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Staphylococcus aureus Flashcards

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1
Q

Staphylococcus aureus

A

gram +ve bacteria (monoderm)

causes >120,000 deaths a year
- near a million when attributable to death in people with underlying health conditions

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2
Q

Characterisitcs of S.aureus

A

Opportunistic pathogen

Infections are mainly nosocomial

Very antibiotic resistant

Good at surviving abiotic environment

Very stress resistant

Form biofilms

Colonises nasal carriage

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3
Q

Diseases caused by S.aureus

A

Furuncles (boils)

Pyomyositis

Endocarditis

Toxic Shock Syndrome

Food poisoning

Scalded skin syndrome

Septicemia

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4
Q

Furuncles

A

Self-limiting minor infection

Characterisitc pus containing dead neutrophils

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5
Q

Pyomyositis

A

When staph gets through skin into muscles
Causes abscess; a biofilm of S.aureus

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6
Q

Endocarditis

A

S.aureus grows biofilm on heart
Valves can’t function
Potentially fatal

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7
Q

Toxic Shock Syndrome

A

A new tampon provided perfect environment for S.aureus to grow anaerobically
- produced TSS toxin

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8
Q

Food poisioning

A

Different to other bacterial food poisioning as not caused by ingestion of bacteria and colonisation/replication

Caused by preformed toxin on food
- emetic toxins (induce vomiting)

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9
Q

Scalded skin syndrome

A

Exfoliative toxin A and B (proteases) destroy epithelial layer

Sloughing of skin

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10
Q

Septicemia

A

Bacteria in blood
Underlying biofilm abscess shed bacteria into blood

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11
Q

How can S.aureus cause so many different diseases?

A

High adaptable

Multiple virulence factors

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12
Q

S.aureus infection

A

initial abscess –> acute inflammatory reaction

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13
Q

Neutrophil recruitment

A

Chemotactic signals
- IL-8, C5A, LTA and formyl peptides

Lipoteichoic acid (LTA) - component of S.aureus membrane

Formly peptides - humans don’t make this

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14
Q

Neutrophil phagocytosis

A

Opsonisation
- bacteria marked with small molecules so they can be recognised for phagocytosis

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15
Q

Neutrophil killing

A

Phagosome contains proteases, antimicrobial peptides and generates ROS through NADPH oxidase

Phagosome fuses with lysosome inside cell
Lysosome contains lysozyme and digestive enzymes

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16
Q

S.aureus prevent neutrophil recognition

A

Produce virulence determinants that bind and inhibit activity of all components on neutrophil surface

Evolved an inhibitor for every protein involved in recognition and chemotaxis

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17
Q

S.aureus prevent neutrophil phagocytosis

A

Inhibit opsonisation
Cell surface is coated in Staphylococcal protein A

SpA captures Fc domain of Ig
Sequesters anti-S.aureus antibodies

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18
Q

S.aureus prevents neutrophil killing

A

S.aureus have evolved virulence determinants to resist all properties involved in killing within phagosome

i.e. KatA detoxifies H2O2
i.e. OatA changes PG
i.e. protease inhibitors

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19
Q

OatA for immune evasion

A

Carries out O-acetylation on MurNAc

Produces steric hinderance to inhibit lysozyme

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20
Q

Adhesion stage of S.aureus biofilm formation

A

Express cell-wall anchored proteins, adhesin and eDNA to promote combination with host

Proteins inserted into PG cell wall by SrtA

Bind to exc. proteins on eukaryotic cells

Form shell of human proteins around it

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21
Q

Aggregation stage of S.aureus biofilm formation

A

Begin to divide and accumulate in presence of sufficient nutrient source

Bacteria continue to proliferate and thicken to form biofilm

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22
Q

Maturation stage of S.aureus biofilm formation

A

Biofilm is 3D structure with large number of pipes constructed to promote transport of nutrients to deeper layers

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23
Q

Dispersion stage of S.aureus biofilm formation

A

Phenol-soluble modulins (PSMs) are a key effector of dispersion
- destroy the non-covalent force in biofilm matrix

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24
Q

Toxins

s. aureus

A

Used for nutrient acquisition

Hemolysins (alpha-hemolysin)

Entertoxins

TSS-toxin

Exfoliative toxin A and B

Leukocidin

Phenol soluble modulins

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25
alpha-hemolysin
heptameric pore forming toxin Form pore to lyse red blood cells (Fe acquisition) Interacts with ADAM10 (protease) on epithelial cells
26
ADAM10
alpha-hemolysin increases activity of this human protease Cleaves E-caherin - involved in adherence junctions between epithelial cells
27
Enterotoxins
Affect immune system Super antigen - end up with IL-2
28
TSS-toxin
Toxic shock syndrome toxin super antigen - induces proinflammatory cytokines - leads to fever, shock and death
29
Super antigens
Enterotoxins and TSS-toxin bypass normal route of antigen presentation Directly link antigen-presenting cell to T cell Produce oligo non-specific T cell activation
30
Exfoliative toxin A and B
Proteases Destroy epithelial layer - lead to skin sloughing (scalded skin syndrome)
31
Leukocidin
Panton Valentine Leukocidin (PVL) Associated with killing neutrophils
32
Phenol soluble modulins
Associated with community acquired MRSA MRSA in a community where people are not being treated with methicillin
33
Coagulase
Specific to S.aureus - can be used as diagnostic test Coa and vWbp Interact with prothrombin --> becomes staphylothrombin Staphylothrombin converts fibrinogen to fibrin - forms fibrin coat around S.aureus
34
Growth phase dependent production of virulence determinants
Exponential growth phase Surface proteins (+++); Exoproteins (-) Stationary growth phase Surface proteins (-); Exoproteins (+++)
35
Why does expression of surface proteins and exoproteins switch during growth phase?
Surface proteins are adhesins involved in immune evasion - beginning of infection - bacteria are nutritionally happy As they proliferate in abscess they use up nutrients; need to so damage - switch to making toxins
36
S. aureus regulatory components
194 DNA binding proteins in S. aureus genome Allows coordinated response to large number of environmental stimuli
37
Main regulator hubs in S. aureus
SarA and agr Both discovered using transposon mutagenesis looking for proteins that reduce toxin production
38
agr
Accessory gene regulator +ve regulator of toxin production -ve regulator of surface proteins COMPLEX DIVERGON
39
SarA
staphylococcal accessory regulator upregulates agr expression and repressor of proteases
40
agr as a complex divergon
comprised of two functionally linked operons that are divergently transcribed agrBDCA controlled by P2 hld controlled by P3
41
agrB
AgrD processing enzyme - cleaves C terminus of AIP
42
agrD
Encodes prepeptide of exc. signalling molecule (45aa) Signalling molecule (8aa): Autoinducing peptide (AIP) Cleaved by AgrB and MroQ
43
AIP
encoded by agrD different AIP depending on strain but ALL post-translationally cyclized by thioester linkage interacts with agrC to induce downstream effects
44
agrC
Transmembrane sensor domain Histidine kinase domain senses [AIP] HK domain autophosphorylation Transduces signal to AgrA
45
agrA
Regulator protein Controls change in gene expression Transcriptional activator Phosphorylated by active AgrC Upregulates expression from P2 and P3
46
Quorum sensing by S.aureus
Density dependent signalling Ability of a bacteria to adjust gene expression in response to their population density - detected using [AIP]
47
agr operon promoters
P2 constituently expressed at low level during exponential growth phase - slow build up of AIP until threshold reached P3 requires activated AgrA for expression - controls expression of RNA III transcript - encodes alpha-hemolysin
48
RNA III action
1. Transcription - regulatory RNA molecule produced as cells go into post-exponential phase 2. Translation (spa and hla) - able to control translation of many different virulence factors - antisense RNA binds mRNA encoding virulence factors
49
-ve regulation of spa translation
RNA III binds antisense to spa transcript Covers SD-sequence (RBS) Induces stem loop - mRNA will be degraded
50
+ve regulation of hla transcript
RNA III stops stem loop formation Binds antisense to hla transcript RBS free --> translated
51
SarA action on proteases
acts via or independently of agr - proteases are part of agr regulon Proteases control virulence determinant stability - cleave surface proteins to allow bacteria to move - adapt quickly
52
Bacterial interference with AIP
Competition between related strains Mediated by AIP AIP from one strain will inhibit toxin production in other strains Gives competitive advantage in mixed infections
53
S. aureus antibiotic resistance
Can become resistant to penicillin, methicillin and vancomycin
54
Mechanism of MRSA
PBP2a (MecA) has low affinity for beta-lactam MecA only present in MRSA isolates Possibly gained by horizontal transfer from S.sciuri - Mec element flanked by insertion sequences - Transferred by transduction using phages
55
Regulation of mecA expression
Regulatory system also carried on mec element along with mecA gene mecI - dimer represses mecA transcription by binding promoter region mecR - senses beta-lactam - metalloprotease --> hydrolyses mecI upon activation
56
Vancomycin
Only effective drug against S. aureus Glycopeptide Binds terminal D-ala-D-ala of peptide sidechain of PG subunit - prevents PG crosslinking
57
VISA
Vancomycin insensitive S. aureus Change in permeability led to insensitivity to vancomycin - number of different mutations led to thicker cell wall Has to cross membrane to reach presursor - quite a big drug - more difficult for vancomycin to get into cell
58
VRSA
Vancomycin resistant S. aureus Acquired from Enterococcus Plasmid mediated system Change terminal D-ala-D-ala to D-ala-D-lac - inhibits vanc binding - become resistant quickly
59
Issues with drug discovery
Pharmacokinetics Toxicity Expensive
60
Key characteristics for new drugs
Stop resistance Broad spectrum Cost-effective
61
Methods for drug discovery
Screening - take soil from different environments - screen organisms to see if they inhibit target pathogen Existing targets - analogues of existing drugs - understand molecular basis of resistance to prevent it
62
Modifications of existing drugs
Drug analgous stable to degradation i.e. amikacin (kanamycin analogue) Inhibit inactiviting enzymes i.e. clavulanic acid (beta-lactamase inhibitor) Analogues not effluxed i.e. glycylcyclines (tetracycline analogues) Analogues binding to modified target i.e. carbapenem derivatives binds to MecA
63
Novel drugs for S. aureus
Daptomycin Linezolid Ceftobiprole Ceftaroline Teixobactin
64
Daptomycin
Cyclic lipopeptide membrane acting - inserts into membrane and allows release of K+ - organism can't make ATP (dies) Also binds some intermediates involved in PG biosynthesis - more than one mode of action Resistance has appeared
65
Linezolid
Oxazolidinone Binds ribosome 50S - prevents formation of initiation complex - prevents translation Resistance has appeared
66
PBP2a (MecA) Cause of MRSA
Has an allosteric site and an active site Active site has low affinity got antibiotics Active site is hidden until substrate binds allosteric site - causes conformational change that opens active site
67
Ceftobiprole
cephalosporin binds active site of PBP2a clinical resistance has appeared
68
Ceftaroline
cephalasporin binds active site AND allosteric site of PBP2a clinical resistance has appeared
69
Teixobactin
Antimicrobial compound Produced by E. terrae - gram -ve proteobacterium; discovered from screening soil Non-ribosomally encoded - produced from building blocks
70
Production of Teixobactin
Produced via two biosynthetic proteins that have multiple enzyme activities Peptide synthetase proteins - Txo1 and Txo2
71
Teixobactin mode of action
Binds Lipid II and Lipid III Biosynthetic subunits that make PG-carried molecules - difficult to change structure of these - good to prevent resistance

Bacterial Pathogenicity (4 decks)

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