Preclinical Development of Novo29; a New Antibiotic
Award last edited on: 9/21/2022

Sponsored Program
Awarding Agency
Total Award Amount
Award Phase
Solicitation Topic Code
Principal Investigator
Losee L Ling

Company Information

NovoBiotic Pharmaceuticals LLC

767C Concord Avenue
Cambridge, MA 02138
   (617) 864-2880
Location: Single
Congr. District: 05
County: Middlesex

Phase I

Contract Number: 1R43AI136137-01
Start Date: 1/10/2018    Completed: 6/30/2018
Phase I year
Phase I Amount
The overall goal of this project is to conduct preclinical studies on Novo29, our newly-discovered bactericidal compound. As drug-resistance continues to spread, new classes of antibiotics are needed to combat infections by pathogens such as methicillin resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococci (VRE). Novo29 is a novel class of peptidoglycan synthesis inhibitor with favorable drug properties. It shows excellent activity against Gram-positive pathogens, has not shown resistance to date, and is well tolerated in mice. Interestingly, Novo29 shares structural features with teixobactin, another new class of antibiotic that we discovered in 2015. Teixobactin, which is currently in development, kills bacteria by binding to two bacterial cell wall precursors (lipid II and lipid III), and no resistance to the compound has been shown. Part of this grant will examine whether Novo29 works through the same mechanism as teixobactin. Although structurally similar, Novo29 may offer an advantage over teixobactin as it is a smaller compound (902D compared to 1242D), and does not gelate in serum, which has narrowed teixobactinÂ’s safety window. In Aim 1, Novo29 will be tested against an expanded panel of important pathogens, including contemporary clinical isolates. Time-kill profiles and expanded resistance studies effects will be studied in relevant pathogens. In addition, we will determine protein binding and microsomal stability of Novo29. In Aim 2, Novo29 will be tested for binding to the lipid II and lipid II precursors. If Novo29 does not bind to these compounds, we will analyze the accumulation of peptidoglycan nucleotide precursors and perform muropeptide analysis of Novo29-treated cells to identify the target. Finally, in Aim 3 we will conduct pharmacokinetic studies in mice that will inform the design of an efficacy study in a mouse thigh infection model using MRSA. The vast majority of antibiotics entering the market over the last several decades are simply incremental modifications of known structures. As resistance to common scaffolds is a major health concern, our discovery of yet another antibacterial compound with novel structure and important mode of action meets a critical, unmet goal in antibiotic drug discovery. In this project, Novo29 will advance through early preclinical studies in preparation for Investigational New Drug (IND)-enabling studies.

Public Health Relevance Statement:
NARRATIVE One of our most serious health threat is the loss of effective antibiotics due to antimicrobial resistance. The preclinical development of a newly discovered antibiotic in this proposed study addresses the urgency of this problem.

Project Terms:
Acute; Address; Anti-Bacterial Agents; Antibiotics; Antimicrobial Resistance; Bacteremia; Bacteria; bactericide; Binding; Binding Proteins; Cell Wall; Cells; Clinical; combat; cytotoxicity; design; Development; drug discovery; Drug Kinetics; Drug resistance; efficacy study; Evaluation; Formulation; Goals; Grant; Health; Hospitals; In Vitro; in vitro testing; in vivo; Infection; inhibitor/antagonist; Investigational Drugs; Killings; Lipid Binding; Lipid III; Lipids; Metabolic; methicillin resistant Staphylococcus aureus; microbiota; microorganism; Modeling; Modification; Molecular; Multi-Drug Resistance; Mus; mutant; novel; Nucleotides; pathogen; Peptides; Peptidoglycan; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pneumonia; preclinical development; preclinical study; Preparation; Property; Proteobacteria; Resistance; Safety; scaffold; Serum; Skin; Solubility; Staphylococcus aureus; Structure; Tail; Technology; Teichoic Acids; Testing; Thigh structure; Time; Vancomycin resistant enterococcus; Ventilator; Work

Phase II

Contract Number: 2R44AI136137-02A1
Start Date: 1/10/2018    Completed: 3/31/2022
Phase II year
(last award dollars: 2021)
Phase II Amount

The goal of this program is to continue developing our novel antimicrobial, Novo29, into a therapeutic for treating a wide range of infections caused by Gram-positive pathogens including Staphylococcus aureus, Streptococcus pneumoniae, and Bacillus anthracis. Using our iChip culturing technology, NovoBiotic has been exploiting previously uncultivable bacteria that make up 99% of all environmental microorganisms for production of new antibiotics. In 2015, NovoBiotic reported the discovery of teixobactin, the first member of a novel class of peptidoglycan synthesis inhibitors. We have since discovered Novo29, yet another promising and potent inhibitor of Gram-positive pathogens. Like teixobactin, Novo29 rapidly kills bacteria by inhibiting bacterial cell wall synthesis. However, Novo29 is significantly smaller than teixobactin, shows different target binding characteristics, and does not have serum gelation issues that require special formulations. Novo29 showed excellent efficacy against MRSA in two mouse models of infection (septicemia and thigh infection). The compound showed promising pharmacokinetic properties in mice, and is metabolically stable when incubated with liver microsomes. No spontaneous resistance (<10-10) occurred against S. aureus, and serial passaging in sublethal concentrations of drug failed to generate resistance. All these results demonstrate promising potential for Novo29 to treat drug-resistant infections. The goal of this project is to continue advancing Novo29 through preclinical research in preparation for IND-enabling studies. This work will include: (Aim 1) produce enough compound through fermentation to conduct all proposed studies in this grant, and for IND-enabling studies; (Aim 2) establish expanded MIC90s for pathogens isolated from recent clinical infections. Determine MBCs, time-kill profiles and post antibiotic effect (PAE) against relevant pathogens; (Aim 3) continue evaluating toxicity and pharmacokinetic (PK) profiles in animal models. Identify and characterize any major microsomal metabolites. Evaluate drug-drug interactions, genotoxicity, and cardiac safety in in vitro assays. Determine which PK/PD parameter(s) best correlate with efficacy; (Aim 4) examine efficacy of Novo29 in animal models of pulmonary infection with MRSA and anthrax; (Aim 5) explore the structure activity relationship (SAR) of Novo29 through medicinal chemistry. Design and test back-up analogs that may have increased potency and oral bioavailability. At the conclusion of this grant, Novo29 will be prepared to enter formal IND-enabling studies and advance to the clinic.

Public Health Relevance Statement:
NARRATIVE Infections caused by drug-resistant bacteria continue to be a public health threat. The focus of this project is to perform preclinical studies on our newly-discovered bactericidal compound in preparation for IND-enabling studies with the goal of developing an antibiotic against multidrug resistant infections.

Project Terms:
Acute; Ames Assay; analog; animal efficacy; Animal Model; Anthrax disease; Anti-Bacterial Agents; Antibiotics; antimicrobial; Bacillus anthracis; Back; Bacteremia; Bacteria; bactericide; base; Binding; Biodistribution; Biological Availability; Cardiac; Cell Wall; Characteristics; Clinic; Clinical; design; Dose; drug discovery; Drug Interactions; Drug Kinetics; Drug resistance; drug resistant bacteria; Evaluation; Exposure to; Fermentation; Formulation; genotoxicity; Goals; Grant; Health; Hospitals; Human; Hybrids; improved; In Vitro; in vitro Assay; in vivo; Incubated; Infection; inhibitor/antagonist; inorganic phosphate; Lead; Lipid III; Lipids; Liver Microsomes; Lung infections; member; Metabolic; metabolic profile; methicillin resistant Staphylococcus aureus; Methods; microbial; Microbiology; microorganism; Modeling; Modification; mouse model; Multi-Drug Resistance; multi-drug resistant pathogen; Mus; novel; Oral; pathogen; Pathogenicity; Peptides; Peptidoglycan; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Pneumonia; pre-clinical research; preclinical development; preclinical study; Preparation; Production; programs; Property; Proteobacteria; Public Health; Rattus; Regimen; Reporting; repository; research and development; Resistance; Safety; scaffold; Septicemia; Serial Passage; Serum; Site; Skin; Small Business Innovation Research Grant; Staphylococcus aureus; Streptococcus pneumoniae; Structure; Structure-Activity Relationship; Tail; Technology; Testing; Therapeutic; Thigh structure; Time; Tissues; Toxic effect; Toxicology; undecaprenyl pyrophosphate; Ventilator; Work