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Review
. 2021 Feb 3;2(2):387-409.
doi: 10.1039/d0cb00205d. eCollection 2021 Apr 1.

Modulators of protein-protein interactions as antimicrobial agents

Rashi Kahan  1 , Dennis J Worm  1 , Guilherme V de Castro  1 , Simon Ng  1 , Anna Barnard  1
Affiliations
Review

Modulators of protein-protein interactions as antimicrobial agents

Rashi Kahan et al. RSC Chem Biol. .

Abstract

Protein-Protein interactions (PPIs) are involved in a myriad of cellular processes in all living organisms and the modulation of PPIs is already under investigation for the development of new drugs targeting cancers, autoimmune diseases and viruses. PPIs are also involved in the regulation of vital functions in bacteria and, therefore, targeting bacterial PPIs offers an attractive strategy for the development of antibiotics with novel modes of action. The latter are urgently needed to tackle multidrug-resistant and multidrug-tolerant bacteria. In this review, we describe recent developments in the modulation of PPIs in pathogenic bacteria for antibiotic development, including advanced small molecule and peptide inhibitors acting on bacterial PPIs involved in division, replication and transcription, outer membrane protein biogenesis, with an additional focus on toxin-antitoxin systems as upcoming drug targets.

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Conflict of interest statement

There are no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1. (A) Crystal structure (PDB: 1F47) of the C-terminus of E. coli FtsZ (green) bound to E. coli ZipA (magenta). The interaction is driven by a solvent exposed hydrophobic patch (blue surface, right chart) present in ZipA. (B) Crystal structure (PDB: 1Y2F) of inhibitor 1 bound to E. coli ZipA. The compound interacts at the same site as FtsZ (right chart). (C) Chemical structures of FtsZ–ZipA PPI inhibitors.
Fig. 2
Fig. 2. (A) Crystal structure (PDB: 3C94) of E. coli ExoI (magenta) bound to a E. coli SSB Ct peptide (green). ExoI can interact simultaneously with two peptide molecules via the binding sites A (yellow surface) and B (pink surface), as shown in the upper chart. (B) Chemical structures and activity of inhibitors 3 and 4. The E. coli ExoI-bound crystal structures of inhibitors 3 (PDB: 3HP9) and 4 (PDB: 3HL8) are shown in (C) and (D), respectively.
Fig. 3
Fig. 3. Crystal structure (PDB: 3D1E) of the E. coli β-sliding clamp dimer (one monomer is shown in magenta and the second monomer is shown in cyan) bound to the E. coli Pol II C-terminus peptide (green). The binding site is divided into two subsites (1 and 2, shown in yellow and pink, respectively) with the Pol II peptide extending over both regions (right chart).
Fig. 4
Fig. 4. (A) Chemical structures of small molecule and peptidic inhibitors of the β-sliding clamp PPI site. The crystal structures of 5, 6, 8 and 10 bound to the E. coli β-sliding clamp (PDB accession codes 3D1G,3QSB,4PNU and 3Q4L, respectively) are shown in (B), (C), (D) and (E), respectively. Subsites 1 and 2 are shown as yellow and pink surface, respectively, and the remaining regions are shown as magenta surface.
Fig. 5
Fig. 5. (A) Crystal structure of E. coli RNAP holoenzyme (PDB: 4LJZ) with RNAP core enzyme coloured in magenta and σ70 coloured in green. Enlarged picture (right chart) shows the critical interaction of the β′ clamp-helix (CH) region (blue) of RNAP with the N-terminal domain of σ70. (B) Small molecule and peptide inhibitors of RNAP–σ PPI.
Fig. 6
Fig. 6. (A) Crystal structure of the E. coli NusB–NusE complex (PDB: 3D3B) with NusE coloured in green and NusB in magenta. Enlarged picture (right chart) shows the NusB–NusE PPI interface with residues (shown as sticks) H15, R16, D19 and V26 of the α1-helix of NusE interacting with Y18, L22, E75 and E81 of NusB; key hydrogen bonds are indicated by dashed orange lines. (B) Small molecule inhibitors of the NusB–NusE PPI.
Fig. 7
Fig. 7. (A) Crystal structure of the E. coli BamA with the region mimicked by peptide 22 highlighted in magenta (PDB: 5D0Q). (B) Peptide and small molecule inhibitors of the BamA–BamD complex.
Fig. 8
Fig. 8. (A) Compounds targeting PPIs of the Lpt complex. (B) Crystal structure of the E. coli homodimer LptA complex (PDB: 2R1A). (C) NMR solution structure of the E. coli LptA bound to compound 24, the N-terminal β1 strand of LptA binds to the N-terminal β1 strand of 24 in a similar manner to the LptA–LptA binding interface (PDB: 6GD5).
Fig. 9
Fig. 9. (A) Crystal structure (PDB: 4XGQ) of the complex between VapB30 (green) and VapC30 (magenta). A representation of the regions selected for the design of peptides 28 (VapB30 helix α1 mimic), 29 (VapC30 helix α2 mimic) and 30 (VapC30 helix α4 mimic) is shown (B), (C) and (D), respectively.
Fig. 10
Fig. 10. (A) Crystal structure (PDB: 5X3T) of the complex between VapB26 (green) and VapC26 (magenta). A representation of the regions selected for the design of peptides 31 (VapB26 coil mimic), 32 (VapB26 helix α3 mimic), 33 (VapC26 α1 mimic), 34 (VapC26 α3 mimic), 35 (VapC26 α4 mimic), 36 (VapC26 partial α3/α4 mimic) and 37 (VapC26 α3/α4 mimic) is shown in (B), (C), (D), (E), (F), (G) and (H), respectively.
Fig. 11
Fig. 11. (A) Crystal structure (6A7V) of the complex between VapB11 (green) and VapC11 (magenta). A representation of the regions selected for the design of VapB11 peptides 38 (helix α3 mimic), 39 (linker mimic), 40 (linker and helix α4 mimic) and 41 (helix α4 mimic) is shown in (B), (C), (D) and (E), respectively.
Fig. 12
Fig. 12. Crystal structure (PDB: 5YRZ) of the complex between HicA (magenta) and HicB (green) from S. pneumoniae. The region of HicA mimicked by peptide 48 is highlighted in blue.
Fig. 13
Fig. 13. Crystal structure of the E. coli MazEF TA complex (PDB: 1UB4) with MazF toxin monomers shown in magenta and cyan, and MazE antitoxin in green. Enlarged picture (right chart) highlights MazE residues 71–75 (IDWGE, in green) that are crucial for the interaction with MazF (magenta and cyan surfaces represent, respectively, monomers 1 and 2).
Fig. 14
Fig. 14. Crystal structure of MoxT dimer (PDB: 4HKE) with monomers 1 and 2 shown in magenta and cyan, respectively. Interaction sites 1 and 2 are shown as yellow and pink surfaces, respectively.
Fig. 15
Fig. 15. Crystal structure of the E. coli HipAB TA complex bound to DNA (PDB: 3HZI) with HipA toxin monomers shown in magenta and HipB antitoxin monomers shown in green. The DNA and HipA-bound ATP are shown as sticks.
Fig. 16
Fig. 16. Small molecule inhibitors of HipA toxin.
Fig. 17
Fig. 17. (A) Binding interface between the ε antitoxin (green) and the ζ toxin (magenta) observed in the crystal structure of the tetrameric ε2ζ2 complex (PDB: 1GVN). (B) Representation of the regions selected for the design of ζ-derived peptides 74 (helix α1 mimic), 75 (helix α2 mimic) and 76 (helix α3 mimic).
Fig. 18
Fig. 18. (A) Crystal structure (PDB: 4R1D) of P. aeruginosa TplEi (green) in complex with P. aeruginosa TplE (magenta). The antitoxin TplEi can be subdivided in two domains (I and II), with TplE helices α1 and α2 (blue) shown to interact with domain II. (B) Crystal structure (PDB: 5H7Y) of P. aeruginosa TplE-derived L-peptide 78 (magenta) bound to P. aeruginosa TplEi (green).
None
Rashi Kahan
None
Dennis J. Worm
None
Guilherme V. de Castro
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Simon Ng
None
Anna Barnard
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