Development of a Novel Antibiotic Targeting Multi-Drug-Resistant Staphylococcus Aureus
Abstract
Objectives and theoretical reasoning: This project is focused on the development of berkeleylactone A (BA), a novel fungal metabolite recently discovered by researchers at the University of Montana to address the escalating need for new antibiotics to fight the growing threat of multidrug resistance in bacterial infections. BA specifically targets multidrug-resistant S. aureus (MDRSA), including those strains that are resistant to MLSB (macrolides-lincomycin-streptonigrin B) antibiotic agents at clinically relevant levels. However, there are several important preclinical studies and development activities that must be conducted for this compound to join the fight against infectious diseases caused by MDRSA. These studies include compound optimization, in vivo toxicity and efficacy studies, and determination of the mechanism of action. Problem to be addressed: Infectious diseases are the second-leading cause of death worldwide and the third-leading cause of death in the United States. According to the Centers for Disease Control and Prevention, at least two million people are infected with antibiotic-resistant bacteria every year, and over 23,000 die annually as a direct result of these infections. Antibiotic resistance is a growing global threat that desperately requires novel approaches for rapid identification and development of new lead molecules for both military and civilian use in combatting this serious threat. The current proposal will advance a new class of antibiotics and establish the dose, toxicity, and therapeutic efficacy for these compounds. We will identify the most promising molecules and test them in in vitro and in vivo models of disease. What types of patients will be helped: A new, safe and effective treatment for MRSA and other drug-resistant bacteria could change the landscape of available antibiotic treatments and significantly reduce the burden of bacterial infections in both military and civilian populations. Wound infections in deployed personnel have long posed a major challenge for military medicine, and as improvements in the care provided to casualties continue to enhance survival rates, infectious complications, such as those by multidrug-resistant strains of pathogenic bacteria, remain a major cause of morbidity and mortality. Even minor injuries or burns in deployed military personnel can result in severe infections requiring hospitalization, which significantly impact operational readiness. A review of bacterial isolates associated with skin and soft-tissue infections at a Level II military treatment facility in Iraq over a 5-month period showed that 85% of skin abscesses were positive for S. aureus, and 70% were positive for MRSA. Studies have shown that during military training, approximately 5% of all individuals will experience skin and soft-tissue infections, with a strain of MRSA isolated in 70% of these cases. Antibiotic resistance is a growing global threat that desperately requires novel approaches for rapid identification and development of new lead molecules to improve military readiness and combat this growing and serious threat to all deployed personnel. In this application, we propose the development of a newly discovered antibiotic targeting multidrug-resistant bacterial infections of significant concern to both military and civilian populations. Potential clinical applications, benefits, and risks: The candidate drug molecules we are testing and developing are BA analogues. BA targets MDRSA at clinically relevant levels through a potentially novel mechanism of action with no detectable signs of resistance. The key objective of this proposal is to prepare a small targeted library of fully synthetic BA derivatives targeted towards optimizing the safety and efficacy of BA for advancement to human clinical trials. Project timeline: Drug development is a lengthy process. However, data generated from this 2-year award will result in an optimized
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010096
Entities
People
- Andrea Stierle
Organizations
- United States Army
- University of Montana