Use of lysin to restore/augment antibacterial activity in the presence of pulmonary surfactant of antibiotics inhibited thereby
Inventors
Wittekind, Michael • Schuch, Raymond
Assignees
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Publication Number
US-12144845-B2
Publication Date
2024-11-19
Expiration Date
Abstract
The present disclosure relates to methods for restoring or augmenting bactericidal activity of an antibiotic in an organ or tissue in which pulmonary surfactant is present. More specifically, the present disclosure describes that inhibition of antibiotics due to environmental factors, such as the presence of pulmonary surfactant in an organ or tissue such as the respiratory epithelium can be sidestepped or overcome and the effectiveness of the antibiotic in that milieu restored or augmented by co-administration of an antibiotic and a lysin.
Core Innovation
The disclosure addresses loss of bactericidal antibiotic activity in pulmonary-surfactant-containing tissues. It describes that pulmonary surfactant inhibits the activity of antibiotics, including daptomycin, tobramycin, and colistin, particularly in respiratory infection contexts.
The core concept is co-administration of a lysin polypeptide with an antibiotic whose activity is inhibited by pulmonary surfactant, such that the combination restores bactericidal activity and treats the infection. The disclosure describes synergy between CF-301 lysin (PlySs2) and daptomycin to re-enable daptomycin activity against Staphylococcus aureus strains including MRSA, MSSA, and VISA, including effects consistent with restored drug function in the presence of surfactant.
The disclosure further supports this approach with stated experimental support, including reduced MIC and combination MIC reductions, promoted antibiotic binding in surfactant, reduced biofilm-like structures, and improved murine pneumonia survival in a Staphylococcus aureus pneumonia model. It also lists lysin candidates including CF-301 and other lysins and artenylsin GN-series, including GN37, GN2, GN14, and GN43, mapped to respiratory infection contexts.
Additional embodiments are described across Gram-positive and Gram-negative respiratory infections and polymicrobial disease, including mention of Gram-negative pathogens such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. The approach is framed around restoring or augmenting bactericidal antibiotic activity in pulmonary-surfactant-containing tissues by co-administering a lysin with the surfactant-inhibited antibiotic.
Claims Coverage
The provided claim set includes 2 independent claims. Both claim methods for treating Gram-negative bacterial infections in pulmonary-surfactant-present tissues using co-administration of a surfactant-inhibited antibacterial antibiotic with a lysin polypeptide defined by selected sequences.
Co-administering a pulmonary-surfactant inhibited antibiotic with a sequence-selected lysin polypeptide
Administering an antibiotic having antibacterial activity against the Gram-negative bacteria responsible for the infection, the antibiotic activity being inhibited by pulmonary surfactant, and co-administering a lysin polypeptide such that the antibiotic and lysin polypeptide in combination are effective to kill the Gram-negative bacteria responsible for the infection and thereby treat the infection; wherein the lysin polypeptide comprises the sequences selected from SEQ ID NO: 6 (GN37); SEQ ID NO: 7 (GN2); SEQ ID NO: 9 (GN14); or SEQ ID NO: 10 (GN43).
Restoring bactericidal activity of an already-administered antibiotic by commencing lysin co-administration
For a subject afflicted with Gram-negative bacterial infection of the lower respiratory tract in which pulmonary surfactant is present and where the subject has already been administered an antibiotic suitable for treating the infection, continuing administration of the antibiotic and commencing co-administration of a bactericidal activity-restoring amount of a lysin polypeptide having activity against the Gram-negative bacteria responsible for the infection in the subject and thereby restoring bactericidal activity of the antibiotic against the Gram-negative bacteria responsible for the infection; wherein the lysin polypeptide comprises the sequences selected from SEQ ID NO: 6 (GN37); SEQ ID NO: 7 (GN2); SEQ ID NO: 9 (GN14); or SEQ ID NO: 10 (GN43).
Across the two independent claims, the coverage centers on restoring effective bactericidal activity against Gram-negative bacteria in pulmonary-surfactant-present tissues by combining an antibiotic whose activity is inhibited by pulmonary surfactant with a lysin polypeptide comprising selected GN sequences, including either co-administration or commencing lysin co-administration while continuing an already-administered antibiotic.
Stated Advantages
Restoring bactericidal activity of the antibiotic against the Gram-negative bacteria responsible for the infection.
Treating the infection by effective killing of the Gram-negative bacteria responsible for the infection using the antibiotic-lysin combination.
Documented Applications
Treating a subject afflicted with Gram-negative bacterial infection of an organ or tissue in which pulmonary surfactant is present.
Treating a subject afflicted with Gram-negative bacterial infection of the lower respiratory tract in which pulmonary surfactant is present, including where the subject has already been administered an antibiotic and lysin co-administration is commenced to restore bactericidal activity.
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