Molecular Targets for Antibody-Based Anti-Biofilm Therapy in Infective Endocarditis

Abstract

Infective endocarditis (IE) is a heart disease caused by the infection of heart valves, majorly caused by Staphilococcus aureus. IE is initiated by bacteria entering the blood circulation in favouring conditions (e.g., during invasive procedures). So far, the conventional antimicrobial strategies based on the usage of antibiotics remain the major intervention for treating IE. Nevertheless, the therapeutic efficacy of antibiotics in IE is limited not only by the bacterial drug resistance, but also by the formation of biofilms, which resist the penetration of antibiotics into bacterial cells. To overcome these drawbacks, the development of anti-biofilm treatments that can expose bacteria and make them more susceptible to the action of antibiotics, therefore resulting in reduced antimicrobial resistance, is urgently required. A series of anti-biofilm strategies have been developed, and this review will focus in particular on the development of anti-biofilm antibodies. Based on the results previously reported in the literature, several potential anti-biofilm targets are discussed, such as bacterial adhesins, biofilm matrix and bacterial toxins, covering their antigenic properties (with the identification of potential promising epitopes), functional mechanisms, as well as the antibodies already developed against these targets and, where feasible, their clinical translation.

Keywords: antibiotic resistance; antibodies; biofilms; epitopes; immunotherapy; infective endocarditis.

Figure 1

The local spreading of IE infection. IE originates from the aortic valve and can spread to the ventricular wall (A) and atrium wall (B). Adapted with permission from Thiene and Basso [16]. 2006, Elsevier.

Figure 2

The molecular mechanisms of biofilm formation. Attachment (a), biofilm formation (b), maturation (c) and dispersion (d). Adapted from Jiang et al. [34]. The different colours and shapes model the different bacterial cells composing the biofilm.

Figure 3

The antibodies against biofilm can disrupt ongoing biofilm formation and/or disperse established biofilms by different mechanisms: (A) neutralisation, (B) opsonophagocytosis, (C) complement activation and (D) destabilisation of biofilm matrix. Adapted with permission from Raafat et al. [42]. 2019, Elsevier.

Figure 4

Potential molecular targets involved in Staphylococcus biofilm formation. The biofilm could be disrupted by generating antibodies against functional proteins involved in each stage of biofilm formation. Adapted with permission from Raafat et al. [42]. 2019, Elsevier.

Figure 5

The protein structure of ClfA and its functional mechanism. (A) From the N- to C- terminus, ClfA is composed of signal sequence (S), A region with subdomains N1, N2 and N3, repeated serine-aspartate residues (Sdr) region, wall spanning (W) region, LPXTG motif (LPXTG) and sorting sequence (M). The binding site of Fg is between N2 (green) and N3 (yellow). (B) The γ-chain of Fg (red) binds to the trench between N2 and N3. Adapted from Herman-Bausier et al. [97].

Figure 6

Domain organisation of FnBPA and FnBPB. From the N- to C- terminus, the FnBPs are composed of signal sequence (S), A domain with subdomains N1, N2 and N3, repeat region that is an unstructured region consisting of tandemly arranged motifs (11 in FnBPA and 10 in FnBPB), proline repeated region (PRR), wall-spanning (W) region, LPXTG motif (LPXTG) and sorting sequence (SS). Adapted with permission from O’Neill et al. [54]. 2008, American Society for Microbiology.

Figure 7

Chemical structure of PNAG (top) and the Ica system (bottom), which is responsible for the synthesis, translocation and deacetylation of PNAG. Adapted with permission from Nguyen et al. [119]. 2020, Elsevier.

Figure 8

The overall interactions between F598 antigen-binding fragment (Fab)–GlcNAc and Fab–9NAc crystal structures. Fabs are depicted as thin sticks for the L (blue) and H (magenta) chains. Carbohydrate ligands are shown as thicker sticks with carbon atoms of GlcNAc in green and 9NAc in yellow. Adapted with permission from Soliman et al. [128]. 2014, IUCr.

Figure 9

HU structure and the arginine residues involved in its DNA-binding site. (A) Ribbon diagram of the SHU homodimer. The α–helices, β–sheets and the N– and C–termini are labelled. The residue Arg55 is labelled in a circle. (B) The flexible β–ribbon arms deviate with a distance of 18.4 Å and with a bending angle of approximately 44.9°. (C) The binding free energies in the SHU–DNA complex, as determined by MD simulation. The three Arg residues (Arg53, Arg55 and Arg61) that show low free energies are marked with red points. Adapted from Kim et al. [139].

Figure 9

HU structure and the arginine residues involved in its DNA-binding site. (A) Ribbon diagram of the SHU homodimer. The α–helices, β–sheets and the N– and C–termini are labelled. The residue Arg55 is labelled in a circle. (B) The flexible β–ribbon arms deviate with a distance of 18.4 Å and with a bending angle of approximately 44.9°. (C) The binding free energies in the SHU–DNA complex, as determined by MD simulation. The three Arg residues (Arg53, Arg55 and Arg61) that show low free energies are marked with red points. Adapted from Kim et al. [139].

Figure 10

The structure of AT heptameric complex. Adapted from Oscherwitz et al. [141].

Figure 11

Interface between MEDI4893 HC (green) and AT (olive) (A) and MEDI4893 LC (blue) and AT (olive) (B). Both HC and LC are in close contact with the rim of AT and create several hydrogen bonds (dotted lines) and one stacking interaction between MEDI4893 Fab Trp32 (LC) and AT Trp187. AT residues in contact with MEDI4893 are shown in orange. Adapted from Oganesyan et al. [86].

Figure 12

Superimposition of monomeric AT bound to MEDI4893 Fab (green) with monomeric AT bound to mAb LTM14 (PDB code 4IDJ, blue). Both Fab molecules bind to the same rim domain, though on opposite sides. Residues known to be critical for AT interaction with the cell surface receptor are shown as red spheres. Adapted from Oganesyan et al. [86].