The world market for antimicrobial drugs is over $42 billion, and represents 5% of the global pharmaceutical market with a 4% annual growth rate over the past 5 years. A growing component of this market is for therapies targeting drug-resistant organisms, for which methicillin-resistant Staphylococcus aureus (MRSA) is a major and increasing portion. Multiply-resistant bacterial pathogens cause serious community and hospital- acquired infections with around 500,000 hospitalizations annually in the US of which MRSA now accounts for over 60% and results in over 19,000 deaths. As a result, the disease burden caused by S. aureus and MRSA infections has been reported to account for $25 to 34 billion dollars in healthcare costs annually, indicating a huge market for effective therapeutics. Therefore, new therapeutic options for treatment of infections caused by multi-drug resistant S. aureus are urgently needed. HAMLET (human alpha-lactalbumin made lethal to tumor cells), is a protein-lipid complex from human milk with both tumoricidal and bactericidal activities. Preliminary evidence have shown that HAMLET acts as an antimicrobial adjuvant that can increase the activity of a broad spectrum of antibiotics (methicillin, vancomycin, gentamicin and erythromycin) against several different bacterial species, including multi-drug resistant S. aureus, to a level where they become sensitive to those same antibiotics both in vitro and in vivo. There is no such adjuvant therapy on the market. Importantly, HAMLET inhibits the increased resistance of methicillin seen under antibiotic pressure and the bacteria do not become resistant to the adjuvant, which is a major advantage of the molecule. Finally, HAMLET is a human milk protein fed to infants and has been used safely for other purposes in human patients, highlighting the increased chance of success for the development pathway for HAMLET as a novel and safe antimicrobial adjuvant. The objective of the proposed research is to validate HAMLET's antibiotic potentiation effect for formerly effective and safe antibiotics on collection both nosocomial and community-acquired S. aureus strains in vitro during the R21 phase of the program. Additionally, during this phase we will validate that decreased resistance development towards vancomycin is seen in the presence of HAMLET as we have observed for methicillin. In parallel, optimization of production of HAMLET for commercial purposes will be conducted. The R33 phase of the program will scale up HAMLET production and test HAMLET/antibiotic combinations with best results in vitro for proof of principle in in vivo models to treat wound infections and pneumonia caused by drug resistant S. aureus strains. Addition of a potent new weapon against multidrug resistant infections to the diminishing arsenal of antimicrobials active against these organisms will benefit the lives of hundreds of millions of people.
The project proposed herein advances the development of HAMLET, a protein-lipid complex from human milk, with high safety profile, which can sensitize both Gram-positive and Gram-negative organisms to various classes of antibiotics. This novel therapeutic molecule can act as an adjuvant in combination with formerly effective and safe antibiotics for the treatment of methicillin-resistant and vancomycin intermediate Staphylococcus aureus (MRSA and VISA) infection, which will be validated in this project by showing HAMLET's antibiotic potentiation effect using relevant in vitro assays and in vivo mice models. Addition of potent new weapon against multidrug resistant infections to the diminishing arsenal of antimicrobials active against these organisms will benefit the lives of hundreds of millions of people.