Multimodal antimicrobial therapy

Inventors

Fischer, Gerald W. • Schuman, Richard F.

Assignees

Longhorn Vaccines and Diagnostics LLC

Abstract

The present invention is directed to compositions and methods for preventing and/or treating diseases and disorders of patients caused by non-Staphylococcal microorganisms. In particular, compositions and methods contain lysostaphin, altered forms of lysostaphin as compared to wild-type, and synergistic combinations of lysostaphin plus additional conventional treatments such as other enzyme, antibiotic and/or antibody treatment. The invention is also directed to detecting and identifying altered forms of lysostaphin that possess increased efficacy against infections as compared to wild-type lysostaphin, and forms that generate a minimal or no immune response in a patient. The invention is also directed to method of manufacturing lysostaphin and altered forms of lysostaphin, and compositions that direct the lysostaphin to the site of the infection such as aerosolized nanoparticles.

Core Innovation

The invention relates to a multimodal antimicrobial therapy for preventing or treating non-Staphylococcal infections using lysostaphin, including wild-type lysostaphin and altered and/or recombinant forms. The disclosed approach emphasizes lysostaphin as a glycyl-glycine endopeptidase that enzymatically targets the pentaglycine bridge for antimicrobial activity, and focuses on Mycobacteria, including Mycobacterium tuberculosis, as a target area beyond Staphylococcus.

A key aspect is synergistic combination therapy in which the glycyl-glycine endopeptidase acts synergistically with an anti-Mycobacterial compound and optionally with antibodies against Mycobacteria. The anti-Mycobacterial compound is selected from cycloserine, isoniazid, and ethambutol, and the document also describes synergy with conventional treatments including additional antibiotics and antibodies.

The invention further provides that the encapsulated enzyme composition is biodegradable and provides slow-release or timed-release when administered to a patient. Delivery and formulation options described include encapsulation/biodegradable slow or timed release, aerosolized nanoparticles to lungs, coating objects or catheters, and targeting using lysostaphin coupled to an antibody for site-directed release.

The disclosure also describes generating altered lysostaphin forms via culture/selection and/or recombinant methods to increase efficacy and minimize immune response, including comparisons of immunogenicity and binding between recombinant versus natural lysostaphin forms.

Claims Coverage

The independently claimed subject matter centers on a pharmaceutical composition with a recombinantly engineered glycyl-glycine endopeptidase, an anti-Mycobacterial compound that synergizes with the enzyme, and antibodies against Mycobacteria, with an encapsulated biodegradable slow- or timed-release format. The main inventive features described in the independent claim are reinforced by dependent claim refinements including reduced immune response relative to wild-type lysostaphin, antibody specificity to Mycobacterium tuberculosis, identification of the enzyme as lysostaphin, equivalence to wild-type lysostaphin from Staphylococcus staphylolyticus, and specified pharmaceutically acceptable carrier/excipient options.

Overall, the claim set is directed to an encapsulated biodegradable pharmaceutical composition that combines a recombinantly engineered glycyl-glycine endopeptidase with an anti-Mycobacterial compound selected from cycloserine, isoniazid, and ethambutol acting synergistically, together with antibodies against Mycobacteria, and provides slow-release or timed-release upon administration. Dependent coverage further narrows immune response relative to wild-type lysostaphin, specifies antibody targeting including Mycobacterium tuberculosis, identifies the enzyme as lysostaphin, includes engineered equivalence to wild-type lysostaphin from Staphylococcus staphylolyticus, and expands carrier/excipient options.

Stated Advantages

Documented Applications