This $2,308,174 Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855) is funding research to develop new antimicrobial combinations and strategies to combat the threat of drug-resistant Acinetobacter baumannii and Klebsiella pneumoniae. The key products and services being delivered include: Generating novel mechanistic insights into antibiotic resistance mechanisms and bacterial...
This Project Grant award, totaling $1,000,000 and funded by the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855), supports Curza Inc.'s development of a new class of broad-spectrum oral antibiotics focused on treating multidrug-resistant (MDR) Gram-negative bacterial infections. The key objectives of this 3-year project are to: 1) optimize the oral bioavailability of Curza's CZ-02 antibiotic candidates...
This National Science Foundation (NSF) Small Business Innovation Research (SBIR) Phase I award to Bactria Pharmaceuticals LLC is providing $274,937 to develop therapeutic drugs that restore antibiotic sensitivity in bacteria that cause severe healthcare-associated infections. The goal is to combat antimicrobial resistance in gram-negative pathogens through the use of small molecule efflux pump inhibitors (EPIs). The project involves three key activities: cryo-electron microscopy to understand...
The National Institute of Allergy and Infectious Diseases (NIAID) awarded a $299,170 Project Grant under the Allergy and Infectious Diseases Research program (CFDA 93.855) to Latde Diagnostics Corp., a woman-owned small business, to demonstrate the feasibility of a rapid, equitable antibiotic susceptibility test (AST) for urinary tract infections (UTIs). The goal of this Phase I project is to develop a metabolic amino acid phenotyping (MAAP) test kit that can provide susceptibility profiles...
This $254,478 Project Grant awarded by the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855) supports research to identify mechanisms of resistance to pathogen-specific antibacterial antisense compounds known as peptide-phosphorodiamidate morpholino oligomers (PPMOs). The goal is to determine resistance mechanisms for lead PPMO compounds in the bacterial pathogens Klebsiella pneumoniae, Acinetobacter...
This Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855) provides $802,798 to develop a novel class of antibiotics called Biamyxins (BMX) to target multidrug-resistant Gram-negative bacterial infections. The 5-year award supports research to identify a qualified lead development candidate and pursue an Investigational New Drug (IND) candidate that can treat infections caused by...
This Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID), under the Allergy and Infectious Diseases Research program (CFDA 93.855), provides $747,763 to develop small molecule inhibitors of the LpxH enzyme as novel antibiotics for treating multidrug-resistant Enterobacterales infections. The goal is to design and synthesize potent LpxH inhibitors with optimal drug-like properties, and to demonstrate the safety and efficacy of a lead LpxH inhibitor...
This Project Grant award from the National Center for Advancing Translational Sciences (CFDA 93.350) provides $317,029 in funding to Chemia Biosciences, Inc., a small disadvantaged business, to develop advanced computational methods and software tools for discovering novel antimicrobial natural products. The project aims to leverage high-throughput mass spectrometry and genome mining techniques to identify new polysaccharides and aminoglycosides, a class of antibiotics, to address the growing...
This $299,163 Project Grant award from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855) aims to develop a novel antimicrobial approach combining endolysin proteins with self-replicating mRNA (RepRNA) delivery using lipid nanoparticles. The Phase I proof-of-concept study has two key objectives: 1) to evaluate whether RepRNA can successfully express a lysin targeting vancomycin-resistant Enterococcus...
The federal Project Grant award of $490,093 from the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855) will fund the development of a rapid, culture-free antibiotic susceptibility testing platform. The proposed technology leverages selective blood cell lysis and nanogap trapping to isolate small numbers of bacteria directly from whole blood samples. This will enable identification of bacterial pathogens and...
DEVELOPMENT OF A MECHANISTICALLY NOVEL GRAM-NEGATIVE ANTIBIOTIC TARGETING MSBA-MEDIATED LIPOPOLYSACCHARIDE BIOGENESIS - RECENTLY, WHO AND CDC DESIGNATED CARBAPENEM-RESISTANT ENTEROBACTERIACEAE (CRE) A PRIORITY 1 'CRITICAL SUPERBUG' AND AN 'URGENT THREAT', AND WARNED THAT NEW TREATMENTS FOR SUPERBUGS, WHICH KILL NEARLY 50,000 AMERICANS AND EUROPEANS A YEAR, ARE UNLIKELY TO BE DEVELOPED IN TIME IF LEFT TO MARKET FORCES ALONE. FEW THERAPEUTIC OPTIONS ARE LEFT TO TREAT CRE, AND THE FEAR OF 'PAN-RESISTANT' CRE HAS EMERGED. CURRENTLY, MOST CRE INFECTIONS OCCUR IN A HOSPITAL SETTING, BUT THE POTENTIAL SPREAD OF CRE IN THE COMMUNITY ALSO EXISTS. ENTIRELY NEW AGENTS WITH NOVEL MECHANISMS OF ACTION LANGUISH; COMPLETELY NOVEL ANTIBACTERIALS WITH A NEW MECHANISM OF ACTION AND LACKING CLINICAL CROSS-RESISTANCE TO EXISTING DRUG CLASSES ARE URGENTLY NEEDED. OUR PROPOSAL AIMS TO DEVELOP A MECHANISTICALLY NOVEL, IV AND PO ADMINISTERED AGENT TO TREAT UNCOMPLICATED AND COMPLICATED UTI CASES CAUSED BY ANTIBIOTIC SUSCEPTIBLE AND MULTIDRUG-RESISTANT ENTEROBACTERIACEAE, INCLUDING EXTENDED SPECTRUM BETA-LACTAMASE PRODUCERS AND CRE. USING AN INNOVATIVE OVEREXPRESSION-BASED CO-CULTURE SCREEN IN ESCHERICHIA COLI (EC), WE IDENTIFIED FOUR STRUCTURALLY DISTINCT SERIES OF SMALL MOLECULE INHIBITORS TARGETING MSBA, AN ESSENTIAL AND BROADLY CONSERVED GRAM-NEGATIVE (GN) ABC TRANSPORTER RESPONSIBLE FOR LIPOPOLYSACCHARIDE (LPS) BIOGENESIS AND CONSTRUCTION OF THE GRAM-NEGATIVE OUTER MEMBRANE (OM). A PRIORITIZATION OF THE FOUR SERIES THROUGH OUR CURRENT R21AI146541-SUPPORTED PROGRAM HAS ENABLED SELECTION OF A SERIES TO ENTER THE LEAD IDENTIFICATION (ID) PHASE OF DEVELOPMENT. WE PROPOSE THE FOLLOWING AIMS TO DEVELOP THIS SERIES: AIM 1 (2 YEARS) - LEAD ID TO SELECT A SINGLE LEAD SERIES WITH WT ACTIVITY AND EFFICACY FOR AIM 2 LEAD OPTIMIZATION (OP): 1.1) EXPLORATORY MED CHEM TO IMPROVE WT ACTIVITY, 1.2) OBTAIN HIGH RESOLUTION MSBAI-MSBA X-RAY CO-CRYSTAL STRUCTURE TO GUIDE STRUCTURE-BASED DRUG DESIGN (SBBD) USING THE SCHRODINGER DISCOVER SUITE, 1.3) MONITOR WHOLE CELL (MIC) ACTIVITY, 1.4) TRACK IN VITRO IC50 POTENCY, 1.5) TEST PPB, MAMMALIAN CYTOTOXICITY, AND P-GP INHIBITION/STIMULATION, 1.6) FOR, TIME KILL CURVES, AND LPXC INHIBITOR SYNERGY STUDIES, 1.7) MEASURE PK, 1.8) DETERMINE ENTEROBACTERIACEAE MIC90, 1.9) SYNTHETIC SCALE UP, 1.10) DOSE-RANGING MOUSE PK/FORMULATION STUDIES, AND 1.11) DEMONSTRATE IN VIVO EFFICACY IN A MOUSE PERITONITIS MODEL OF WT EC INFECTION. AIM 2 (3 YEARS) - LEAD OP TO PREPARE A PRE-CLINICAL CANDIDATE (PCC) FOR SUBSEQUENT SAFETY STUDIES: 2.1) MED CHEM OPTIMIZATION OF DRUG-LIKE PROPERTIES, 2.2) TRACK MIC, IC50, AND CYTOTOXICITY, 2.3) CONDUCT IN VITRO ADME, 2.4) SINGLE MOUSE (IV, IP, PO) PK, 2.5) VALIDATE MOA AND FOR, 2.6) TEST IN VITRO MAMMALIAN OFF TARGET-ACTIVITY, 2.7) EXPANDED ENTEROBACTERIACEAE MIC90, 2.8) DOSE-RANGING MOUSE PK, 2.9) SYNTHETIC SCALE UP, 2.10) EFFICACY IN MURINE UTI MODEL, 2.11) IDENTIFY PK/PD INDEX, 2.12) EXPANDED OFF TARGET-ACTIVITY AS IN 2.6.