified only two WalKR-regulon genes whose expression restored cell viability in the absence of WalKR: lytM and ssaA. Neither of these two genes are essential under our conditions and a ΔlytM ΔssaA mutant does not present any growth defect. LytM is a glycyl–glycyl endopeptidase, hydrolyzing the pentaglycine interpeptide crossbridge, and SsaA belongs to the CHAP amidase family, members of which such as LysK and LytA have been shown to have D-alanyl-glycyl endopeptidase activity, cleaving between the crossbridge and the stem peptide. Taken together, our results strongly suggest that peptidoglycan crosslinking relaxation through crossbridge hydrolysis plays a crucial role in the essential requirement of the WalKR system for cell viability.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Peptidoglycan Crosslinking Relaxation Plays an Important Role in Staphylococcus aureus WalKR-Dependent Cell Viability

et al. 2011

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“…These factors are often directly or indirectly involved in cell envelope biosynthesis and turnover. Examples of fem/aux factors linked to the cell envelope include cell wall biosynthesis enzymes like GlmM [11], MurE [12], MurF [13], FemABX [14], PBP2 [15], PBP4 [16]; and wall teichoic acid biosynthesis enzymes including TagO/TarO [17], the dlt operon [18] and the wall teichoic acid ligase MsrR [19], [20]. Fem/aux factors indirectly connected or with no obvious connection to the cell envelope include regulators like SigB [21], SpoVG [22], agr [23], SarA [23], XdrA [24], CcpA [25], SecDF [26] or two component systems like VraSR [27], [28].…”

Section: Introductionmentioning

confidence: 99%

Mutation in the C-Di-AMP Cyclase dacA Affects Fitness and Resistance of Methicillin Resistant Staphylococcus aureus

et al. 2013

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Faster growing and more virulent strains of methicillin resistant Staphylococcus aureus (MRSA) are increasingly displacing highly resistant MRSA. Elevated fitness in these MRSA is often accompanied by decreased and heterogeneous levels of methicillin resistance; however, the mechanisms for this phenomenon are not yet fully understood. Whole genome sequencing was used to investigate the genetic basis of this apparent correlation, in an isogenic MRSA strain pair that differed in methicillin resistance levels and fitness, with respect to growth rate. Sequencing revealed only one single nucleotide polymorphism (SNP) in the diadenylate cyclase gene dacA in the faster growing but less resistant strain. Diadenylate cyclases were recently discovered to synthesize the new second messenger cyclic diadenosine monophosphate (c-di-AMP). Introduction of this mutation into the highly resistant but slower growing strain reduced resistance and increased its growth rate, suggesting a direct connection between the dacA mutation and the phenotypic differences of these strains. Quantification of cellular c-di-AMP revealed that the dacA mutation decreased c-di-AMP levels resulting in reduced autolysis, increased salt tolerance and a reduction in the basal expression of the cell wall stress stimulon. These results indicate that c-di-AMP affects cell envelope-related signalling in S. aureus. The influence of c-di-AMP on growth rate and methicillin resistance in MRSA indicate that altering c-di-AMP levels could be a mechanism by which MRSA strains can increase their fitness levels by reducing their methicillin resistance levels.

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“…This is in contrast to the mechanism by which Staphylococcus aureus is known to ensure adequate provision of Gly-tRNA Gly for cell wall cross-linking and protein synthesis. In S. aureus , peptidoglycan is indirectly cross-linked by virtue of a pentaglycine bridge that is formed by the activity of the glycyl-tRNA-dependent FemXAB proteins (46). It has been established that there are four fully annotated tRNA Gly isoacceptors encoded in the genome of this bacterium plus a fifth pseudogene that encodes an unusual Gly isoacceptor.…”

Section: Discussionmentioning

confidence: 99%

Relaxed Substrate Specificity Leads to Extensive tRNA Mischarging by Streptococcus pneumoniae Class I and Class II Aminoacyl-tRNA Synthetases

Shepherd

Ibba

2014

mBio

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Aminoacyl-tRNA synthetases provide the first step in protein synthesis quality control by discriminating cognate from noncognate amino acid and tRNA substrates. While substrate specificity is enhanced in many instances by cis- and trans-editing pathways, it has been revealed that in organisms such as Streptococcus pneumoniae some aminoacyl-tRNA synthetases display significant tRNA mischarging activity. To investigate the extent of tRNA mischarging in this pathogen, the aminoacylation profiles of class I isoleucyl-tRNA synthetase (IleRS) and class II lysyl-tRNA synthetase (LysRS) were determined. Pneumococcal IleRS mischarged tRNAIle with both Val, as demonstrated in other bacteria, and Leu in a tRNA sequence-dependent manner. IleRS substrate specificity was achieved in an editing-independent manner, indicating that tRNA mischarging would only be significant under growth conditions where Ile is depleted. Pneumococcal LysRS was found to misaminoacylate tRNALys with Ala and to a lesser extent Thr and Ser, with mischarging efficiency modulated by the presence of an unusual U4:G69 wobble pair in the acceptor stems of both pneumococcal tRNALys isoacceptors. Addition of the trans-editing factor MurM, which also functions in peptidoglycan synthesis, reduced Ala-tRNALys production by LysRS, providing evidence for cross talk between the protein synthesis and cell wall biogenesis pathways. Mischarging of tRNALys by AlaRS was also observed, and this would provide additional potential MurM substrates. More broadly, the extensive mischarging activities now described for a number of Streptococcus pneumoniae aminoacyl-tRNA synthetases suggest that adaptive misaminoacylation may contribute significantly to the viability of this pathogen during amino acid starvation.

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Increased Overall Antibiotic Susceptibility in Staphylococcus aureus femAB Null Mutants

Cited by 35 publications

References 12 publications

Peptidoglycan Crosslinking Relaxation Plays an Important Role in Staphylococcus aureus WalKR-Dependent Cell Viability

Peptidoglycan Crosslinking Relaxation Plays an Important Role in Staphylococcus aureus WalKR-Dependent Cell Viability

Mutation in the C-Di-AMP Cyclase dacA Affects Fitness and Resistance of Methicillin Resistant Staphylococcus aureus

Relaxed Substrate Specificity Leads to Extensive tRNA Mischarging by Streptococcus pneumoniae Class I and Class II Aminoacyl-tRNA Synthetases

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