Protein-protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

Abstract

Antibiotics are potent pharmacological weapons against bacterial infections; however, the growing antibiotic resistance of microorganisms is compromising the efficacy of the currently available pharmacotherapies. Even though antimicrobial resistance is not a new problem, antibiotic development has failed to match the growth of resistant pathogens and hence, it is highly critical to discover new anti-infective drugs with novel mechanisms of action which will help reducing the burden of multidrug-resistant microorganisms. Protein-protein interactions (PPIs) are involved in a myriad of vital cellular processes and have become an attractive target to treat diseases. Therefore, targeting PPI networks in bacteria may offer a new and unconventional point of intervention to develop novel anti-infective drugs which can combat the ever-increasing rate of multidrug-resistant bacteria. This review describes the progress achieved towards the discovery of molecules that disrupt PPI systems in bacteria for which inhibitors have been identified and whose targets could represent an alternative lead discovery strategy to obtain new anti-infective molecules.

Keywords: new antibiotics; protein–protein interactions; resistance.

Figure 1

Illustration of a PPI modulator (stabilizer or inhibitor) vs a traditional drug target.

Figure 2

Examples of protein–protein interaction modulators in clinical trials or in clinical use.

Figure 3

Small-molecule inhibitors of PPIs in the β-sliding clamp.

Figure 4

Crystal structure of the RU7 (9)-sliding clamp complex (PDB code 3D1G; adapted from Georgescu et al. [58]). Essential residues R152, M362, S346 and R246 are highlighted (sticks).

Figure 5

Peptidic inhibitors of PPIs in the sliding clamp.

Figure 6

SSB protein–protein interaction inhibitors identified by HTS.

Figure 7

SSB protein–protein interaction inhibitors identified by FBDD.

Figure 8

Examples of molecules that disrupt the ZipA/FtsZ interaction.

Figure 9

Inhibitors of the NusB/NusE interaction.