Trustees Of Boston University

CARB-X GLOBAL ANTIBACTERIAL ACCELERATOR OTA

RESEARCH SERVICES PER 36C24E20D0016

TUITION AND FEES FOR FALL SEMESTER 2022

CENTAURI IS A PRIVATELY-OWNED BIOTECH COMPANY DEVELOPING NOVEL IMMUNOTHERAPEUTICS TO TREAT LIFE-THREATENING DISEASES. CENTAURI HAS A DEVELOPED AN IMMUNOTHERAPEUTIC PLATFORM (ALPHAMERS) THAT REDIRECTS PRE-EXISTING NATURAL ANTIBODIES TO TARGET SPECIFIC DISEASES WITH APPLICATIONS FOR CANCER AND INFECTIOUS DISEASE. ALPHAMERS ARE PART OF A LARGER FAMILY OF ANTIBODY RECRUITING MOLECULES (ARMS) DESIGNED TO REDIRECT A POTENT PRE-EXISTING IMMUNE RESPONSE AND THEREBY BRING ABOUT AN IMMEDIATE (WITHIN MINUTES) IMMUNOTHERAPEUTIC BENEFIT TO PATIENTS. THE ALPHAMER PLATFORM COMPRISES A TARGETING DOMAIN, THAT BINDS TO SPECIFICALLY TO THE BACTERIA, AN ANTIBODY-RECRUITING EFFECTOR DOMAIN THAT RECRUITS PRE-EXISTING NATURAL ANTI-GAL ANTIBODIES, AND PROPRIETARY LINKER TECHNOLOGY. ANTI-GAL ANTIBODIES ARE THE MOST ABUNDANT ANTIBODIES IN HUMANS, CONSTITUTING ABOUT 1% OF ALL IMMUNOGLOBULINS. THE ALPHAMER IS INTENDED TO RE-DIRECT THESE NATURALLY OCCURRING EFFECTOR ANTIBODIES WHICH ARE ALREADY PRESENT AT HIGH CONCENTRATIONS IN ALL PEOPLE TO TARGET BACTERIA FOR IMMUNE-MEDIATED DESTRUCTION, BY ACTIVATING THE COMPLEMENT CASCADE AND DESTROYING THE PATHOGEN THROUGH DIRECT LYSIS AND OPSONOPHAGOCYTOSIS. OUR LEAD PROGRAM (CTL-ABX01) TARGETS DRUG-SENSITIVE AND MULTI-DRUG RESISTANT (MDR) GRAM-NEGATIVE BACTERIA, INCLUDING CLINICALLY RELEVANT STRAINS OF ENTEROBACTERIACEAE, PSEUDOMONAS AERUGINOSA, AND ACINETOBACTER BAUMANNII. IN ADDITION TO RECRUITING THE IMMUNE SYSTEM, THE TARGETING DOMAIN OF THE ALPHAMER OF THE ABX01 PROGRAM HAS ALSO A DIRECT ANTIBACTERIAL EFFECT IN COMBINATION WITH ITS IMMUNOMODULATOR FUNCTION. AS SUCH, THE ALPHAMER SERVES AS A METHOD TO COMBINE THE POWER OF THE IMMUNE SYSTEM WITH DIRECT ANTIBACTERIAL ACTION IN ONE DRUG. THE AIM OF THIS PILOT PROJECT IS TO BETTER UNDERSTAND THE IMMUNE-MEDIATED TRANSLATION AND EFFICACY OF THE ALPHAMER IN VIVO BY EXECUTING APPROPRIATE DISEASE MODELS IN ORDER TO PREDICT AN EFFICACIOUS DOSE FOR HUMAN. PROJECT SUCCESS WOULD ENABLE US TO SELECT LEAD COMPOUNDS FOR CLINICAL CANDIDATE SELECTION STUDIES, COMPLETION OF PRE-IND-ENABLING STUDIES, AND CONDUCT OF A FIRST-IN-HUMAN STUDY.

PEPTILOGICS IS A BIOTECHNOLOGY COMPANY THAT UTILIZES AN INNOVATIVE PLATFORM TO DEVELOP NOVEL PEPTIDE THERAPEUTICS TO ADDRESS UNMET MEDICAL NEEDS. OUR PIPELINE INCLUDES A NOVEL CLASS OF ENGINEERED CATIONIC ANTIBIOTIC PEPTIDES. OUR LEAD CANDIDATE, PLG0206, BASED ON NATURALLY OCCURRING ANTIMICROBIAL PEPTIDES, EXHIBITS BROAD-SPECTRUM ACTIVITY AGAINST CLINICALLY IMPORTANT MDR GRAM-POSITIVE (S. AUREUS, INCLUDING MRSA, AND E. FAECIUM, INCLUDING VRE) AND GRAM-NEGATIVE (P. AERUGINOSA, E. COLI, AND A. BAUMANNII) PATHOGENS. PLG0206 EXHIBITS THE ABILITY TO RAPIDLY INACTIVATE BOTH PLANKTONIC AND BIOFILM PATHOGENS. THIS WITH ITS BROAD-SPECTRUM ACTIVITY MAKE IT AN IDEAL DEVELOPMENT CANDIDATE FOR PREVENTING INVASIVE INFECTIONS. PLG0206 TARGETS AND DISRUPTS THE BACTERIAL MEMBRANE, CAUSING RAPID BACTERIAL DEATH VIA CELLULAR CHEMICAL IMBALANCE. SINCE BACTERIAL MEMBRANES ARE A CONSERVED EVOLUTIONARY TARGET, THIS MOA APPEARS TO LIMIT THE RISK FOR RESISTANCE COMPARED TO OTHER ANTIBIOTICS. WITH RAPID BACTERICIDAL AND ANTI-BIOFILM ACTIVITY ON CONTACT, PLG0206 IS BEING DEVELOPED FOR THE PREVENTION OF TRAUMATIC FRACTURE-RELATED INFECTIONS (FRI) VIA LOCAL ADMINISTRATION IN CONJUNCTION STANDARD SURGICAL CARE. FRI IS A SERIOUS, LIFE-THREATENING INFECTION WITH SIGNIFICANT ECONOMIC BURDEN. FRI TREATMENT REQUIRES HOSPITALIZATION AND ONE OR MORE REPEAT SURGICAL PROCEDURES. MICROORGANISMS THAT CAUSE FRI INCLUDE S. AUREUS, COAGULATE-NEGATIVE STAPHYLOCOCCUS SPP., ENTEROCOCCUS SPP., AND AEROBIC GRAM-NEGATIVE BACILLI. THE POTENTIAL INFECTING PATHOGEN IS UNKNOWN AT THE TIME OF TRAUMATIC INSULT AND INITIAL SURGERY. CLINICAL PRACTICE GUIDELINES RECOMMEND 2-5 DAYS OF SYSTEMIC ANTIBIOTICS FOLLOWING TRAUMATIC INJURY TO PREVENT FRI. DESPITE THIS, TRAUMATIC FRACTURES HAVE A HIGH INFECTION RATE (UP TO 40%). FRI OFTEN REQUIRES MULTIPLE SURGICAL PROCEDURES, LEADING TO SUBSTANTIAL MORBIDITY AND MORTALITY WITH AN UP TO 25% 5-YEAR MORTALITY RISK. CURRENT STRATEGIES DO NOT ADEQUATELY PREVENT THE INFECTIONS THAT LEAD TO FRI'S HIGH MORBIDITY AND MORTALITY BURDEN, AND FRI REMAINS AN UNMET MEDICAL NEED AND REQUIRES A DIFFERENT APPROACH TO THAT CURRENTLY EMPLOYED. PLG0206, ADMINISTERED AT THE TIME OF INJURY, THROUGH ITS RAPIDLY ACTING BROAD-SPECTRUM ACTIVITY AGAINST THE PATHOGENS COMMONLY CAUSING FRI HAS THE POTENTIAL TO ADDRESS THIS UNMET NEED. PLG0206 WILL BE ADMINISTERED FOLLOWING TRAUMATIC INJURY IN THE OPERATING THEATER AFTER SURGICAL DEBRIDEMENT AND BONE FIXATION AS A LONG-ACTING CONTROLLED RELEASE FORMULATION. IT IS EXPECTED TO BE MORE EFFECTIVE THAN THE CURRENT STANDARD OF CARE BY PROVIDING LONG-LASTING PATHOGEN-INACTIVATING DRUG LEVELS TO PREVENT INFECTION NIDI (DEVITALIZED AND CONTAMINATED BONE AND SOFT TISSUE AND METAL FIXATION DEVICES) THAT LEAD TO INVASIVE INFECTION. THE EXPECTED LIMITED SYSTEMIC EXPOSURE WITH LOCAL DRUG DEPOT SHOULD ENSURE A GOOD SAFETY PROFILE. THE DEVELOPMENT PLAN WILL ASSESS THE IN VITRO AND IN VIVO RELEASE CHARACTERISTICS OF VARIOUS PLG0206 CONTROLLED-RELEASE FORMULATIONS ALONG WITH PK, TOLERABILITY, AND EFFICACY IN ANIMAL MODELS OF FRI. ADDITIONAL STUDIES WILL IDENTIFY THE MOST EFFECTIVE, WELL-TOLERATED CONCENTRATION TO BE USED IN HUMAN TRIALS TO ESTABLISH SAFETY AND EFFICACY OF LOCAL ADMINISTRATION IN THE PREVENTION OF FRI IN CONJUNCTION WITH CURRENT STANDARD OF CARE.

DAY ZERO DIAGNOSTICS IS DEVELOPING A CULTURE-FREE, SEQUENCING-BASED DIAGNOSTIC THAT IDENTIFIES WITHIN HOURS BOTH THE SPECIES AND THE ANTIBIOTIC RESISTANCE PROFILE OF A BACTERIAL INFECTION. WE HAVE DEVELOPED AN ULTRA-HIGH ENRICHMENT SAMPLE PREPARATION PROCESS (BLOOD2BAC‎¢) THAT CAN EXTRACT BACTERIAL WHOLE GENOME SEQUENCES FROM PATIENT BLOOD SAMPLES EVEN WHEN THERE ARE JUST A HANDFUL OF BACTERIAL CELLS PRESENT IN THE SAMPLE. WE HAVE ALSO DEVELOPED A PROPRIETARY MACHINE LEARNING ALGORITHM (KEYNOME®) THAT CAN USE THE DNA SEQUENCES TO IDENTIFY A BACTERIAL PATHOGEN AND PREDICT ITS ANTIBIOTIC SUSCEPTIBILITY PROFILE. KEYNOME IS TRAINED ON A LARGE SCALE DATABASE (MICROHMDB®) THAT CONTAINS THE WHOLE GENOME SEQUENCES OF BACTERIAL PATHOGENS MATCHED TO THEIR KNOWN ANTIBIOTIC RESISTANCE PROFILE. OUR APPROACH ALLOWS FOR THE SIMULTANEOUS TESTING OF A VAST NUMBER OF BACTERIAL SPECIES AND KNOWN RESISTANCE MARKERS, ALONG WITH THE ABILITY TO IDENTIFY NOVEL RESISTANCE DETERMINANTS AS THEY EMERGE. WITH DAY ZERO DIAGNOSTICS, PHYSICIANS CAN TREAT PATIENTS WITH THE MOST EFFECTIVE DRUG IN HOURS, AVOIDING THE COMPLICATIONS, COSTS, AND FRUSTRATION ASSOCIATED WITH EMPIRIC THERAPY.

MELIO IS COMMITTED TO REVOLUTIONIZING THE HEALTHCARE INDUSTRY BY OFFERING RAPID INFECTIOUS DISEASE DIAGNOSTIC SOLUTIONS. BY REDEFINING STANDARDS OF CARE, MELIO AIMS TO DRIVE A SHIFT TOWARD PRECISION HEALTHCARE, EMPOWERING CLINICIANS TO MAKE INFORMED, TIMELY DECISIONS FOR TREATMENT FOR INFECTIONS, REDUCING HEALTHCARE COSTS, AND THE OVERPRESCRIPTION OF ANTIBIOTICS. MELIO’S FIRST PRODUCT FOCUSES ON PROVIDING A BREAKTHROUGH IN BOTH SPEED AND PATHOGEN COVERAGE FOR DIAGNOSING BLOOD STREAM INFECTIONS DIRECTLY FROM A PATIENT’S BLOOD SAMPLE FOR NEONATES. UNLIKE THE STANDARD CULTURE METHOD, WHICH SERVES AS A BOTTLENECK BY TAKING DAYS TO DELIVER RESULTS, MELIO’S TECHNOLOGY OFFERS AN EXPEDITED ALTERNATIVE THAT COULD TRANSFORM PATIENT CARE.

THE OVERALL GOAL OF THIS PROJECT IS TO DEVELOP AN IV + ORAL AGENT WITH A NOVEL MECHANISM OF ACTION (MOA) FOR THE TREATMENT OF COMPLICATED URINARY TRACT INFECTIONS (CUTI) CAUSED BY MDR ENTEROBACTERALES. ARREPATH HAS IDENTIFIED A SERIES OF INHIBITORS OF A HIGHLY CONSERVED ENZYME IN GRAM-NEGATIVE BACTERIA WITH NO HUMAN HOMOLOG THAT HAS NEVER BEEN CLINICALLY EXPLOITED AND IS THEREFORE CONSIDERED A NOVEL MOA. IF SUCCESSFULLY DEVELOPED, AN ANTIBIOTIC THAT INHIBITS THIS ENZYME WOULD BE ACTIVE AGAINST THE VAST MAJORITY OF ANTIBIOTIC-RESISTANT INFECTIONS CAUSED BY TARGET PATHOGENS, REPRESENTING AN IMPORTANT NEW TOOL IN THE FIGHT AGAINST ANTIMICROBIAL RESISTANCE. THE CURRENT PROPOSAL SEEKS TO OPTIMIZE PROPERTIES OF OUR INHIBITORS TO ALLOW FOR THE SELECTION OF A DEVELOPMENT CANDIDATE SUITABLE FOR IND-ENABLING STUDIES.

QMAP (QUICK MULTIPLEXED ASSAY PLATFORM) IS A CHEAP, FAST, ACCURATE, AND HIGHLY SCALABLE FULLY AUTOMATED SYSTEM FOR NEONATAL SEPSIS SCREENING. IT CAN OFFER BROAD-SPECTRUM ANALYSIS OF MOLECULAR MARKERS REPRESENTING PATHOGEN SPECIES AND ANTIMICROBIAL RESISTANCE THROUGH A SINGLE-POT REACTION. THIS ENABLES RAPID DIAGNOSIS, PROVIDING ACCURATE RESULTS WITHIN 6 HOURS FROM LESS THAN 2 ML OF WHOLE BLOOD. THE SYSTEM EMPLOYS GRAPHICALLY ENCODED MICRODISKS, EACH ENGINEERED TO DETECT SPECIFIC ID/AST GENE MOLECULES THROUGH THE ATTACHMENT OF COMPLEMENTARY DNA PROBES, WHICH ARE SUBSEQUENTLY POOLED FOR EACH ASSAY. THE SYSTEM IS HIGHLY SCALABLE AND MULTIPLEXED, ENABLING THE INTEGRATION OF BOTH PATHOGEN ID AND AST AT A SINGLE RUN. EACH ID OR AST SPECIFIC MICRODISKS CAN BE MASS-PRODUCED AT A LOW COST. THE ONE-POT APPROACH ALLOWS PARALLEL DETECTION OF 71 GENES(ID 44 GENES AND AST 27 GENES) WITH MINIMAL USAGE OF REAGENTS AND ASSOCIATED KITS. COMPARED TO EXISTING TECHNOLOGIES, OVERALL REAGENT COSTS CAN BE REDUCED BY 4 TO 5- FOLD, WHILE ACHIEVING 2 TO 10 TIMES GREATER ID/AST GENE COVERAGE, MAKING IT IDEAL FOR A COMPREHENSIVE NEONATAL SEPSIS SCREENING PLATFORM THAT IS ALSO AFFORDABLE FOR LMICS. WITH MINIMAL SAMPLE PREPARATION AND OUR ONE-POT REACTION DESIGN, EACH STEP IS SIMPLIFIED, MINIMIZING THE RISK OF SAMPLE DILUTION OR BACTERIAL LOSS DURING TRANSFER, DISTRIBUTION, OR REACTIONS. THIS CAN POTENTIALLY REDUCE THE REQUIRED BLOOD SAMPLE VOLUME BY MORE THAN 50% COMPARED TO CONVENTIONAL DIAGNOSTICS AND ALSO ENHANCE THE SENSITIVITY OF ASSAY. FURTHERMORE, THE SYSTEM ULTIMATELY ENABLES THE DETECTION OF OVER 100 DISTINCT PROBES BY INCORPORATING ADDITIONAL TYPES OF MICRODISKS. THIS FLEXIBILITY ALLOWS QMAP TO EXPAND ITS PANEL LIBRARY TO INCLUDE NEW PATHOGENS OR AMR GENES, PROVIDING AN ADAPTABLE SOLUTION FOR EVOLVING CLINICAL REQUIREMENTS. MANY COMPANIES HAVE DEVELOPED METHODS(FLUORESCENCE-BASED PRINCIPLE, NMR-BASED PRINCIPLE, ELECTROCHEMICAL-BASED PRINCIPLE) TO MAXIMIZE THE DETECTION COVERAGE FOR COMPREHENSIVE PROFILING OF PATHOGEN SPECIES AND ANTIMICROBIAL RESISTANCE. HOWEVER, THE NUMBER OF MOLECULES BEING ANALYZED IN SINGLE WELL HAS BEEN SEVERELY LIMITED BY THE TYPE OF DETECTION SIGNAL, SPATIAL SEPARATION REQUIREMENTS (COMPARTMENTALIZATION), OR THE INCREASING CONSUMABLES AND EQUIPMENT COSTS. THE QMAP TECHNOLOGY OVERCOMES THE LIMITATIONS OF TARGET MULTIPLEXITY, OPERATING ENTIRELY IN A SINGLE WELL WHILE MINIMIZING SAMPLE LOSS, DILUTION, COMPLEXITY OF OPERATION, AND REAGENT USAGE. QMAP ENABLES ONE-POT SIMULTANEOUS SCREENING OF OVER 100 UNIQUE TARGETS, DEMONSTRATING STRONG POTENTIAL FOR NEONATAL SEPSIS DIAGNOSTICS, WHERE RAPID AND COMPREHENSIVE PATHOGEN IDENTIFICATION AND RESISTANCE PROFILING ARE CRITICAL.

SERES IS DEVELOPING A NOVEL LIVE BIOTHERAPEUTIC PRODUCT (LBP) OF HUMAN COMMENSAL BACTERIA FORMULATED FOR ORAL LIQUID DELIVERY, TO ADDRESS THE UNMET NEED FOR PREVENTION OF GUT-SEEDED AMR INFECTION IN THE MEDICAL ICU. INFECTIONS WITH PATHOGENIC (OFTEN MULTIDRUG RESISTANT, MDR) BACTERIA ARE THE LEADING CAUSE OF MORTALITY IN THE MEDICAL INTENSIVE CARE UNIT (ICU), CAUSING UP TO 9 DEATHS FOR EVERY 100 ICU PATIENTS ADMITTED (VINCENT, 2009). MOST PATIENTS ARE ADMITTED TO THE MEDICAL ICU WITH A KNOWN OR SUSPECTED INFECTION (I.E., SEPSIS) BUT, WITH TARGETED OR EMPIRIC ANTIBIOTICS, MOST RECOVER FROM THIS INITIAL INFECTION. WHAT CAUSES DEATHS—AND WHAT THIS PROJECT PROPOSES TO PREVENT—ARE THE SECONDARY, HEALTHCARE- ASSOCIATED INFECTIONS THAT FREQUENTLY DEVELOP DURING THE PROLONGED RECOVERY FROM SEPSIS. A NOVEL APPROACH THAT ADDRESSES BOTH GUT COLONIZATION AND SUBSEQUENT TRANSLOCATION BY E. COLI AND OTHER GUT SEEDED PATHOGENS COULD PREVENT A SIGNIFICANT PROPORTION OF THESE INFECTIONS. IF GUT COLONIZATION AND TRANSLOCATION BY E. COLI COULD BE AMELIORATED BY A LBP SUCH AS SER-155, A LARGE PROPORTION OF THESE INFECTIONS COULD BE PREVENTED. SER-155 IS CURRENTLY IN CLINICAL DEVELOPMENT AND HAS BEEN EVALUATED IN ALLOGENEIC HCT PATIENTS. DATA FROM OUR PHASE 1B STUDY SUPPORTS THE SAFETY AND EFFICACY OF SER-155 IN PREVENTING INFECTION IN IMMUNE COMPROMISED, HOSPITALIZED PATIENTS. THE PROPOSED WORK WILL EXTEND THESE FINDINGS BY DEVELOPING A LIQUID FORMULATION OF SER-155 (“SER-155-LF"), A NECESSARY STEP IN THE MEDICAL ICU AS PATIENTS ARE COMMONLY INTUBATED WITH NARROW-CALIBER GASTRIC OR DUODENAL FEEDING TUBES, PLACED FOR THE DELIVERY OF MEDICATIONS AND ENTERAL NUTRITION. UPON SUCCESSFUL DEVELOPMENT OF A LIQUID FORMULATION WHICH IS SUITED FOR DELIVERY IN THE ICU VIA NG TUBE, THE PROPOSED WORK PLAN WILL NEXT FOCUS ON GMP MANUFACTURING OF SER-155-LF FOR CLINICAL STUDY AND PREPARATION OF AN EARLY PHASE TRIAL IN ICU PATIENTS WITH A PRIMARY OUTCOME OF SAFETY AND ENGRAFTMENT, EXPLORATORY ENDPOINTS AROUND E. COLI COLONIZATION AND AMR, AND DENSE DOWNSTREAM CLINICAL AND MECHANISTIC ANALYSES.

PEARL DIAGNOSTICS INC. (PEARLDX) DEVELOPS NOVEL IN VITRO DIAGNOSTIC (IVD) TESTS THAT AID NON-INVASIVE DIAGNOSIS OF LIFE-THREATENING LUNG INFECTIONS. PEARLDX€„¢S TECHNOLOGY LEVERAGES THE DISCOVERY THAT MICROBIAL EXTRACELLULAR VESICLES (EVS) RELEASED FROM ORGANISMS GROWING IN THE LUNGS ARE EXCRETED IN URINE. IDENTIFICATION OF SPECIFIC LUNG PATHOGENS SUCH AS PSEUDOMONAS AERUGINOSA (PSA) AS A CAUSE OF PNEUMONIA IS CRITICAL IN MITIGATING THE IMPACT OF ANTIMICROBIAL DRUG RESISTANCE. WHILE A LESS COMMON CAUSE OF COMMUNITY-ACQUIRED PNEUMONIA (CAP), THIS GRAM-NEGATIVE ROD (GNR) IS INTRINSICALLY RESISTANT TO SEVERAL ANTIBIOTIC CLASSES, INCLUDING B-LACTAMS, AND EXHIBITS FREQUENT MULTIDRUG RESISTANCE (MDR). THE PREVALENCE OF PSA IN CAP IS REPORTED AS VARIABLE, RANGING FROM 0 TO 23%, WITH A POOLED PREVALENCE OF 8.6% IN PEOPLE WITH IDENTIFIED RISKS FOR MDR INFECTIONS. IDENTIFICATION OF PSA IN CULTURES ENABLES SUSCEPTIBILITY TESTING AND TAILORING OF EMPIRIC THERAPY FOR BOTH CAP AND HOSPITAL- AND VENTILATOR-ACQUIRED PNEUMONIA (HAP, VAP) IN HIGH-RISK PATIENTS. HOWEVER, THIS FREQUENTLY REQUIRES BAL SAMPLING AND CULTURE YIELD IS VARIABLE. IDENTIFICATION OF THE ORGANISM IS NOT AN ASSURANCE OF ACUTE DISEASE ETIOLOGY, AS COLONIZATION IS COMMON IN PEOPLE WITH POOR AIRWAY CLEARANCE, SUCH AS IN THOSE WITH BRONCHIECTASIS AND CYSTIC FIBROSIS (CF). VARIABLE PERFORMANCE, NON-SPECIFICITY OF CLINICAL FINDINGS, RELIANCE ON INVASIVE SAMPLING, AND TIME TO CULTURE DRIVE A HIGH AMOUNT OF ANTIBIOTIC EMPIRICISM, ULTIMATELY GENERATING AND PROPAGATING ANTIMICROBIAL RESISTANCE (AMR). PEARLDX€„¢S PRODUCTS PROVIDE ADVANTAGES WITH REGARD TO ACCESS (REFERENCE LABS VS. LOW-RESOURCE SETTINGS), COSTS (> $2000/TEST VS. < $20), AND TIME TO RESULT (3-5 DAYS VS. < 2 HR.). OTHER TECHNOLOGIES TYPICALLY RELY ON LARGE INSTRUMENTS AND/OR REFERENCE TESTING. THEREFORE, THERE REMAIN CRITICAL UNMET NEEDS AND OPPORTUNITIES TO IMPROVE PATIENT OUTCOMES WITH EASIER-TO-DEPLOY, LESS EXPENSIVE IVDS USING URINE AS AN ADJUNCT DIAGNOSTIC AID FOR PNEUMONIA. THE AVAILABILITY OF ADJUNCTIVE NON-CULTURE-BASED TESTS (NCBT) TO AID IN THE DIAGNOSIS OF PNEUMONIA IS A LONG-APPRECIATED PRIORITY. PEARLDX, WITH SUPPORT FROM CARB-X, INTENDS TO DEVELOP A LOW-COST, LOW TURNAROUND TIME (TAT) URINE ASSAY FOR THE DETECTION OF PSEUDOMONAS PNEUMONIA (PMA). THE INITIAL AIM OF THIS PROJECT IS TO DEVELOP A PROTOTYPE ASSAY. ALL ASSAYS DEVELOPED BY PEARLDX, INCLUDING THE PROPOSED CARB-X-SUPPORTED PSA ASSAY, ARE ADVANCED USING CLINICAL SAMPLES FROM PATIENTS, WITH ITERATIVE IMPROVEMENTS OF THE ASSAY INFORMED BY THE CHARACTERIZATION OF URINARY ANTIGENS AND BY REDUCING MATRIX INTERFERENCE.

PNEUMONIA IS A COMMON CLINICAL DIAGNOSIS THAT OFTEN LACKS A MICROBIOLOGICAL DIAGNOSIS BECAUSE NO PATHOGEN IS IDENTIFIED. WITHOUT A MICROBIOLOGICAL DIAGNOSIS, ANTIBIOTICS TARGETING A BROAD RANGE OF PATHOGENS ARE USED, INCREASING THE RISKS FOR RESISTANCE ALONG WITH POOR OUTCOMES IF INAPPROPRIATE ANTIBIOTICS ARE CHOSEN. THIS RESEARCH PROGRAM PROPOSES TO DIAGNOSE LOWER RESPIRATORY TRACT BACTERIAL INFECTIONS AND THEIR ASSOCIATED ANTIMICROBIAL RESISTANCE IN FOUR HOURS, MUCH FASTER THAN CURRENT CULTURE TECHNIQUES. THE LONG-TERM GOAL OF THIS RESEARCH PROGRAM IS TO DEVELOP RAPID DIAGNOSTIC TESTS THAT WILL BE INDICATED IN ALL PATIENTS WITH A CLINICAL SUSPICION FOR PNEUMONIA. THE SHORT-TERM OBJECTIVE WILL FOCUS ON PNEUMONIAS CAUSED BY STAPHYLOCOCCUS AUREUS, PSEUDOMONAS AERUGINOSA, AND HAEMOPHILUS INFLUENZAE, WITH THE GOAL OF HAVING RESULTS AVAILABLE IN 4 HOURS. THE STRATEGY USED IN THIS DIAGNOSTIC TEST DISTINGUISHES IT FROM COMPETITORS AND ALTERNATIVES. THIS DIAGNOSTIC IS BASED ON DETECTING RNA SEQUENCE(S) SPECIFIC FOR THE PATHOGEN CAUSING PNEUMONIA IN A HUMAN PATIENT. TESTING WILL BE DONE ON BLOOD DRAWN DIRECTLY FROM THE PATIENT, MAKING IT LESS INVASIVE THAN OTHER METHODS THAT OBTAIN SAMPLES FROM THE AIRWAYS, SUCH AS BRONCHOSCOPY OR DEEP SUCTIONING. THIS TEST WILL NOT REQUIRE THE SPECIMEN TO BE CULTURED, ALLOWING FOR FASTER RESULTS THAN TRADITIONAL MICROBIOLOGICAL METHODS. THE RNA TARGETED BY THE TEST IS IDENTIFIED VIA RNA SEQUENCING OF BLOOD FROM PATIENTS WITH THE INFECTION. RNA SEQUENCING DATA SHOWS RNA SPECIFIC TO THE PATHOGEN OF INTEREST (S. AUREUS., P. AERUGINOSA, AND H. INFLUENZAE) THAT IS ALSO SPECIFIC FOR AN ACTIVE INFECTION. TARGETING RNA ALSO ENSURES THAT THE INFECTION IS CURRENT SINCE RNA IS LESS STABLE THAN DNA, LASTING MINUTES TO HOURS WHEN FROM A BACTERIUM. THE METHOD, HOWEVER, IMMEDIATELY STABILIZES THE RNA FOR TESTING. RNA ALSO IDENTIFIES BACTERIA THAT ARE ACTIVELY MAKING RESISTANCE PROTEINS, RATHER THAN BACTERIA WITH THE POTENTIAL FOR RESISTANCE BASED ONLY ON GENOMIC DNA. AT THE END OF THIS PROJECT, PCR BASED TESTS WILL BE CREATED THAT ARE INFORMED BY RNA SEQUENCING DATA. THESE WILL DIAGNOSE PNEUMONIA DUE TO S. AUREUS., P. AERUGINOSA, AND H. INFLUENZAE, ALONG WITH RELEVANT ANTIBIOTIC RESISTANCE, USING BLOOD FROM THE PATIENT. THIS PCR TESTING PLATFORM USES FDA-APPROVED INSTRUMENTATION TO FACILITATE TRANSITIONING FROM A RESEARCH LABORATORY TO A CLINICAL MICROBIOLOGY LABORATORY.

THE PROPOSAL IS TO PERFORM TARGETED FEASIBILITY STUDIES SUPPORTING EFFORTS TO DEVELOP AND BRING TO MARKET A ROBUST, LOW-COST INSTRUMENT FOR NEONATAL SEPSIS DIAGNOSIS THAT PERFORMS PATHOGEN DETECTION, PATHOGEN IDENTIFICATION (ID), AND PHENOTYPIC ANTIMICROBIAL SUSCEPTIBILITY TESTING (AST) DIRECTLY FROM WHOLE BLOOD IN 3-8 HOURS FROM BLOOD DRAW TO RESULT, WITH =5 MINUTES€„¢ HANDLING TIME, IN A SINGLE INSTRUMENT. COMPETITIVE ADVANTAGES INCLUDE DIAGNOSTIC SPECIMEN, CAPABILITY, AST MODALITY, SPEED, EASE OF USE, AND AFFORDABILITY.

IN THIS CARB-X PROJECT, WE AIM AT DEVELOPING OUR NOVEL CLASS OF COMPOUNDS TARGETING THE BACTERIAL SLIDING CLAMP (DNAN) AS ANTIBIOTIC LEAD CANDIDATES FOR THE TREATMENT OF GRAM-POSITIVE BACTERIAL INFECTIONS. IT WILL BE GUIDED BY A PRIMARY TPP OF A STANDALONE THERAPY FOR THE TREATMENT OF COMMUNITY ACQUIRED BACTERIAL PNEUMONIA (CABP) CAUSED BY SUSCEPTIBLE AS WELL AS MULTIDRUG-RESISTANT (MDR) STREPTOCOCCUS PNEUMONIAE. WITHIN THE FRAME OF CARB-X FUNDING FOR THIS HIT-TO-LEAD BASE STAGE, WE WILL FOCUS IN THE FIRST PLACE ON THREE GOALS, NAMELY OPTIMIZATION OF TARGET AFFINITY AND ANTIBACTERIAL ACTIVITY AGAINST MAINLY TWO KEY GRAM-POSITIVE TPP PATHOGENS (STREPTOCOCCUS PNEUMONIAE AND STAPHYLOCOCCUS AUREUS), DEMONSTRATION OF TARGET ENGAGEMENT IN A GRAM-POSITIVE BACTERIAL STRAIN, AND PROOF-OF-CONCEPT IN A MURINE INFECTION MODEL. IF THESE AIMS ARE ACHIEVED, WE WILL THEN CONCENTRATE ON OPTIMIZATION OF BOTH THE PHARMACOKINETIC (PK) PROPERTIES AND THE ANTIBIOTIC SPECTRUM OF OUR COMPOUND CLASS IN ORDER TO COVER OTHER GRAM-POSITIVE TPP-RELEVANT GERMS, INCLUDING MDR CLINICAL ISOLATES, AS WELL AS OPPORTUNISTIC GRAM-NEGATIVE PATHOGENS INVOLVED IN CABP INFECTIONS. MOREOVER, WE WILL IMPLEMENT IN VITRO SAFETY PHARMACOLOGY AGAINST HUMAN OFF-TARGETS AND IN VIVO SAFETY AND EFFICACY PROFILING TO IDENTIFY THE MOST PROMISING 2€€Œ3 LEAD CANDIDATES. THE ENVISAGED LEAD COMPOUNDS WILL DEMONSTRATE POTENT ANTIBIOTIC ACTIVITY AGAINST MULTIPLE GRAM-POSITIVE STRAINS, IN VITRO AND IN CELLUO TARGET ENGAGEMENT, PROMISING IN VITRO ADME-TOX PROFILE, AS WELL AS FAVORABLE IN VIVO PK AND PHARMACODYNAMICS (PD) PROPERTIES.

COMPANY WILL PROVIDE DRAPER WITH TECHNICAL SUPPORT FOR PROGRAM.