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.

Insights into the potential dual-antibacterial mechanism of Kelisha capsule on Escherichia coli

“…Due to the different structures of ATP synthase between bacteria and mammalian [ 68 ], selectively targeting bacterial ATP synthase offers a safe and effective antibacterial approach that does not harm mammalian cells. Betaquiline is a successful ATP synthase inhibitor against multi-drug-resistant (MDR) and extensively drug-resistant (XDR) strains without causing toxic effects on ATP production in mammalian cells [ 20 , 69 ]. Developing ATP synthase inhibitors is therefore viewed as a promising potential solution to overcome drug resistance.…”

“…Affecting the energy metabolism process is another way for TCM to inhibit bacteria. Bacterial ATP synthase is a potential therapeutic target for developing a new solution to treat bacterial infections [ 20 ]. ATP synthase, also called F 0 F 1 ATP synthase, plays a vital role in cellular bioenergetics by facilitating the production of ATP from ADP and inorganic phosphate (Pi) [ 21 ].…”

Deciphering the Intracellular Action of the Antimicrobial Peptide A11 via an In-Depth Analysis of Its Effect on the Global Proteome of Acinetobacter baumannii

“…ATP synthases, also known as F0F1-ATPases, are enzyme complexes that catalyze the synthesis of ATP from ADP and phosphate. 68,69 A previous study indicated that F0F1-ATPase is a promising target for the development of novel therapeutics for combating A. baumannii infections. Indeed, the F0F1-ATPase structure and function are largely conserved across bacteria, including Escherichia coli (the most studied model) and A. baumannii.…”

State-of-the-art strategies to prioritize Mycobacterium tuberculosis drug targets for drug discovery using a subtractive genomics approach

“…All bacteria use ATP as their primary source of energy (Mackieh et al, 2023). ATP production differs significantly amongst bacteria.…”