Scotland’s Contribution to the Fight Against

Antimicrobial Resistance

Highlights from the SULSA AMR Conference

Federica Giordani and Allison Jackson

AMR Conference: 26-27th April 2018

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1. SULSA’sAMRConference

2. TheSearchforNewAntimicrobials 2.1 MajorQuestionsFacingtheField 2.2 KeyChallengesinDrugDiscovery

3. AOneHealthProblemwithUnresolvedDynamics

4. TheDiagnosticProblem–SurveillanceisKey

5. AntibioticStewardshipandEducation–AClinicalandPublicHealth

Perspective

6. FundingAMRResearch

7. PosterPrizes

8. SULSAActivitiestoAddressAMRChallenges

8.1Seed-FundingCall 8.2Scottish(SULSA)AssayDevelopmentFund8.3AMRComic8.4SULSAReport:Scotland’sWaronGerms8.5PublicHealthEngland’sAntibioticGuardianAwards

9. AMRConsultation

10. X-AMR–NewMicrobiologySocietyPop-upJournal

11. SpecialThanks

AppendixA–SULSAAMRConsultation

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1.SULSA’sAMRConferenceResistancetotheantimicrobialsweusetocontrolpotentiallydeadlyinfectionscausedbybacteria,fungi,virusesandparasiteshasbecomeasignificantthreattoglobalhealth.Keypointsstilltobeaddressedbyresearchandpolicy,andpotentialsolutionstofightthisthreatwererecentlydiscussedduringameetingheldbySULSAinGlasgow.

Overtwodays160delegates;123researchersfromUniversitiesacrossScotland,including54earlycareerresearchers,plus37otherrepresentativesfromtheWellcomeTrust,theMedicalResearchCouncil,governmentbodiesandindustrycametogetherattheTechnologyandInnovationCentreat the University of Strathclyde, Glasgow. Delegates shared their expertise and explored howScotlandcanworktogethertoaddressantimicrobialresistance(AMR).

The conference, organised by the Scottish Universities Life Sciences Alliance (SULSA,www.sulsa.ac.uk),aimedatfacilitatingcollaborationsandcommonapproachestotacklewhatisrecognisedinternationallyasafundamentalthreattoglobalhealth.Thefirstdayfocusedonresearch,thesecondonpolicyandintegratingstrategies(includingfunding)tocounterdrugresistance.

Scotland,with itswell-establishedandhighly respectedantimicrobial researchandproductdevelopmentlandscape,hasalreadybeguntograpplewiththeproblemofAMR,andisnowtryingtofurtherboostresearchandinnovationinthefield.Themeetingaffordeddelegatesthe opportunity to discuss issues related to AMR (both from a clinical and a researchperspective)andtoseeanoverviewoftheprogressbeingmade.

2.TheSearchforNewAntimicrobials

SincethediscoveryofpenicillinbytheScottish-bornAlexanderFlemingin1928wehavetakenantibioticsforgranted.However,thingsarenowchanging.Aworryingrise indrugresistantbugs means we risk losing these “wonder drugs” which protect us from potentially life-threateninginfections.

Thisstateofaffairscallsforreinvigoratedeffortsinthepursuitofnovelantimicrobials,anareaofresearchwhichhassufferedapharma“discoveryvoid”sincethelate1980s.NewweaponsareneededtofightresistantpathogenicbacteriabutalsoothernastymicroorganismssuchasfungiCandidaauris,the“MRSAofmycology”.Unfortunately,aspointedoutbyProfessorNeilGow from the University of Aberdeen, fungal infections attract little attention or funding,despiteaffectingoverabillionpeoplegloballyandcausingtwiceasmanydeathsasmalaria.

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Source:SlidefromDrDeborahO’Neill,Novabiotics,SULSAAMRConference(April,2018)

Antibacterialdrugdiscoveryisequallychallenging.Researchershavetotakeintoaccountthemultiplemechanismsthatbugshaveevolvedtoescapebeingkilled,asexplainedbyProfessorIanGilbert,fromtheUniversityofDundee.Thesedefencemechanismsincludeeffluxpumpsandtheformationofbiofilms,whichthensupportpersisters:metabolicallyinactivebacteriaeitherresistantortoleranttodrugs.DrAlisonMatherfromtheQuadramInstituteexplainedhowthisnewinterdisciplinaryinstituteisworkingattheinterfaceoffoodscience,gutbiology,humanhealthanddiseasetoaddressAMR.

Despite the difficulties, some innovative tools are being developed. Professor ColinSuckling(TheUniversityofStrathclyde)presentedacollaborationwithMGB-Biopharmaandtheirnewclassofanti-infectiveminorgroovebindercompoundsagainstClostridiumdifficile.ThesecompoundsarecurrentlyinphaseIIclinicaltrials.SucklingbelievesthatS-MGBs,whenfullydeveloped,havethepotentialtomakeasubstantialcontributiontoanti-infectivetherapywith a greatly reduced risk of the rapid emergence of resistance. A truly new class ofcompoundswithnovelmodeofaction,liketheseminorgroovebinders,waslastseenintheyear2000.

Source:SlidefromProf.ColinSuckling,UniversityofStrathclyde,SULSAAMRConference(April,2018)

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Acompletelydifferent approachwas illustratedbyDrDeborahO’Neil (Novabiotics)who istargeting infection by using host-derived non-antibiotic antimicrobials. Novabiotics iscapitalising on host defence systems that have co-evolved with microbes, developed tomitigateresistance.Twooftheirre-engineeredhumanimmunedefencemoleculesarealreadyinclinicaltrialsandmoreareinpreclinicaldevelopment.InMarch2018,theFDAgrantedFastTrackDesignationforNovaBiotics’orallyadministeredformofLynovex®forthetreatmentofacutepulmonaryexacerbationsincysticfibrosis.Lynovex®isafirst-in-classdualmucoactive-antibiotictherapyforCF,currentlyinaglobalPhaseIIbclinicaltrial.

Source:SlidefromDrDeborahO’Neill,Novabiotics,SULSAConference(April,2018)

In the near future novelmedicinesmight be discovered among the unknownmetabolitesofactinomycetes,thesamebacteriathatproducemostoftheantibioticswecurrentlyuse,asshownbytheworkofDrKatherineDuncan(TheUniversityofStrathclyde).Therewasalotofdiscussionaroundnaturalproductsduringthemeeting.

During thebreakoutsessionSpeeding theantibioticdiscoverypipeline, ledbyProfessor IanGilbert, themajor questions facing the fieldwere identified and discussed, alongwith keychallengesresearchersface.MappingofScottishexpertisewasalsodone–weareverystronginareassuchasdrugdiscoveryandnaturalproducts.Thediscussionidentifiedaneedforaworld-wide facility like the Synchrotron for structure elucidation of natural products. E.g.NationalCentreforMetaboliteAnalysis

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2.1MajorQuestionsFacingtheField

• Whatarethekeychallengestodevelopingnewantibioticsandhowdowesolvethem?• Howdowefindthebestdrugtargets?• Arethereanyquickwins?• Howcanwespeedupthedrugdiscoveryprocess?• DowehavetherightTargetProductProfiles/CompoundProgressionCriteria?• Sideeffects(lowtoleranceforthem)• Reviewofdrugsthathavefailed• Deliveryapproaches• De-replication• Doweneedstaticorcidalantimicrobials?Doweneednarroworbroadspectrum?

2.2KeyChallengesinDrugDiscovery

§ Obtainingsufficientcompoundlevelsincellso Difficultygettingcompoundsintobacteriao Moleculesareoftensubjecttoefflux

§ Resistance(anditsrapidgeneration)§ Biofilms§ Persisters (dormant or slow growing bacteria that are often resistant to current

antibiotics)§ Funding,particularlygapsinfundingdrugdiscovery

o Ofnote,theSULSAAssayDevelopmentFundrunbytheEuropeanLeadFactoryinNewhouse,hashadanotherfundinground(closed1stJuly2018).Thisfundhelpsresearchers progress assays to readiness for industry-standard HTS campaigns.

3.AOneHealthProblemwithUnresolvedDynamics

TheintroductionofnovelantimicrobialsisonlyonepartofthesolutiontocombatAMR.Historytellsusthatforeverynewantibioticintroduced,resistanceissoontobefound.AMRisfoundeverywhere in our environment as bugs evolve these defences to compete with othermicrobes.

Humans, farm animals and the environment interactwith each other and their respectivebacterial partners. Bacteria, theirmobile genetic elements and drug residues canmove inbetweenthesethreeinterconnectedplayersinwaysweareonlystartingtounravel.AMRisaquintessentialOneHealthissue.Onlyanintegratedapproach,withinterventionsinallthreeofthesedomains,willhaveanimpact,ProfessorMarkWoolhouse(UniversityofEdinburgh)stressed.Hepointedoutthatfailuresinglobalsurveillancemaybepreventingearlydetectionofantibioticresistantisolates.

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Source:AMRinaOneHealthIssue,Woolhouse&Ward(2013)

DuringthebreakoutsessionAOneHealthapproachtotacklingAMR,ledbyProfessorDominicMellor(UniversityofGlasgow),delegatesexploredwhatexactlytheterm“OneHealth”means,andhowtheuseofthisterminologycanconfusetheissue.DelegatesagreedthattheAMRcommunityneedstofindawaytobringpeopletogethertofosternetworking,tomakepeopleawareofeachother’sworkandbroadentheirownunderstanding,becauseofthebreadthoftopicsthatcomeundertheOneHealthumbrella.Itwasagreedthatthelackofconsensusinthedataformatbetweenagencies,andthewayinwhichdataisinterpretedforpeople’sownusecanbeaproblem.Whilstthereisgoodfundingfordatageneration,thereremainsverylittlefordataanalysisandmining,andintegrationofdatafromdifferentsources.Finally,thelackofcommunicationbetweentheresearchandpolicycommunitiesshouldbeaddressed.Humanhealthis inextricablylinkedtoenvironmentalhealth,andtherewasagreementthattheAMRcommunityshouldworktogethertoinitiateastrategicformulationofsolutions.

4.TheDiagnosticProblem–SurveillanceisKey

Ofallthekeypointsexploredduringtheconference,theabilitytohavefaster,cheaperandmore sensitive diagnostic abilitywas a clear priority.When it comes to the clinic, the firsthurdleisthecorrectandpromptidentificationoftheinfectiousagentanditspotentialdrugresistance spectrum. This information is needed to allow the selection of the appropriatetreatment,avoidingthemisuseofantibioticswhichisassociatedwithresistancedevelopment.

However, as Dr Till Bachman, from The University of Edinburgh, pointed out, rapiddiagnostics is still an unmet need in clinical microbiology. He and his team are working

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onseveralprojectsaimedatshorteningthetimerequiredforadiagnosisthatcurrentlycantakeupto72hours.ProfessorStephenGilliespiefromTheUniversityofStAndrewsreiteratedtheclinicalneedstressinghow inGPsurgeriesandclinicsmostdiagnostics fail tomakeanimpactbecausetheytake longerthanthe ideal30minutesforaresult.Fundingchallengessuchasthe£10mLongitudePrize(www.longitudeprize.org/challenge),whichisawardedforinvention of an affordable, accurate, fast and easy-to-use test for bacterial infections, arehelpingdriveresearcheffortsindiagnostics.

DespitetheglobalrecognitionofAMRasaproblemandthelaunchofinitiativessuchasGlobalAMR Surveillance System (GLASS) and Global PPS we have no clear picture of how AMRspreads.AsProfessorDilipNathwani(NHSTayside,UniversityofDundee)emphasised,bettersurveillancedataarerequired.DuringthepanelsessiondelegatedexploredthequestionIsanAMRArmageddonreallyuponusorarereportsexaggerated?Theanswer?Wedonotreallyknowasexhaustiveepidemiologicaldataisnotavailable.Sofar,mostofourdataonAMRisbasedonreportedclinicalcaseswith littleknownontheextentofresistantbacteria inthegeneralpopulation.

DuringtheDiagnosticsbreakoutsession,ledbyDrTillBachmann,delegatesexploredtheissueofidentifyingthemicrobe,orhavingenoughsensitivity,andhowthislinkstoconfidencelevelsrequiredbydoctorstonotprescribeadrug.Attendeesalsodiscussedthevalueofdata–andifmorewas better and if all datawas valuable, as bad data can lead to bad choices andsometimesitmightbebettertonothaveanydata.Thisisoftenhighlightedinthedifferencesbetweenaresearcherandclinician’spointofview,aswellashowdataisinterpreted.5.AntibioticStewardshipandEducation–AClinicalandPublicHealthPerspective

Professor Dilip Nathwani also explored how we could improve antibiotic stewardship andimprovepatientoutcomesbyaskingwhatdatadocliniciansneed?Itwasagreedtheyrequirea multitude of information: Good informatics including local epidemiology, genomic andphenotypicinformation,otherdatatosupportriskprofiling,rapiddiagnostics,backedupbygoodstewardshipwhichrequireslearningfromimplementationscience.Theeffectivenessofinterventionsmustbemeasuredby their impactonpatientoutcomes.George Leahy fromPublicHealthEngland (PHE)described theUK’sAMRStrategy2018-2023andPHE’s role indeliveringit.PHEdoesthisviasurveillanceandintelligence,generatingandusingtheevidence-base, analytics and modelling, providing advice on setting ambitions, designing incentiveschemes, behavioural insights,marketing, and advocacy through theirAntibioticGuardiansandKeepAntibioticsWorkingcampaigns.

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Source:PublicHealthEngland,2018

Equality and social issuesmust alsobepartof theequationwhen tacklingAMR.ProfessorEleanorAndersonfromHealthProtectionScotlandpointedoutthatinScotland,1in8peopleareadmittedtoahospitaleachyear,andofthosepatients,1in3areprescribedanantibiotic.ToreducethisHPSsuggeststhatallpractices(notjustthehighprescribers)shouldengageinefforts to improve antimicrobial stewardship. Better diagnostic coding, more preciseprescribingguidelines, andadeeperunderstandingofappropriate long-termantibioticusewouldallowidentificationoffurtherpossibilitiesforreductionsinuse.

DrJonathanPearcefromtheMRCsaid“AMRis‘glocal’”:asharedproblemwithdifferentlocaldrivers.Eachdriverwillneedtobeconsideredwhenplanninginterventionssuchasrestrictionsontheuseofantibiotics.Ontheotherhand,accesstoantibioticsforthosewhocannotaffordthemshouldbeaninternationalpriority.

DrClareTaylor(EdinburghNapierUniversity)showedthateducationofnotjustmedicalstaffandveterinarians,butalsoofthegeneralpubliconthetopicofAMRandtheresponsibleuseofantibioticsisessentialaspartoftheefforttoprolongthelifespanoftheselife-savingdrugs.Ultimately,whileAMRisprimarilytheconsequenceofinappropriateprescribing,itoccursinthe wider context of many public health considerations, including an ageing population,multimorbidityandsocio-economicdriversonhealth.

Oneissuethatwasdiscussedthroughouttheconference,wasside-effectsofantimicrobials.Patientswilltoleratequitesevereside-effectsofcancertreatmentforexample,butarenotpreparedtoendurelittle/anyside-effectsofanantibiotic,whichthereforemakestheapprovalofnewtreatmentsevenmoredifficult.Duringthebreakoutsession,ClinicalconsiderationsinAMR, ledbyProfessorDilipNathwani, delegatesexploredwhydoctors areoverprescribing

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antibiotics,aswellasthelackofdiagnostictestsavailableelsewhere-forexampleinAmericayoucanperformaquickdiagnostictesttoidentifyifaninfectionisviral.Therewasalotofdiscussionaroundwhypatientsareoftennon-compliant,versuswhattheevidenceisforthedurationoftreatment,andhowthesefeedthedevelopmentofresistance.

During the breakout session led by Dr Eleanor Anderson, Public Health considerations indealingwithAMR,delegatessurveyedwaysinwhichevidenceofenvironmentalimpactcouldbeintegratedintopublichealth.ItwasagreedthatAMRisineffecta“primer”towardsamoreintegratedoutcomeofpublichealth:eatinghabits,lifestyleandthegutmicrobiome,andthatAMRneedstobesetinthecontextofsocio-economicdeterminants.

6.FundingAMRResearch

Jonathan Pearce of UKRI (Medical Research Council) presented the UKRI’s AMR initiativefundingportfolio,whichspansthemedfundingcalls,JPIAMRcalls,NewtonfundingandGlobalChallengeResearchFundingcalls.Jonathansaidthatitappearedthathealtheconomicswasbeingunderutilisedandthattherewereprospectsforleveraginghealthrecorddata(andthatgivenScotlandhasexcellentmedicalrecords,thiscouldbeanopportunity).Inaddition,giventhevalueinprioritizingdrivers/interventionsinasystemsapproach,multi-scalemodellingmaybeworthyofpromoting.Healsopointedouttherecouldbebetterintegrationoftransmissionstudieswhilstensuringtheyarelinkedtoimpacts(forexampleontheenvironment).Healsostresseditisimportanttopromotefurtherintegrationbetweenthesocialandbio-sciences.

Source:MedicalResearchCouncil,2018

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MikeTurnerfromtheWellcomeTrusthighlightedthatWellcome’sapproachtofundingAMRgenerallyreliedonsupportinglarge-scaleinitiativeswheretheconsortiumisinvitedtoapplyforfunding,andtheyhavecommitted£175mover5yearsfortargeted,outcomeledprojects.However, Turner stressed that responsive-mode funding will continue to support AMRresearch.Wellcome has spent £287m in AMR since 2004, including: basic science (£108),translation (£122m), and epidemiology (£34m). He said that there had been significantinvestmentintranslationalresearchfortherapeuticsinasmallernumberofprojectscomparedtobasicscience,butthattheyhavegivenlittlesupportfordiagnosticsorpublicengagement.He highlighted the CARB-X Drug discovery pipeline project, to whichWellcome has given£125min5years,whichhassupported34projectstodatein7countries.DuringthebreakoutsessionMaximisingfundingopportunitiesforAMRresearch,ledbyDrNickTucker,delegatesexploredwaysinwhichAMRresearchcouldgetfurtherfunding,forexampleviaDTPprogrammes,aswellastheneedfor interdisciplinaryworking.Whilsttherewasanagreementthatnetworkswereagoodidea,achallengeidentifiedwasidentifyingwhoshouldbe involved.ForAMRresearch,whichrequiresabroadspectrumofdisciplines, thiscanbedifficult.Onetake-homemessagefromthefunders’talkswasthatfundersarehappytodiscussresearchideasandthatresearchersshouldnotshyawayfrommakingcontactwiththefunderstodiscusstheirideas.7.PosterPrizesTherewere49posters displayedduring the conference. Prizeswere awarded for thebestpostersasjudgedbythesteeringcommittee:

Winners:RuthBowness(StAndrews)-Usingindividual-basedmathematicalmodelstostudyantibioticresistanceRebeccaTonnerandFionaHenriquez(UniversityoftheWestofScotland)-Genesofpast,presentandfuture:doeslegacypollutioncontributetoantibioticresistanceinindustrialisedestuaries?HighlyCommended:MadhuriBarge(Glasgow)–DevelopingproteinantibioticsfortreatmentofAMRPseudomonasaeruginosaRebecca McHugh (Strathclyde) – Exploring Aurodox, Apotential anti-virulence compound for the treatment ofEscherichiacoliinfectionsofthegut

Image:Prof.MikeBarrett,SULSADirector,andRebeccaMcHugh,winnerofhighlycommendedprize

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8.SULSAActivitiestoHelpAddresstheChallengesofAMR

8.1Seed-FundingCallTo continue themomentum started at our AMR conference, the Scottish Universities LifeSciences Alliance (SULSA) are providing funding for collaborative projects to address thechallenges surroundingantimicrobial resistance.This funding is toenable researchers fromdifferentScottishUniversitiestocollaboratetogatherpreliminarydataanddevelopproposalswiththeaimofattractingfurtherfundingfromexternalsources.Thesuccessfulapplicationswere:• Prof.RosalindAllen(Edinburgh),Prof.GailMcConnell(Strathclyde)andNicholasBommer

(Edinburgh):Catheter-associatedurinarytractinfections:linkingAMRtobiofilmformation.• Dr Stephen Fox (Glasgow), Dr Cosmika Goswami (Glasgow) and Dr Kerry Pettigrew (St

Andrews):GenomeSequencingofCarbapenemase-ProducingEnterobacteriaceae(CPE)fromScottishHospitalsforAMRgenesandtheirmobileelements.

• DrGillianHalket(Strathclyde)andProf.CarolMunro(Aberdeen):AntifungalpotentialofcompoundsproducedbythermophilicActinobacteriafromcompost,uponstrainsofazoleresistantAspergillusfumigatus.

• DrCharlesKnapp(Strathclyde),DrFionaHenriques(UniversityoftheWestofScotland),Prof.RosalindAllen (Edinburgh),DrAndrewFree (Edinburgh),DrEulynPagaling (JamesHuttonInstitute),DrLisaAvery(JamesHuttonInstitute)andDrRichardAllan(JamesHuttonInstitute):Theeffectofdrinkingwatertreatmentonantimicrobialresistance.

• DrKatherineDuncan(Strathclyde),DrEulynPagaling(JamesHuttonInstitute),Prof.TimDaniell (JamesHutton Institute),Prof.RosalindAllen (Edinburgh)andDrSimonTitmuss(Edinburgh):Microbialmicrofluidicdrugdiscovery–21stCenturyinnovationtoacceleratetheFlemingantibioticdiscoverypipeline.

• DrTillBachmann(Edinburgh),Prof.AndrewPorter(Aberdeen),DrSoumyaSomanPalliyil(Aberdeen)andDrHolgerSchulze(Edinburgh):Electrochemicalbiosensorforthedetectionofbacterialquorumsensingcompoundsinrespiratorydiseases.

8.2Scottish(SULSA)AssayDevelopmentFundThis fund, runby theEuropeanLeadFactory inNewhouse,hashadanother fundinground(closed1stJuly2018).Manyscientists inSULSAuniversitieshavediscoveredscientifically interesting,highquality,novel molecular targets and assays. However, they are a long way from being in an HTScompatibleassayformat.Thisfundhelpsresearchersprogressassaystoreadinessforindustry-standardHTScampaigns.Thefundcoversconsultancybyexperiencedscreeningscientists,apilotscreenofca.5000compounds,andconsumables.

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8.3AMRComicSULSAhasproducedacomichighlightingthehistoryofantimicrobialdiscovery,howantibioticresistanceisspreading,andtheimpactoveruseantibioticsarehaving. IncollaborationwithPublicHealthEngland,thesecomicswillbefreelyavailablefordistribution.

Credit:WrittenbyIsabelVincent,drawnbyGaryErskineandcolouredbyYelZamor

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8.4SULSAReport:Scotland’sWaronGermsSULSADirector,MikeBarrett,haswrittenaSULSAreportScotland’sWaronGerms,detailingScotland’sroleinthehistoryofantibioticdiscovery,andinassuringanantimicrobialfuture.Thisreporthasbeensenttofunders,journalistsandgovernmentofficials,andisavailabletodownloadatwww.sulsa.ac.uk/sulsa-reports.

8.5PublicHealthEngland’sAntibioticGuardianAwards

Because of the conference, SULSA was shortlisted for the2018PublicHealthEngland’sAntibioticGuardianAwards inthe research category. These awards champion thoseorganisations and individuals who have demonstratedachievement in tackling antimicrobial resistance at a local,regionalornationallevel.

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9.AMRConsultationSULSAResponsePleaseseeAppendixAtoreadourAMRconsultationresponse.10.X-AMR–NewMicrobiologySocietyPop-upJournalAntimicrobial resistance (AMR) is a cross-disciplinary issue, with ground-breaking studiescurrently bringing together clinicians and modellers, veterinary and soil scientists,microbiologistsandanthropologists.Yetfindingahomefortheuniquepublicationsfromthisresearch isdifficult.TheMicrobiologySociety isprovidingsuchahomewithanewpop-upjournalforcross-disciplinaryresearchonantimicrobialresistance:X-AMR.

X-AMRisauniqueplatformforallresearchersfrommicrobiologists,clinicians,epidemiologists,socialscientistsandpolicymakerstophysicists,chemistsandengineers,toensurethatcross-disciplinaryantimicrobial resistance (AMR) researchacrossdisciplinesgets thevisibilityandimpactthatitdeserves.Allourcontentwillbefree-to-readimmediatelyonpublicationwithoutanyrestrictions.

Simply choose theMicrobiology Society journal (Microbiology, Journal ofGeneral Virology,JournalofMedicalMicrobiology,orMicrobialGenomics) thatbest fitswithyourarticleandsubmit your work as normal through the journal’s online submission system, mentioning‘SubmissiontoX-AMR’inthecoverlettertohelpassignittothecorrectEditor.Anyarticlesthat are outside the typical scope, for example material sciences, should be submittedtoMicrobiology.Formoreinformationseewww.microbiologyresearch.org/about/xamr.11.SpecialThanksWewouldliketothanktheConferenceSteeringCommittee:• DrEleanorAnderson(HealthProtectionScotland)• DrTillBachmann(TheUniversityofEdinburgh)• Professor Mike Barrett (SULSA and Wellcome Centre for Molecular Parasitology, The

UniversityofGlasgow)• ProfessorTomEvans(UniversityofGlasgow)• ProfessorIanGilbert(DrugDiscoveryUnit,TheUniversityofDundee)• ProfessorStephenGillespie(TheUniversityofStAndrews)• ProfessorNeilGow(MRCCentreforMedicalMycology,TheUniversityofAberdeen)• DrPaulHerron(UniversityofStrathclyde)• ProfessorDominicMellor(TheUniversityofGlasgow)• ProfessorDilipNathwani(TheUniversityofDundeeandNHSTayside)• ProfessorDavidSmith(HeriotWattUniversity)

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Wewouldliketothankourspeakers:§ Professor Neil Gow, University of Aberdeen: Medical Mycology and AMR: A Rapidly

EmergingProblemandGlobalHealthChallenge§ DrClareTaylor,EdinburghNapierUniversity:ApplyingMicrobiologytotheAntimicrobial

Problem§ ProfessorMarkWoolhouse,UniversityofEdinburgh: IsThereaLinkBetweenAntibiotic

UsageinLivestockandAMRinHumanPatients?§ DrKatherineDuncan,UniversityofStrathclyde:OmicsGuidedAntibioticDiscoveryfrom

OurOceans§ ProfessorIanGilbert,UniversityofDundee:ChallengesinAntibacterialDrugDiscovery§ DrDeborahO’Neil,Novabiotics:Novel,ImmuneSystemBasedApproachestoTacklingAMR§ Dr Till Bachmann, University of Edinburgh: Rapid Diagnostics to Combat Antimicrobial

Resistance§ Dr Alison Mather, Quadram Institute: Whole Genome Sequencing to Understand the

EpidemiologyandTransmissionofAntimicrobialResistance§ ProfessorColinJSuckling,UniversityofStrathclyde:StrathclydeMinorGrooveBinders(S-

MGBs),AFamilyofAnti-InfectiveAgents§ ProfessorMikeTurner,WellcomeTrust:FundingforAntimicrobialResistanceResearchat

Wellcome§ DrJonathanPearce,MRC:AMR–ACross-DisciplinaryandGlobalChallenge§ Professor Dilip Nathwani OBE, University of Dundee, NHS Tayside: Global and UK

EpidemiologyandBurdenofMulti-DrugResistantBacteria§ DrEleanorAnderson,HealthProtectionScotland:ControlofAMRinScotland§ GeorgeLeahy,PublicHealthEngland:ShapingPHE’sRoleintheDevelopmentoftheNext

5YearActionPlanWewouldliketothankoursponsorsfortheirsupport:• GlasgowPolyomics• MarksandClerk• SEFARI• TheSocietyofMicrobiology

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AppendixA.SULSAAMRConsultationResponseWrittenevidencefromtheScottishUniversitiesLifeSciencesAlliance(SULSA)

WrittenevidencesubmittedbyScottishUniversitiesLifeSciencesAlliance(SULSA)whichhighlightstheworkofSULSAmemberscontributingtothedeliveryoftheAMRstrategy.

AboutSULSA

1.TheScottishUniversitiesLifeSciencesAlliance(SULSA;www.sulsa.ac.uk)isastrategicpartnershipofnineScottishUniversities(Aberdeen,Dundee,Edinburgh,Glasgow,HeriotWatt,Napier,RobertGordon,Strathclyde,andStAndrews)thataimstodrivethelifesciencesresearchsectorinScotlandtoensureitsglobalcompetitiveness.Ourmainstrategicaimsaretobuildcompetitiveconsortiaandwinmajorresearchfunding,supportresearchfacilitiesandnetworks,andhelpearlycareerresearchersadvancetheircareers.WealsoprovidepolicyadviceonbehalfoftheScottishlifesciencescommunity.

Response:

2.TheUKAMRStrategy2013-18setoutthefollowing3strategicaims:

i)ImprovetheknowledgeandunderstandingofAMR

ii)Conserveandstewardtheeffectivenessofexistingtreatments

iii)Stimulatethedevelopmentofnewantibiotics,diagnosticsandnoveltherapies

Withinthesethreeaims,therewere7keyareasforfutureactionidentified.BelowwehavegivenexamplesofwhereSULSAmembershavecontributedtothesefocusedstrategicareas.

Area1:Improvinginfectionpreventionandcontrolpractices

3.SULSAmembersattheUniversityofAberdeen1haveproducedfindingswhichhavehelpedunderpintheEuropeanFoodSafetyAuthority(EFSA)scientificopiniononquantifyingtheriskofhumancampylobacteriosisposedbyconsumptionofbroilermeatintheEU(EFSAPanelonBiologicalHazards(BIOHAZ).ThisprovidedtheimpetusforEFSAtoproduceanopiniononcontroloptionsandperformanceobjectivesinbroilermeatproductionforCampylobacterwhichresultedintheCommissionsettingperformanceobjectivesforCampylobacterinbroilerproductionwithintheEU.TheresultsfromtheCaMPSstudieshavefedintothelatestAdvisoryCommitteeontheMicrobiologicalSafetyofFoodreportonCampylobacterthatisduetobereleasedlaterthisyearandpublished/presented/citedbyFoodStandardsScotlandandFoodStandardsAgency.

1www.abdn.ac.uk/smmsn/research/impact/combating-campylobacter.php

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Area2:Optimisingprescribingpractice4.SULSAmembersattheUniversityofStrathclydehavebeeninvolvedinthedevelopment,implementationandevaluationofantibioticguidelines2.AdultguidelinesforvancomycinandgentamicinprescribingandmonitoringweredevelopedandimplementedthroughoutScotlandin2009.Evaluationoftheseguidelinesidentifiedpracticeissuesthatledtothedevelopmentandimplementationofnewprescribingsupportresources.Arecentre-audithasdemonstratedimprovementsinpractice.Furtherdevelopmentofvancomycinguidelinesforobesepatientsisunderway.Otherstudieshaveachievedanimprovementintheuseofvancomycininneonatalandpaediatricintensivecarepatients.Currentworkisunderwaytoevaluateamikacindosingguidelinesforthetreatmentofmycobacterialinfectionsandantibioticdosageregimensforinfectionprophylaxisincolorectalsurgery.

Area3:Improvingprofessionaleducation,trainingandpublicengagement

5.InApril2018,SULSAheldatwo-dayconferenceonAMR3withtheaimofinformingandcoordinatingfundamentalandappliedresearchactivityonAMRwithinSULSAuniversitiesandotherrelevantorganisationsinScotland.Themeeting,with160delegates,coveringbothresearchandpolicyrelatedtoAMRisfeaturedinablog4.Becauseoftheconference,SULSAwasshortlistedfor2018PublicHealthEngland’sAntibioticGuardianAwards5intheresearchcategory.Theseawardschampionthoseorganisationsandindividualswhohavedemonstratedachievementintacklingantimicrobialresistanceatalocal,regionalornationallevel.

6.SULSAcommissionedacomic6(WrittenbyIsabelVincent,drawnbyGaryErskineandcolouredbyYelZamor)highlightingthehistoryofantimicrobialdiscovery,howantibioticresistanceisspreading,andtheimpactoveruseantibioticsarehaving.IncollaborationwithPublicHealthEngland,thesecomicswillbefreelyavailablefordistributioninthenearfuture.

7.SULSADirector,MikeBarrett,haswrittenaSULSAreportScotland’sWaronGerms7,detailingScotland’sroleinthehistoryofantibioticdiscovery,andinassuringanantimicrobialfuture.Thisreporthasbeensenttofunders,journalistsandGovernmentstakeholders.

8.SULSAmembersatUniversityofStrathclyde,EdinburghandEdinburghNapierUniversityareactivewithinMicrobiologySocietyandSocietyforAppliedMicrobiologybothofwhichpromoteeducationandengagementwithAMR,primarilythroughLearnedSocietiesPartnershiponAntimicrobialResistance(LeSPAR).

2http://impact.ref.ac.uk/CaseStudies/CaseStudy.aspx?Id=422873http://www.sulsa.ac.uk/amr/4http://blogs.biomedcentral.com/bugbitten/2018/05/18/scotlands-contribution-to-the-fight-against-antimicrobial-resistance-highlights-from-the-sulsa-meeting/5http://antibioticguardian.com/antibiotic-guardian-2018-awards-shortlist/6http://www.sulsa.ac.uk/amrcomic7http://www.sulsa.ac.uk/sulsa-reports/

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9.TheMicrobiologySociety’sAntibioticsUnearthed8programmehasbeenadoptedintoundergraduatecurriculaatGlasgow,EdinburghandEdinburghNapierUniversities9topromotestudentengagementwithAMR.

Area4:Developingnewdrugs,treatmentsanddiagnostics

10.Followingthetwo-dayAMRconference,SULSAlaunchedacallforseedfundingtostimulatecollaborativeprojectstoaddressthechallengessurroundingantimicrobialresistance10.

11.TheScottishBiologicsFacility(SBF)11atUniversityofAberdeenhasdevelopedaportfolioofmonoclonalantibody-basedbiologicsfortheearlydetection,diagnosisandtreatmentofbacterialandfungalinfections.TheSBFhasastrongresearchinterestindevelopingnoveltherapeuticsthatcanpreventbacterialinfectionsbycontrollingtheexpressionofvirulencefactorsinGramnegativeorganisms.These‘anti-pathogenic’drugsarelesslikelytoencouragethedevelopmentofresistanceinbacteriacomparedtoconventionalantibiotics.

12.WithfundingfromInnovateUK12,theUniversityofDundeehascreatedanAntibacterialDrugDiscoveryAccelerator(ADDA)13withtheaimofcarryingoutearlyphaseantibacterialdrugdiscovery.ThisinvolvestranslatingfundamentaldiscoveriesfrommicrobiologistsacrosstheUKintodrugdiscoveryprojects,todevelopnoveldrug-leadstopartnerwithnot-for-profitorcommercialpartners.Thisisanareaforwhichitisdifficulttoobtainfunding,butiscriticaltotheAMRagendatodevelopnovelmode-of-actionantibacterials.

13.ResearchersattheUniversityofGlasgow14havebeeninvolvedinresearchtoimprovethesynthesisofTeixobactin-derivedcompoundswithpotentactivityagainstStaphylococcusaureus.

14.AnantibioticdevelopedatUniversityofStrathclydeisabouttoenteraphase2clinicaltrial.IncollaborationwithMGB-BioPharma,InnovateUKhasawarded£2.78milliontofundthephase2clinicaltrialofMGB-BP3,thefirstinanewclassofdrugsfortreatingClostridiumdifficile15.

8https://microbiologysociety.org/education-outreach/antibiotics-unearthed.html9https://microbiologysociety.org/education-outreach/antibiotics-unearthed/undergraduate-programme.html10http://www.sulsa.ac.uk/seed-funding/11www.abdn.ac.uk/sbf12https://www.dundee.ac.uk/news/2017/innovate-uk-grant-to-boost-discovery-of-new-antibacterial-drugs.php13http://www.drugdiscovery.dundee.ac.uk/portfolio/antibacterial-drug-discovery-accelerator-adda14http://www.chem.gla.ac.uk/jamiesonlab/#15https://www.strath.ac.uk/whystrathclyde/news/fundingof278mforclinicaltrialsoftreatmentdiscoveredatstrathclyde/

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15.SULSA/MSDfundingcontributedtothedevelopmentofthestudiesofminorgroovebindersforDNAdiscoveredattheUniversityofStrathclyde(knownasS-MGBs).S-MGBsincludeindividualcompoundsactiveagainstbacteria16,fungi,andparasites.TheSULSA/MSD17fundingprincipallypavedthewayforasuccessfulcollaborativebidtoBBSRCfortheproject'AnewdrugdiscoveryplatformforanimalAfricantrypanosomiasis'18,aprojectinvolvingtheUniversitiesofEdinburgh,Glasgow,andStrathclyde.Thedrugdiscoverycomponentofthisprojectismovingwelltowardsidentifyingdevelopmentcandidates.

16.LongitudePrizeDiscoveryAwardtoresearcherattheUniversityofStrathclydetodevelop‘TheMicroplate’toanewdiagnostictestforantimicrobialsusceptibility19.Usinganinterdisciplinaryapproach(electricalengineeringandmicrofabricationwithmicrobiology),theprojectcombinescutting-edgeaspectsoftheseresearchareastodevelopanewantibioticsusceptibilitytestingthatcanrapidlytestantibioticsensitivityonasinglemicrochip.

17.TillBachmann20fromTheUniversityofEdinburghiscontributingtotheUKstrategyonAMRdiagnosticsthroughtheUKAMRDiagnosticsCollaborativeandhisadvisoryandjudgingrolesfortheLongitudePrizeandDiscoveryAward.

18.FundingfromtheIndustrialBiotechnologyInnovationCentre21incollaborationwithGSKisbeingusedtodevelopstablestrainsofStreptomycestoimproveclavulanicacidproductionatUniversityofStrathclyde.

19.FundingfromtheDaphneJacksonTrustissupportingafellowtoinvestigatenovelActinobacteriafortheproductionofnovelantibioticsattheUniversityofStrathclyde.

20.DrTillBachmannfromTheUniversityofEdinburghistheCoordinatoroftheTransnationalWorkingGroupRapidDiagnosticTests(AMR-RDT)22fundedthroughtheJointProgrammingInitiativeonAntimicrobialResistance(JPIAMR)23.Formedin2017,AMR-RDT24

isamulti-sectoral,multi-stakeholderandinterdisciplinaryworkinggroupwithglobalreach.Itbringstogetherover50keyindividualsandorganisationsfrom15countriesworldwidethatareactiveinthefieldofdiagnosticsandantimicrobialresistance.ThisgroupaimstoidentifybarriersforthedevelopmentandimplementationofrapiddiagnosticteststotackleAMR.

16https://pure.strath.ac.uk/portal/en/projects/the-differing-biological-fates-of-dna-minor-groovebinding-mgb-antibiotics-in-gramnegative-and-grampositive-bacteria(be25e1ea-f41d-48ac-b3f7-48d845d114e7).html17http://www.msd.com/about/our-work/amr.html18https://pure.strath.ac.uk/portal/en/projects/a-new-drug-discovery-pipeline-for-animal-african-trypanosomiasis(ea4465e8-c3b6-4e8e-be03-1131f5c63a1b).html19https://www.strath.ac.uk/whystrathclyde/news/discoveryawardforteamworkingtotackleantibioticresistance/20

https://www.research.ed.ac.uk/portal/en/persons/till-bachmann(4c731049-5ce7-4f71-9984-fb216ee36fab).html21http://www.ibioic.com/22https://www.ed.ac.uk/pathway-medicine/antimicrobial-resistance/jpiamr-amrrdt23https://www.jpiamr.eu24https://www.ed.ac.uk/pathway-medicine/antimicrobial-resistance/jpiamr-amrrdt/overview

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21.TheScottish(SULSA)AssayDevelopmentFundhasacallcurrentlyopen25.ManyscientistsinSULSAuniversitieshavediscoveredscientificallyinteresting,highquality,novelmoleculartargetsandassays.However,theyarealongwayfrombeinginanHTScompatibleassayformat.Thisfundhelpsresearchersprogressassaystoreadinessforindustry-standardHTScampaigns.Thefundcoversconsultancybyexperiencedscreeningscientists,apilotscreenofca.5000compounds,andconsumables.

Area7:Strengthenedinternationalcollaboration

22.ExamplesofinternationalcollaborationsofSULSAmembersatUniversityofStrathclydeinclude:

i)Santander/UniversityofStrathclydeInternationalResearchFellowshiptoFedericoSantaMaríaTechnicalUniversity,Valparaiso,Chile;2018

ii)SULSAEarlyCareerResearchExchange(PECRE)toWageningenUniversity,TheNetherlands“Bioinformaticsapproachestoantibioticdiscovery);2017

iii)MarineAllianceofScienceandTechnologyVisitingFellowship(Mexico),AssessingthebiotechnologicalpotentialofAntarcticandsub-Arcticsedimentcores-anewresourceforsustainableantibioticdrugdiscovery;2016–2017

iv)KMITLAcademicMeltingPot,CharacterisationofantimicrobialactivityfromMangroveSwampsinThailand;2018–2019

v)GenomiccharacterisationofantibioticproducingbacteriafromtheChileanaltiplano;2015–2019

23.InternationalcollaborationofSULSAmembersatUniversityofGlasgowandCIDEIM,Cali,Colombiatoexaminedrugresistanceinparasites,bacteriaandmosquitoes.Institutionallinkswereachievedbyavarietyofbilateraltrainingexchanges,togetherwithworkshopsandsymposia(NewtonFund).Morethan100neglectedtropicaldiseaseresearchersbenefited,andnewinter-institutionalcollaborationswereestablished,whichcontinuetodevelopandsustainreciprocaltrainingandresearchprogramsbetweenColombianandtheUKtowardsunderstandingandmitigatingtheimpactofneglectedtropicaldiseasesinLatinAmerica.

24.InternationalcollaborationledbyUniversityofEdinburghandresearchersatIndianInstituteofTechnology,Delhi.Theproject‘UserDrivenDiagnosticsSolutionsinaOneHealthApproachtoTackleAMR’(NewtonFund)26willaddressthelackofappropriateaffordablediagnosticsinuseinIndia,byengagingwiththeuserinthecommunityinhumanhealthcare,veterinaryandenvironmentalsettingtomapexistingpractiseandgatheruserneedstogeneratetargetproductprofilesanduserpersonas.Thisinformationwillbeusedtoselectexistingdiagnosticsanddevelopnoveltestinausableformat,andperformanceandprototypeservices.

25http://www.sulsa.ac.uk/z1x2c3/wp-content/uploads/2018/05/More-Information.pdf26https://esrc.ukri.org/files/funding/funding-opportunities/uk-india-amr-shortlisted-summaries/

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25.DrTillBachmann(UniversityofEdinburgh)isthefounderoftheAntimicrobialResistanceDiagnosticsChallenge27(AMRDxC;@AMR_DxC),anannualinternationalcompetitionandeventseriesthataimstogalvanisethenextgenerationofresearchersintoaction.ThiscompetitionisinspiredbytheLongitudePrize28anddrivenbytheideathatinnovationneedsinterdisciplinaryandunbiasedthinkingaswellasinternationalcollaboration.

KeyactionsandprioritiesfortheGovernment’snextAMRstrategythatwereidentifiedattheSULSAAMRConferenceinApril2018were:26.Increasedfundingandsupportforanti-fungalresearchanddevelopment.Thisiscurrentlyanareaofcriticalconcernwiththeincreasingemergenceofresistantfungalpathogens.27.Delegatesidentifiedaneedforaworld-widefacilityliketheSynchrotronforstructureelucidationofnaturalproducts.E.g.NationalCentreforMetaboliteAnalysis.28.Gapsindrugdiscoveryfunding(particularlyintranslationintolargerscreens–SULSAisaddressingthisviatheScottishSULSAAssayDevelopmentFund).29.Bettersurveillancedata(captureandassessment),andintegrationandcollaborationacrossagriculture,healthcareandenvironment.30.Increasedfundingfordata:whilstthereisgoodfundingfordatageneration,thereremainsverylittledataforanalysisandmining,andintegrationofdatafromdifferentsources.31.Improvedcommunicationbetweenresearchersandpolicymakers.32.Increasingsupportfordevelopmentofdiagnostics:ofallthekeypointsexploredduringtheconference,theabilitytohavefaster,cheaperandmoresensitivediagnosticabilitywasaclearpriority.33.Improvededucationaroundantibioticsuseforveterinaryandhealthworkers,aswellasthegeneralpublic.34.AsAMRisaOneHealthissue,whichcrossesmanydisciplinaryboundaries,strongnetworksofresearchersfromdifferentfields,clinicians,industryandpolicymakersareessentialtodriveacoordination,strategicapproachtotacklingAMR.

27https://www.ed.ac.uk/pathway-medicine/antimicrobial-resistance/antimicrobial-resistance-diagnostics-challenge28https://longitudeprize.org

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