Use of lysin to restore/augment antibacterial activity in the presence of pulmonary surfactant of antibiotics inhibited thereby
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.
1. A method for treating a subject afflicted with a Gram-negative bacterial infection of respiratory tract tissue in which pulmonary surfactant is present, the method comprising regardless of order the following steps:
a. administering to the subject a first amount of an antibiotic having antibacterial activity against the Gram-negative bacteria responsible for the infection which activity is inhibited by the pulmonary surfactant;
b. co-administering to the subject a second amount of a lysin polypeptide, wherein said lysin polypeptide does not require an exogenously-derived cationic peptide to have activity against the Gram-negative bacteria responsible for the infection;
wherein said first and second amount in combination are effective to kill the Gram-negative bacteria responsible for the infection and thereby treat the infection in the respiratory tract tissue; and
wherein the lysin polypeptide is selected from the group consisting of Gram-negative lysin polypeptides having the sequences SEQ ID NO: 8 (GN4); SEQ ID NO: 12 (FGN4-1); SEQ ID NO: 13 (FGN4-2); SEQ ID NO: 14 (FGN4-3); and SEQ ID NO: 15 (FGN4-4).
2. The method of claim 1 wherein the first amount would be ineffective to treat the infection if the antibiotic were administered as monotherapy.
3. The method of claim 1 wherein the antibiotic is a cyclic lipopeptide or an aminoglycoside.
4. The method of claim 2 wherein the antibiotic is a cyclic lipopeptide.
5. The method of claim 2 wherein the antibiotic is tobramycin.
6. The method of claim 1 wherein the second amount is a subthreshold amount.
7. The method of claim 1 wherein the first amount is a subthreshold amount.
8. The method of claim 1 wherein said lysin polypeptide is administered parenterally or by inhalation.
9. The method of claim 1 wherein said antibiotic is administered orally or parenterally or by inhalation.
10. The method of claim 1 wherein said subject is a mammalian subject.
11. The method of claim 1 wherein the Gram-negative bacteria is Pseudomonas aeruginosa.
12. The method of claim 1 wherein the antibiotic is colistin.
13. The method of claim 1 wherein the antibiotic is tobramycin.
14. A method for treating a subject afflicted with a Gram-negative bacterial infection of the lower respiratory tract in which pulmonary surfactant is present, which subject has already been administered an antibiotic suitable for treating the infection, the method comprising continuing administration of the antibiotic to the subject and commencing co-administration to the subject 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 of the lower respiratory tract of the subject, wherein said lysin polypeptide does not require an exogenously-derived cationic peptide to have activity against the Gram-negative bacterial responsible for the infection; and
wherein the lysin polypeptide is selected from the group consisting of Gram-negative lysin polypeptides having the sequences SEQ ID NO: 8 (GN4); SEQ ID NO: 12 (GN04-1); SEQ ID NO: 13 (FGN4-2); SEQ ID NO: 14 (FGN4-3); and SEQ ID NO: 15 (FNG4-4).
15. The method of claim 1 , wherein the lysin polypeptide further comprises at least one heterologous peptide segment covalently linked to the lysin polypeptide.
16. The method of claim 15 , wherein the at least one heterologous peptide segment is an exogenous antimicrobial peptide.
17. The method of claim 16 , wherein the lysin polypeptide is SEQ ID NO: 11 (PGN4).