Inhibitors of ATP Synthase as New Antibacterial Candidates

Abstract

ATP, the power of all cellular functions, is constantly used and produced by cells. The enzyme called ATP synthase is the energy factory in all cells, which produces ATP by adding inorganic phosphate (Pi) to ADP. It is found in the inner, thylakoid and plasma membranes of mitochondria, chloroplasts and bacteria, respectively. Bacterial ATP synthases have been the subject of multiple studies for decades, since they can be genetically manipulated. With the emergence of antibiotic resistance, many combinations of antibiotics with other compounds that enhance the effect of these antibiotics have been proposed as approaches to limit the spread of antibiotic-resistant bacteria. ATP synthase inhibitors, such as resveratrol, venturicidin A, bedaquiline, tomatidine, piceatannol, oligomycin A and N,N-dicyclohexylcarbodiimide were the starting point of these combinations. However, each of these inhibitors target ATP synthase differently, and their co-administration with antibiotics increases the susceptibility of pathogenic bacteria. After a brief description of the structure and function of ATP synthase, we aim in this review to highlight therapeutic applications of the major bacterial ATP synthase inhibitors, including animal's venoms, and to emphasize their importance in decreasing the activity of this enzyme and subsequently eradicating resistant bacteria as ATP synthase is their source of energy.

Keywords: ATP synthase; ATP synthase inhibitors; animal venoms; resistant bacteria; therapeutic application.

Figure 1

Simplified comparison between bacterial and mitochondrial ATPases. (a) Bacterial ATPase: comprised of two subunits: F0, inserted in the membrane, and F1, which is present in the bacterial cytoplasm; (b) Bovine mitochondrial ATPase: also comprised of a membrane-inserted F0 and an F1 subunit situated in the mitochondrial matrix. The mitochondrial ATPase is more complex than the bacterial enzyme. Made with BioRender.

Figure 2

Simplified ATP synthase mechanism of action. This figure shows the two functions of ATP synthase, represented as different shapes, synthesis and hydrolysis of ATP. Made with BioRender.

Figure 3

Chemical structure of 3 chemical inhibitors: (a) Piceatannol, (b) Bedaquiline and (c) Tomatidine. Made with BioRender.

Figure 4

Bacterial ATP synthase composition and the subunit targeted by some inhibitors. ATP synthase represents the typical structure identified in bacteria. The number of monomers in c-ring differs between organisms. The inhibitory sites of each inhibitor are showed in red. Made with BioRender.