Staphylococcusaureusisthemostcommoninvasivehumanpathogenwithassociatedinfections originatinginmultiplesettingsandpatienttypes.Infectionsduetomethicillin-resistantS.aureus (MRSA) increase patient morbidity and mortality in part due to limited therapeutic options and increasingantibioticresistancetoprimaryantibiotics.Recentevidencesuggeststhatcertainb?- lactams, traditionally considered inactive against MRSA, can enhance clinical efficacy against bothMRSAandMSSAinfectionsbysynergizingwithdaptomycin(DAP)andcationichostdefense peptides(HDPs)ofwhitecellandplateletorigins.Mechanistically,thisapparent?synergy?was initially attributed to enhancement of binding of these peptide antibiotics to the cell membrane targets in the presence of b?-lactams. Other mechanisms appear to play a role, and we have identifiedthatdiscriminativeinhibitionofpenicillin-bindingproteins(PBPs)withb?-lactamsresults indifferentialdaptomycinsynergy.Ourpreliminaryscreeningindicatesthatblockadeoftheaction ofPBP-1(eitherspecificallyorpromiscuously)isessentialtothisDAP-b?-lactamsynergyoutcome. Giventhesefindings,wepositthatb?-lactamswitheitherselectiveornonselectivePBP-1blocking activity provide multi-mechanistic and synergistic killing against S. aureus when used in combination with DAP. To test this hypothesis, we will conduct studies using three integrated Aims.
In Aim 1, we identify mechanistic interactions of PBP inhibition underlying DAP/HDP synergy with b?-lactams through manipulating PBP function and defining the compensatory impactsofDAP-b?-lactamcombinationsonkeycellwallandcellmembranefunctionalmetricsthat traditionallylinktoantimicrobialpotency.
In Aim2, wedetermineoptimalb?-lactamstrategiesin combination with DAP or HDPs against MRSA using discriminative in vitro modeling with the hollowfiberbioreactorsystem.
Aim3 establishestheoptimalcombinedb?-lactam-DAPtreatment regimens in vivo, utilizing a prototypical endovascular MRSA infection model, experimental infectiveendocarditis.Attheconclusionofthesestudies,ourresultswillidentifynewmechanisms associated with DAP?s lethal pathway and provide a potentially unique option for rescuing continueduseofDAPinclinicalpractice.Ultimately,thisprojectmaywellprovideclinicianswith improvedtreatmentstrategieswithsmarttargetedcombinationsforcomplexandrefractoryMRSA infections.
MethicillinresistantStaphylococcusaureus(MRSA)isbecomingincreasinglydifficulttocurewith primary treatments such as vancomycin and daptomycin. Due to limited new antibiotic development, it is important to identify the potential value of older antimicrobials, traditionally considered inactive, but which have shown some clinical benefit when combined with these primary MRSA antibiotics. This study will identify the antibiotic mechanisms and the optimal pharmacokinetics / pharmacodynamics of b?-lactam antibiotics in combination with daptomycin usingbothinvitroandanimalmodelingtechniques.Thestudywillenhancethetargetedselection ofappropriateantimicrobialregimensandwillhavesignificantimpactontheoutcomesofpatients withsevereMRSAinfections.Further,thisstudywillprovideinsightontreatingbacterialinfections with resistance to daptomycin, which is considered an agent of last resort for severe MRSA infections.
| Berti, Andrew D; Shukla, Neehal; Rottier, Aaron D et al. (2018) Daptomycin selects for genetic and phenotypic adaptations leading to antibiotic tolerance in MRSA. J Antimicrob Chemother 73:2030-2033 |
| Zheng, Xuting; Berti, Andrew D; McCrone, Sue et al. (2018) Combination Antibiotic Exposure Selectively Alters the Development of Vancomycin Intermediate Resistance in Staphylococcus aureus. Antimicrob Agents Chemother 62: |
