Despite the rise of bacterial resistance to antibiotics, the development of new antibiotics is on the decline. Methicillin-resistant Staphococcal aureus infections (MRSA) in the United States has been increasing, causing 19,000 deaths per year in the United States and contributing to $3 billion to $4 billion of additional annual health care costs. The issue of combating resistance has been exacerbated by the relative scarcity of new chemical scaffolds discovered or developed. Most of the antibacterial research at pharmaceutical companies has been towards developing analogs of existing drugs through traditional chemistry driven SAR programs. Very few new classes of antibiotics have been introduced in the past decades, and most antibiotics act on familiar targets. In addition, even though natural products have been a rich source of new antibacterials, many pharmaceutical companies have natural product libraries that have been thoroughly screened and offer little in the way of diversity or novelty. There is a growing awareness that natural product libraries, particularly those with a fungal origin, need to exploit fungal cryptic or secret pathways that normally are not expressed in laboratory conditions. To exploit the largely undiscovered secondary metabolites of mushrooms (basidiomycetes and ascomycetes), LifePharms, Inc. has established a collection of field- collected, environmentally challenged fruiting bodies. LifePharms/Microbiotix collaboration has identified, purified, and characterized two compounds that exhibit potent antibacterial activity (MICs as low as 0.5 5g/ml) against Gram-positive pathogens, including MSSA, MRSA, MRSE, and VRE, and favorable cytotoxicity profiles (CC50 >100 5g/ml). The chemical structures of these two lead compounds indicate they are novel antibacterial compounds. In addition, we have purified and partially characterized three more potent antibacterial compounds that will serve as alternative scaffolds. In this Phase I grant, we will i) evaluate these compounds in a series of in vitro assays that will measure ADMET, ii) chemically optimize these compounds by generating analogs using semi-synthetic methodologies to determine structure activity relationships and to improve potency and selectivity, iii) Data obtained from these assays will inform the design of subsequent analogs, resulting in an iterative process of analog design and evaluation, to improve the efficacy, selectivity, and ADMET properties of the scaffolds. In Phase II, compounds that meet the specified criteria for efficacy, selectivity, and ADMET properties will be tested for acute toxicity and antibacterial efficacy in mice.
Public Health Relevance: Antibacterial infections with drug resistant organisms are a growing threat. LifePharms, Inc., and Microbiotix, Inc. have collaborated to discover structurally and mechanistically novel antibacterial compounds. These compounds are effective against several strains/species of drug resistant Gram (+) bacteria in vitro. The goal of this project is to pursue the preclinical development of these compounds as novel antibiotics.
Thesaurus Terms: Acute;Acute Toxicity Tests;Adverse Effects;Affinity;Agaricales;Anti-Bacterial Agents;Antibacterial Agents;Antibiotic Agents;Antibiotic Drugs;Antibiotic Resistance;Antibiotics;Ascomycetes;Ascomycota;Assay;Awareness;Bacteria;Bacterial Antibiotic Resistance;Basidiomycetes;Basidiomycota;Bioassay;Biologic Assays;Biologic Factor;Biological;Biological Assay;Biological Factors;Biotransformation;Blood Serum;Cessation Of Life;Chemical Structure;Chemicals;Chemistry;Clinical;Collaborations;Collection;Communicable Diseases;Community Hospitals;Data;Death;Development;Drug Resistance;Drugs;Enterococcus;Epidermis;Evaluation;Exhibits;Fruit;Genus Staphylococcus;Goals;Grant;Health Care Costs;Health Costs;Healthcare Costs;Ic50;In Vitro;Infection;Infectious Disease Pathway;Infectious Diseases;Infectious Diseases And Manifestations;Infectious Disorder;Inhibitory Concentration 50;Intermediary Metabolism;Isoforms;Loinc Axis 2 Property;Laboratories;Lead;Libraries;Liver Microsomes;Lytotoxicity;Mrsa;Mammalian Cell;Measures;Medication;Metabolic;Metabolic Biotransformation;Metabolic Processes;Metabolism;Methicillin Resistance;Methicillin Resistant S. Aureus;Methicillin Resistant Staphylococcus Aureus;Method Loinc Axis 6;Methodology;Mice;Mice Mammals;Miscellaneous Antibiotic;Modification;Murine;Mus;Mushrooms;Natural Products;Organism;Pathway Interactions;Pb Element;Permeability;Pharmaceutic Preparations;Pharmaceutical Agent;Pharmaceutical Preparations;Pharmaceuticals;Pharmacologic Substance;Pharmacological Substance;Phase;Preparation;Prevalence;Process;Property;Protein Isoforms;Relative;Relative (Related Person);Research;Resistance;Resistance To Antibiotics;Resistant To Antibiotics;Sbir;Sbirs (R43/44);Screening Procedure;Series;Serum;Small Business Innovation Research;Small Business Innovation Research Grant;Source;Specific Qualifier Value;Specified;Staphylococcus;Streptococcus Enterococcus Group;Structure-Activity Relationship;Testing;Therapeutic Agents;Toxic Effect;Toxicities;Treatment Side Effects;United States;Vancomycin Resistant Enterococcus;Vancomycin-Resistant Enterococci;Analog;Anti-Bacterial;Anti-Microbial;Antibacterial;Antibiotic Resistant;Antimicrobial;Bacterial Antibiotic Resistant;Bacterial Resistance To Antibiotic;Bactericidal;Bactericide;Chemical Structure Function;Combat;Cytotoxic;Cytotoxicity;Design;Designing;Developmental;Dietary Fruit;Drug Candidate;Drug Development;Drug Resistant;Drug/Agent;Experiment;Experimental Research;Experimental Study;Fighting;Heavy Metal Pb;Heavy Metal Lead;Improved;In Vitro Assay;In Vivo;Inhibitor;Inhibitor/Antagonist;Innovate;Innovation;Innovative;Interest;Living System;Meetings;Methicillin Resistant;Methicillin Resistant Staphylococcus Aureus (Organism);Novel;Pathogen;Pathway;Pre-Clinical;Preclinical;Programs;Research Study;Resistance Mechanism;Resistance To Drug;Resistant;Resistant Mechanism;Resistant To Drug;Sac Fungi;Scaffold;Scaffolding;Screening;Screenings;Side Effect;Structure Function Relationship;Therapy Adverse Effect;Treatment Adverse Effect
