Compositions and methods for reducing bacterial aggregation
The present disclosure relates to compositions and methods for inhibiting bacterial aggregation, and in particular, to compositions and methods that inhibit autotransporter-mediated bacterial aggregation or attachment. Described herein are autotransporter binding molecules such as antibodies and antigen binding fragments thereof. The autotransporter binding molecules block self-association between autotransporters and autotransporter-mediated surface attachment.
1. An isolated antibody or antigen binding fragment thereof comprising:
a) a CDRH1 comprising the sequence set forth in SEQ ID NO: 3;
a CDRH2 comprising the sequence set forth in SEQ ID NO: 4;
a CDRH3 comprising the sequence set forth in SEQ ID NO: 5;
a CDRL1 comprising the sequence set forth in SEQ ID NO: 6;
a CDRL2 comprising the sequence set forth in SEQ ID NO: 7; and
a CDRL3 comprising the sequence set forth in SEQ ID NO: 8; or
b) a CDRH1 comprising the sequence set forth in SEQ ID NO: 15;
a CDRH2 comprising the sequence set forth in SEQ ID NO: 16;
a CDRH3 comprising the sequence set forth in SEQ ID NO: 17;
a CDRL1 comprising the sequence set forth in SEQ ID NO: 18;
a CDRL2 comprising the sequence set forth in SEQ ID NO: 19; and
a CDRL3 comprising the sequence set forth in SEQ ID NO: 20.
2. The isolated antibody or antigen binding fragment thereof of claim 1 , further comprising:
a) a heavy chain variable region (VH) comprising the sequence set forth in SEQ ID NO: 9 or a sequence having at least 90% identity to SEQ ID NO: 9, and a light chain variable region (VL) comprising the sequence set forth in SEQ ID NO: 10 or a sequence having at least 90% identity to SEQ ID NO: 10; or
b) a VH comprising the sequence set forth in SEQ ID NO: 21 or a sequence having at least 90% identity to SEQ ID NO: 21, and a VL comprising the sequence set forth in SEQ ID NO: 22 or a sequence having at least 90% identity to SEQ ID NO: 22.
3. The isolated antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment binds to Ag43a (SEQ ID NO: 1) at an epitope comprising one or more residues selected from the group consisting of N83, R113, N114, D133, N150, T151, T152, G169, R254, E270, T291, T310, R330, G332, A333, 5335, T361, N362, R364, T380, T381, S383, N386, S399, T401, D404 and G405.
4. The isolated antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment a) specifically binds to an autotransporter or b) reduces binding of one autotransporter molecule to another autotransporter molecule.
5. An isolated nucleic acid encoding a) the antibody or antigen binding fragment thereof of claim 1 or b) the VH or the VL of the antibody or antigen binding fragment thereof.
6. An isolated nucleic acid encoding a) the antibody or antigen binding fragment thereofof claim 2 or b) the VH or VL of the antibody or antigen binding fragment thereof.
7. An isolated expression vector comprising the isolated nucleic acid of claim 5 or 6 .
8. A host cell comprising the isolated nucleic acid of claim 5 or 6 .
9. A method comprising culturing the host cell of claim 8 under conditions that allow production of the antibody or antigen binding fragment, or VH or VL of the antibody or antigen binding fragment, and purifying the antibody or antigen binding fragment, or VH or VL of the antibody or antigen binding fragment, from the host cell.
10. A composition comprising the isolated antibody or antigen binding fragment thereof of claim 1 and an antibiotic agent.
11. A method of reducing aggregation of two or more bacteria the method comprising contacting the two or more bacteria with an effective amount of the antibody or antigen binding fragment thereof of claim 1 .
12. A method of inhibiting interaction between two or more autotransporter molecules the method comprising contacting at least one of said two or more autotransporter molecules with the antibody or antigen binding fragment thereof of claim 1 .
13. A method of treating a bacterial infection in a subject, the method comprising administering to the subject a therapeutically effective amount of the antibody or antigen binding fragment thereof of claim 1 .
14. A method of treating a disease or disorder associated with a bacterial infection in a subject the method comprising administering to the subject a therapeutically effective amount of the antibody or antigen binding fragment thereof of claim 1 .