nisha ranganathan, rebecca johnson, andrew m....
TRANSCRIPT
Staphylococcal bacteraemia: finding the path of least persistence NishaRanganathan,RebeccaJohnson,AndrewM.Edwards
Background• DespitethefallingincidenceofMRSAbacteraemia,therateofMSSAbacteraemiaisrising1
• Inasignificantpropor@onofcases,bacteraemiapersistsdespiteappropriatetherapy2
• Challengestotreatmentariseasunderthetwinthreatsofan@bio@csandtheimmune
system,bacteriabecomedormant,metabolicallyinac@veandarethusan@bio@ctolerant3
• TheregulatorofthestressresponseinS.aureus,SigB,regulatesentryintodormancy4
Thehostenvironmentmodulatesan7bio7c
suscep7bility
A B
C
Figure2.(A)Titra7ngconcentra7onofAHTinthecomplementedsigBmutantresultedinincreasingsigB expression, as evidencedby increase inpigmentproduc7onand (B)fibronec7nbinding (bothsigBdependentphenotypes). (C)IncreasingsurvivalofS.aureusinbloodonincreasinginduc7onofsigBexpressionwithAHTincomplementedmutantbutnotinemptyplasmidvector.
Figure1.Bloodmodulatesan7bio7csuscep7bilityofS.aureusonexposuretoCloxacillin(A)Gentamicin(B),Vancomycin(C),Ciprofloxacin(D)Clindamycin(E).Withtheexcep7onof(B)theaddi7onofan7bio7cfailedtosignificantlyenhancekillingcomparedtobloodalone,howeveran7bio7csfunc7onedinserum.
A
SigBmodulatesan7bio7csuscep7bilityinthehostcontext
Figure 4. (A) sigB effectors SA2440 and SA2452 promote survival in blood infec7onmodel.IncreasingexpressionofSA2452butnotSA2440increasessurvival inbloodalone(A)andinbloodplus cloxacillin (B) inadosedependentmanner. Increasingexpressionofbothgenesincreasessurvivalonexposuretociprofloxacin(C).SA2440butnotSA2452promotessurvivalonexposuretogentamicin(D).
Conclusions• Bloodappearstohaveaninhibitoryeffectontheac@vityofcertainan@bio@cs.
• SigBpromotessurvivalinbothbloodaloneplusincombina@onwithcloxacillin,ciprofloxacinandgentamicin.
• TwoSigBregulatedgeneshavebeeniden@fiedthatpromotesurvivalinanan@bio@cspecificmanner.
• Rethinkingtherapyinthecontextofthehost-pathogen-druginterac@onsmayleadtoinnova@vesolu@onstoenhanceexis@ngtreatmentstrategies.
References1. HealthProtec@onAgency.VoluntaryRepor2ngofStaphylococcusaureusBacteraemiainEngland,WalesandNorthernIreland,2010.London:HealthProtec@onAgency,20112. Kha@bR,etal.2006.PersistenceinStaphylococcusaureusbacteremia:incidence,characteris@[email protected]:7–143. KLewisMul@drugtoleranceofbiofilmsandpersistercellsCurrTopMicrobiolImmunol,322(2008),pp.107–131BischoffM,DunmanP,KormanecJ,MacapagalD,MurphyE,MountsW,Berger-BachiB,ProjanS.2004.Microarray-basedanalysisoftheStaphylococcusaureusσBregulon.JBacteriol186:4085–4099.
AcknowledgementsMembersofthefi`hflooroftheCentreforMolecularBacteriologyandInfec@onatImperialCollegeLondon,andtheEdwardsgroupinpar@cular,areacknlowedgedfortheir invaluable support. This work is funded by the MRC as part of a clinicalresearchtrainingfellowship
SigBpromotessurvivalinblood
010100010100AHT
WTΔsigB
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gentamicin
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8cloxacillin
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SigBregulatedgenesmodulatesurvivalinblood+/-
an7bio7cs
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0 2 4 610
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B
Figure3.IncreasingsigBexpressionincreasessurvivalofS.aureusinbloodpluscloxacillinciprofloxacinandgentamicin(A,B,C)butnotonexposuretobloodplusvancomycinorclindamycin(D,E).
A
• Aim:TocharacterisetheroleofSigBanditseffectormoleculesinthesurvivalofS.aureusinaclinicalbacteraemiamodelLewisetal3
C D E