SBIR-STTR Award

Antibiotic resistance among common bacterial pathogens is a serious public health problem as it compromises our ability to treat infectious disease. The resistance problem is compounded by the lack of discovery of new antibiotics, especially those with novel mechanisms of action. New antibiotics are critically needed as resistance to recently developed antibiotics is growing. The goal of this project is to develop our triazolononactate antibiotics, as exemplified by our lead compound PBI31G12, as broad spectrum agents active against Gram positive pathogens. Specifically we will improve the antibacterial activity and selectivity of our current lead compounds against S. aureus (including MRSA), E. faecalis (including VRE) and S. pyogenes. We will obtain data that will allow us to make a hypothesis concerning the MOA of the triazolononactate compound class and to identify the target so that we may employ structure-based drug design to achieve our goals of potency and spectrum of activity. In addition to using classic tracer studies we will use several resistant bacterial strains in hand to determine the genetic modifications leading to resistance. Beyond the improvement of potency and identification of the cellular target we will initiate DMPK studies to determine if the triazolononactate compound class has any critical liabilities such as metabolic instability, a poor resistance profile or off target pharmacology. We will determine the maximal tolerated dose and basic pharmacodynamic properties (Cmax, AUC, t1/2, oral bioavailability) of the compound class. We will then assess whether our best compounds show effectiveness in a murine S. aureus infection model. In summary, this Phase I project seeks to obtain analogs of our lead compound that have improved potency and selectivity, identify a mechanism of action and to evaluate DMPK properties. We envisage a Phase II project wherein we fully address ADMET issues and greatly expand animal studies with an improved compound set to move our compound class to our eventual goal of an IND filing.

Public Health Relevance Statement:


Public Health Relevance:
The ability to treat infections has become compromised by growing resistance to current antibiotics and has become a serious threat to public health. The significance of the threat is greater as there have been fewer antibiotics being approved for use in recent years and the discovery of a new class of antibiotic is a rare event. By employing natural product chemistry we have been able to identify a set of novel antibiotics. These compounds are active against a range of pathogens including methicillin-resistant Staphylococcus aureus (MRSA). This project seeks to demonstrate that these compounds can be developed into drugs.

Project Terms:
Address; analog; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacillus anthracis; bacterial resistance; bactericide; base; Biological Assay; Biological Availability; Cell Line; cellular targeting; clinically relevant; Communicable Diseases; Data; Development; Drops; Drug Design; drug development; Drug Kinetics; Drug Targeting; Effectiveness; Enterococcus faecalis; Evaluation; evaluation/testing; Event; Future; Genetic; Goals; Hand; Hour; improved; Infection; Knowledge; Lead; Mammalian Cell; Maximum Tolerated Dose; Measures; Metabolic; Metabolism; methicillin resistant Staphylococcus aureus; Modeling; Modification; Molecular Target; mouse model; Mus; mutant; Natural Products; Natural Products Chemistry; novel; Oral; pathogen; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Plasma; Property; Public Health; public health relevance; Resistance; resistance frequency; Resistance profile; Small Business Innovation Research Grant; Staphylococcus aureus; Staphylococcus epidermidis; Streptococcus pyogenes; Structure; Thigh structure; Tracer; Validation; Vancomycin-resistant S. aureus; Work

SPECIFIC AIMS Antibiotic resistance among common bacterial pathogens is a serious public health problem as it compromises our ability to treat infectious disease. The resistance problem is compounded by the relative lack of discovery of new antibiotics, especially those with novel mechanisms of action. New antibiotics are critically needed as resistance to recently developed antibiotics is growing. The goal of this project is to develop our triazolononactate antibiotics, a novel structural class of compound, as broad spectrum agents active against Gram positive pathogens such as methicillin-resistant Staphylococcus aureus. Based on the success of our Phase I STTR project we will seek to improve both potency and selectivity against important pathogens, identify and validate the molecular target through which our antibiotics exert their bactericidal activity and, after in vitro and in vivo DMPK analysis, demonstrate efficacy in a mouse model of infection. The data obtained will be used to demonstrate the potential of the compound class, the goal of which will be to partner/out- license with others to complete the enabling work for the filing of an IND application. Specific Aim 1 Lead compound improvement and evaluation. We have demonstrated that we can synthesize diverse triazolononactate derivatives and through preliminary SAR studies we have improved the potency (MIC) against clinically relevant pathogens to around MIC values of 1-4 µg/mL. While encouraged by these studies we seek to further improve potency and selectivity through additional synthesis and SAR studies. Specific Aim 2 Target identification and validation. Drug development has been greatly facilitated where knowledge of the drug target can be used to understand SAR. We will determine the discrete molecular target at which our triazolononactate antibacterial agents act. We will use a combination of approaches photoaffinity labeling of the triazolononactate target and the genetic analysis of S. aureus triazolononactate resistance mutants. Specific Aim 3 Compound evaluation procedures. The third aim of this project encompasses all the required analytical methods for compound evaluation, ranging from initial measures of potency through to eventual demonstration of efficacy in a mouse neutropenic thigh burden model. The analytical work is done in conjunction with the SAR studies of specific aim 1 so that iterative cycles of design, synthesis and evaluation will lead to a compound optimized for potency, selectivity, lack of off-target pharmacology, druggability and in vivo efficacy.

Public Health Relevance Statement:
Project narrative The ability to treat infections has become compromised by growing resistance to current antibiotics and has become a serious threat to public health. The significance of the threat is greater as there have been fewer antibiotics being approved for use in recent years and the discovery of a new class of antibiotic is a rare event. By employing natural product chemistry we have been able to identify a set of novel antibiotics. These compounds are active against a range of pathogens including methicillin-resistant Staphylococcus aureus (MRSA). This project seeks to demonstrate that these compounds can be developed into drugs.

Project Terms:
analytical method; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; bactericide; base; clinically relevant; Communicable Diseases; Data; design; drug development; Drug Targeting; Evaluation; Event; genetic analysis; Goals; improved; In Vitro; in vivo; Infection; Knowledge; Lead; Licensing; Measures; methicillin resistant Staphylococcus aureus; Modeling; Molecular Target; mouse model; Mus; mutant; Natural Products; Natural Products Chemistry; novel; pathogen; pathogenic bacteria; Pharmaceutical Preparations; Pharmacology; Phase; Photoaffinity Labels; Procedures; Public Health; Resistance; Small Business Technology Transfer Research; Staphylococcus aureus; Structure; success; Thigh structure; Validation; Work