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. Over the past several years Promiliad Biopharma has been developing new inhibitors that target the enzyme dihydrofolate reductase as a method of treatment for pathogenic bacteria, fungi and protozoa. Through our efforts and those of our collaborators, largely funded by STTR grants, we have discovered a class of antifolates characterized by a 2, 4- diaminopyrimidine and a biaryl domain linked through a three-atom propargyl bridge. This class of molecules is an important lead in the discovery of a new treatment for infectious disease. The current class of compounds, while potent antibacterial agents with activity against antibiotic resistant pathogens, currently lack sufficient metabolic stability. These compounds have short in vivo (and in vitro) half-lives which make progression to lead compound status somewhat difficult. We have found that by substituting a key fragment of the structure with a non-metabolizable bioisostere we can retain potency against a range of Gram positive pathogens while greatly improving selectivity and metabolic half-life. The goal of this project is o design, synthesize and assay additional bioisosteric analogs which display similar or better improvements in potency, metabolism and physical properties. Our goal in this Phase I application is to obtain a clear lead candidate. A Phase II project continuing from this work would then conduct IND-enabling experiments with the clear goal of filing an IND application.
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 medicinal chemistry we have been able to develop a set of second generation folate antibiotics based upon the structure of trimethoprim. These compounds are active against a range of pathogens including methicillin-resistant Staphylococcus aureus (MRSA). This project seeks to develop a clear lead candidate that will undergo preclinical evaluation with the ultimate goal of entering clinical trials.
Project Terms: analog; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; base; Biological; Biological Assay; Clinical Trials; Communicable Diseases; Data; design; Development; diaminopyrimidine; Dihydrofolate Reductase; Dihydrofolate Reductase Inhibitor; Enzymes; Evaluation; Event; Folate; Folic Acid Antagonists; follow-up; Funding; fungus; Generations; Goals; Grant; Half-Life; improved; In Vitro; in vivo; Infection; infectious disease treatment; inhibitor/antagonist; Lead; Link; Maximum Tolerated Dose; Metabolic; Metabolism; methicillin resistant Staphylococcus aureus (organism); Methods; Modeling; mouse model; novel; novel therapeutics; pathogen; pathogenic bacteria; Pattern; Pharmaceutical Chemistry; Phase; physical property; pre-clinical; preclinical evaluation; Protozoa; public health medicine (field); public health relevance; Relative (related person); research study; Resistance; Resistance profile; screening; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Staphylococcus aureus; Structure; Structure-Activity Relationship; Toxic effect; Trimethoprim; Work
