Antibiotic resistance and host immune evasion in
            <i>Staphylococcus aureus</i>
            mediated by a metabolic adaptation

Jiang, Jhih-Hang; Bhuiyan, Saruar; Shen, Hsin‐Hui; Cameron, David R.; Rupasinghe, Thusitha; Wu, Chun; Brun, Anton P. Le; Kostoulias, Xenia; Domene, Carmen; Fulcher, Alex J.; McConville, Malcolm J.; Howden, Benjamin P; Lieschke, Graham J.; Peleg, Anton Y.

doi:10.1073/pnas.1812066116

Cited by 77 publications

(92 citation statements)

References 44 publications

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“…Daptomycin was found to attract and cluster fluid lipids in the membrane, causing membrane depolarization and delocalization of membrane proteins (41). Jiang et al found some clinical daptomycin-resistant mutants had gain-of-function mutations in cls 2, leading to increased CL content and decreased PG content, which then resulted in decreased daptomycin susceptibility (42). Zhang et al have found that CL renders liposomes impermeable to daptomycin and proposed that this could be due to the prevention of flipping of the daptomycin to the inner leaflet of liposomes (43).…”

Section: Discussionmentioning

confidence: 99%

Lipidomic and Ultrastructural Characterization of Cell Envelope ofStaphylococcus aureusGrown in the Presence of Human Serum

Hines

Alvarado

Chen

et al. 2020

Preprint

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26Staphylococcus aureus can incorporate exogenous straight-chain unsaturated and 27 saturated fatty acids (SCUFAs and SCFAs, respectively) to replace some of the normally 28 biosynthesized branched-chain fatty acids and SCFAs. In this study, the impact of human serum 29 on the S. aureus lipidome and cell envelope structure was comprehensively characterized. When 30 grown in the presence of 20% human serum, typical human serum lipids, such as cholesterol, 31 sphingomyelin, phosphatidylethanolamines, and phosphatidylcholines, were present in the total 32 lipid extracts. Mass spectrometry showed that SCUFAs were incorporated into all major S. 33 aureus lipid classes, i.e., phosphatidylglycerols, lysyl-phosphatidylglycerols, cardiolipins, and 34 diglucosyldiacylglycerols. Heat-killed S. aureus retained much fewer serum lipids and failed to 35 incorporate SCUFAs, suggesting that association and incorporation of serum lipids with S. 36 aureus requires a living or non-denatured cell. Cytoplasmic membranes isolated from 37 lysostaphin-produced protoplasts of serum-grown cells retained serum lipids, but washing cells 38 with Triton X-100 removed most of them. Furthermore, electron microscopy studies showed that 39 serum-grown cells had thicker cell envelopes and associated material on the surface, which was 40 partially removed by Triton X-100 washing. To investigate which serum lipids were 41 preferentially hydrolyzed by S. aureus lipases for incorporation, we incubated individual serum 42 lipid classes with S. aureus and found that cholesteryl esters (CEs) and triglycerides (TGs) are 43 the major donors of the incorporated fatty acids. Further experiments using purified Geh lipase 44 confirmed CEs and TGs being the substrates of this enzyme. Thus, growth in the presence of 45 serum altered the nature of the cell surface with implications for interactions with the host. 46 Page 3 of 38 IMPORTANCE 47Comprehensive lipidomics of S. aureus grown in the presence of human serum suggests 48 human serum lipids can associate with the cell envelope without being truly integrated into the 49 lipid membrane. However, fatty acids-derived from human serum lipids, including unsaturated 50 fatty acids, can be incorporated into lipid classes that can be biosynthesized by S. aureus itself. 51Cholesteryl esters and triglycerides are found to be the major source of incorporated fatty acids 52 upon hydrolysis by lipases. These findings have significant implications for the nature of the S. 53 aureus cell surface when grown in vivo. Changes in phospholipid and glycolipid abundances and 54 fatty acid composition could affect membrane biophysics and function and the activity of 55 membrane-targeting antimicrobials. Finally, the association of serum lipids with the cell envelope 56 has implications for the physicochemical nature of the cell surface and its interaction with host 57 defense systems. 58 KEYWORDS 59 Lipidomics, human serum lipids, fatty acid incorporation, lipid association, cell envelope 60 structure 61 62 63 64 65 6...

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Section: Discussionmentioning

confidence: 99%

Lipidomic and Ultrastructural Characterization of Cell Envelope ofStaphylococcus aureusGrown in the Presence of Human Serum

Hines

Alvarado

Chen

et al. 2020

Preprint

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“…However, less is known about how modification of cell membrane biochemistry affects resistance. Changes in membrane phospholipid composition was recently shown to increase Staphylococcus aureus resistance to daptomycin (41), and changes in LPS biosynthesis in E. coli increased sensitivity to bacitracin and rifampicin (30). Our work adds to the evidence that resistance can repeatedly evolve through diverse mechanisms.…”

Section: Discussionmentioning

confidence: 55%

Cross-feeding modulates the rate and mechanism of antibiotic resistance evolution in a model microbial community of Escherichia coli and Salmonella enterica

Adamowicz

Muza

Chacón

et al. 2019

Preprint

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Author contributions: E.M.A, M.A.M., J.M.C. and W.R.H. designed research; E.M.A, M.A.M., and J.M.C. performed research; E.M.A., J.M.C., and W.R.H. analyzed data; and E.M.A., J.M.C., and W.R.H. wrote the paper. AbstractWith antibiotic resistance rates on the rise, it is critical to understand how microbial species interactions influence the evolution of resistance. We have previously shown that in obligate mutualisms the survival of any one species (regardless of its intrinsic resistance) is contingent on the resistance of its cross-feeding partners, setting the community antibiotic tolerance at that of the 'weakest link' species. In this study, we extended that hypothesis to test whether obligate cross-feeding would limit the extent and mechanisms of antibiotic resistance evolution. In both rifampicin and ampicillin treatments, we observed that resistance evolved more slowly in obligate co-cultures of E. coli and S. enterica than in monocultures. While we observed similar mechanisms of resistance arising under rifampicin selection, under ampicillin selection different resistance mechanisms arose in co-cultures and monocultures. In particular, mutations in an essential cell division protein, ftsI, arose in S. enterica only in co-culture. A simple mathematical model demonstrated that reliance on a partner is sufficient to slow the rate of adaptation, and can change the distribution of adaptive mutations that are acquired. Our results demonstrate that cooperative metabolic interactions can be an important modulator of resistance evolution in microbial communities. Significance statementLittle is known about how ecological interactions between bacteria influence the evolution of antibiotic resistance. We tested the impact of metabolic interactions on resistance evolution in an engineered two-species bacterial community. Through experimental and modeling work, we found that obligate metabolic interdependency slows the rate of resistance acquisition, and can change the type and magnitude of resistance mutations that evolve. This work suggests that resistance evolution may be slowed by targeting both a pathogen and its metabolic partners with antibiotics. Additionally, we showed that community context can generate novel trajectories through which antibiotic resistance evolves.

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“…While not directly conferring DAP resistance, it is clear that cls mutations play an important role in the enterococcal counterattack against DAP. The prevalence of these mutations in the clinic, across species (56), across adaptive environment, and across DAP resistance mechanisms suggests that these alleles may act as good diagnostic DAP resistance markers in clinical infections.…”

Section: Discussionmentioning

confidence: 99%

Environment Shapes the Accessible Daptomycin Resistance Mechanisms inEnterococcus faecium

Prater

Mehtaa

Kosgei

et al. 2019

Preprint

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250 words) 22 Daptomycin binds to bacterial cell membranes and disrupts essential cell envelope processes 23 leading to cell death. Bacteria respond to daptomycin by altering their cell envelopes to either 24 decrease antibiotic binding to the membrane or by diverting binding away from vulnerable septal 25 targets to remodeled anionic phospholipid membrane patches. In Enterococcus faecalis, 26 daptomycin resistance is typically coordinated by the three-component cell-envelope-stress- 27 response system, LiaFSR. Here, studying a clinical strain of multidrug-resistant Enterococcus 28 faecium containing alleles associated with activation of the LiaFSR signaling pathway, we found 29 that specific environments selected for different evolutionary trajectories leading to high-level 30 daptomycin resistance. Planktonic environments favored pathways that increased cell surface 31 charge via yvcRS upregulation of dltABCD and mprF, causing a reduction in daptomycin 32 binding. Alternatively, environments favoring complex structured communities, including 33 biofilms, evolved both diversion and repulsion strategies via divIVA and oatA mutations, 34 respectively. Both environments subsequently converged on cardiolipin synthase (cls) mutations, 35 suggesting the importance of membrane modification across strategies. Our findings indicate that 36 E. faecium can evolve diverse evolutionary trajectories to daptomycin resistance that are shaped 37 by the environment to produce a combination of resistance strategies. The accessibility of 38 multiple and different biochemical pathways simultaneously suggests that the outcome of 39 daptomycin exposure results in a polymorphic population of resistant phenotypes making E. 40 faecium a recalcitrant pathogen. 41 42 43 44 48 enterococci (VRE) cause approximately 1,300 deaths annually with the number of infections 49 increasing substantially over the last 15 years (1). The Infectious Disease Society of America has 50 listed E. faecium (Efm) among the no 'ESKAPE' pathogens (Enterococcus faecium, 51 Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas 52 aeruginosa, Enterobacter spp.) for which there is an urgent need for new therapies (2). Efm 53 accounts for a significant amount of enterococcal health-care-associated infections, particularly 54in severely immunocompromised patients. Efm strains that are resistant to all anti-enterococcal 55 antibiotics have been widely described (3-6), making these infections untreatable in certain 56 scenarios (1, 3-5, 7, 8). 57 DAP is a bactericidal cyclic lipopeptide antibiotic approved in 2003 and used widely as a 58 "rescue" drug against MDR Gram-positive organisms such as Staphylococcus aureus, Efm and 59 Enterococcus faecalis (Efc) (4, 9, 10). While the DAP mechanism-of-action remains unclear, 60 DAP acts in a calcium-dependent-manner, where the DAP:Ca +2 complex binds to the cell 61 membrane (CM) in a phosphatidylglycerol-dependent manner with high avidity for division 62 septa. DAP binding has ...

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Antibiotic resistance and host immune evasion in Staphylococcus aureus mediated by a metabolic adaptation

Cited by 77 publications

References 44 publications

Lipidomic and Ultrastructural Characterization of Cell Envelope ofStaphylococcus aureusGrown in the Presence of Human Serum

Lipidomic and Ultrastructural Characterization of Cell Envelope ofStaphylococcus aureusGrown in the Presence of Human Serum

Cross-feeding modulates the rate and mechanism of antibiotic resistance evolution in a model microbial community of Escherichia coli and Salmonella enterica

Environment Shapes the Accessible Daptomycin Resistance Mechanisms inEnterococcus faecium

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