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INTERSPECIES INTERACTION AND ANTIBIOTIC EFFICACY AGAINST STAPHYLOCOCCUS AUREUS

Investigators
Radlinski, Lauren Christine
Institutions
University of North Carolina
Start date
2018
End date
2020
Objective
Abstract Staphylococcus aureus (SA) is a major human pathogen responsible for numerous chronic andrelapsing infections. These infections often do not respond to treatment, leading to 12,000 deaths and $9.5billion in health care cost annually in the US alone. Paradoxically, during in vitro susceptibility testing, isolatesfrom these infections frequently exhibit full sensitivity to administered antibiotics, suggesting that environmentalfactors present in the host may influence SA antibiotic susceptibility. Understanding how these factors controlantibiotic susceptibility will improve the resolution of recalcitrant SA infection, and slow the evolution ofresistance. We have shown that during co-infection, interaction with Pseudomonas aeruginosa (PA) alters SAantibiotic susceptibility through 3 distinct mechanisms. PA LasA endopeptidase potentiates vancomycin-mediated lysis of SA, rhamnolipids (RLs) facilitate tobramycin uptake and killing of SA, and HQNO inducesmultidrug tolerance in SA. Using a panel of clinical isolates we further demonstrated that the ability of PA toantagonize or potentiate antibiotic efficacy against SA is variable and dependent on PA production of thesethree antistaphylococcal exoproducts. Selective pressures during chronic infection of the CF lung drive PAadaptive evolution and result in common phenotypic characteristics among late-stage CF isolates with alteredproduction of LasA, HQNO and RLs. However, the overall effect of these changes on SA antibioticsusceptibility during co-infection is unknown. I hypothesize that mutations that occur during PA adaptation tothe CF lung alter SA antibiotic susceptibility during co-infection. Further, I hypothesize that membranepermeabilization by PA RLs can be exploited to kill SA and clear chronic infection. In AIM1 I will determine how long-term adaptation to the CF lung alters PA influence on SA antibioticsusceptibility. I will use whole-genome sequencing to identify genetic hallmarks of late-stage (chronic) PAisolates that strongly potentiate or antagonize antibiotic activity against SA, relative to early-stage (acute) andreference strains. I will then introduce these and other common mutations associated with chronic PA CFinfection in acute isolates and test for loss antibiotic potentiation or antagonism against SA. In AIM2 I willexpand on our finding that PA RLs facilitate tobramycin-mediated eradication of SA to determine if targetingcell membrane permeability represents a viable treatment strategy against SA. We will identify other cellmembrane-acting agents (CMAs) capable of potentiating aminoglycoside activity, examine the capacity ofRLs/CMAs to re-sensitize tobramycin-tolerant/resistant populations, and examine the feasibility of usingaminoglycosides and CMAs as a combinational therapy against SA using tissue culture and a mouse model ofSA burn wound infection. In all, we expect that our findings will help improve our understanding of SA antibioticsusceptibility, and elucidate how such knowledge can be exploited to resolve currently unresolvable infections.!
Funding Source
Nat'l. Inst. of Allergy and Infectious Diseases
Project source
View this project
Project number
1F31AI140520-01
Accession number
140520
Categories
Bacterial Pathogens
Antimicrobial Resistance