Project Grant R21AI181224

SURFACE DEPENDENT INHIBITION OF MYCOBACTERIUM ABSCESSUS BY PSEUDOMONAS AERUGINOSA - PROJECT ABSTRACT TREATMENT OF BIOFILM-ASSOCIATED INFECTIONS, SUCH AS THOSE CAUSED BY PSEUDOMONAS AERUGINOSA AND NON- TUBERCULOUS MYCOBACTERIA (NTM), CAN BE EXTREMELY CHALLENGING, ESPECIALLY WHEN THESE INFECTIOUS AGENTS CO- INFECT THE LUNGS OF PEOPLE WITH CYSTIC FIBROSIS (CF) OR OTHER DISEASES. THIS APPLICATION SEEKS TO UNDERSTAND COMMUNITY INTERACTIONS BETWEEN P. AERUGINOSA AND THE ANTIBIOTIC RESISTANT NTM MYCOBACTERIUM ABSCESSUS. P. AERUGINOSA AND M. ABSCESSUS ARE BOTH FOUND IN THE SAME ENVIRONMENTAL RESERVOIRS AND ARE CO-ISOLATED FROM INDIVIDUALS WITH CF AND SURGICAL SITE/SOFT TISSUE INFECTIONS. INDEED, STUDIES DEMONSTRATE THAT M. ABSCESSUS POSITIVE CF INDIVIDUALS ARE MORE LIKELY TO BE INFECTED WITH P. AERUGINOSA. DESPITE THIS, THERE IS LIMITED UNDERSTANDING OF THE INTERACTION BETWEEN THESE TWO IMPORTANT OPPORTUNISTIC PATHOGENS. WE RECENTLY INVESTIGATED M. ABSCESSUS AND P. AERUGINOSA INTERACTIONS AND REPORTED SEVERAL NOVEL OBSERVATIONS. P. AERUGINOSA POTENTLY ANTAGONIZES BOTH ROUGH AND SMOOTH M. ABSCESSUS VARIANTS, YET ONLY WHEN CO-CULTURED IN DUAL-SPECIES BIOFILMS; ANTAGONISM WAS NOT OBSERVED IN PLANKTONIC CO-CULTURE. MULTIPLE P. AERUGINOSA STRAINS EXHIBITED ANTAGONISM, AND P. AERUGINOSA-MEDIATED ANTAGONISM WAS OBSERVED WITH ANOTHER NTM STRAIN, MYCOBACTERIUM SMEGMATIS. SURPRISINGLY, ANTAGONISM DID NOT REQUIRE KNOWN P. AERUGINOSA CONTACT-DEPENDENT OR -INDEPENDENT KILLING, MOTILITY, OR OXYGEN/IRON SEQUESTRATION MECHANISMS. THUS, WE HYPOTHESIZE THAT INTER- BACTERIAL ANTAGONISM OF M. ABSCESSUS BY P. AERUGINOSA IN DUAL-SPECIES BIOFILMS IS MEDIATED BY A NOVEL ANTIBACTERIAL STRATEGY. AIM 1 WILL UTILIZE SEVERAL COMPLEMENTARY STRATEGIES TO IDENTIFY THE MECHANISM OF INTERBACTERIAL ANTAGONISM. AIM 2 SEEKS TO INVESTIGATE M. ABSCESSUS AND P. AERUGINOSA INTERACTIONS UNDER CONDITIONS THAT CLOSELY MIMIC THOSE FOUND IN THE HOST. THE GROWING PREVALENCE OF M. ABSCESSUS INFECTIONS AND THEIR RECALCITRANCE TO BOTH HOST CLEARANCE AND ANTIBIOTICS HIGHLIGHT AN URGENT NEED TO FIND NEW STRATEGIES TO SUCCESSFULLY TREAT THESE PERSISTENT INFECTIONS. SUCCESSFUL COMPLETION OF THIS PROPOSAL WILL ADVANCE OUR UNDERSTANDING OF THE NOVEL P. AERUGINOSA ANTAGONISTIC MECHANISM TOWARDS M. ABSCESSUS BIOFILMS AND PROVIDE NOVEL BIOFILM TARGETS THAT COULD BE LEVERAGED TO AUGMENT ANTIMICROBIAL EFFICACY IN PEOPLE WITH INFLAMMATORY AND MUCO-OBSTRUCTIVE LUNG DISORDERS SUCH AS CF, CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), AND NON-CF BRONCHIECTASIS AS WELL AS WITH OTHER NTM LUNG INFECTIONS SUCH AS MYCOBACTERIUM AVIUM.