Breakthroughs in the development of antibiotics, antifungals and antiparasitics targeting the pathogens’ respiratory chain

The aerobic respiratory chain is vital to bacterial and eukaryotic cell energy transformation. Embedded in the mitochondrial inner membrane and the bacterial plasma membrane, the respiratory chain couples sequential redox reactions with ion pumping, thereby generating the motive force that is used to drive ATP synthesis. Due to the essential role of oxidative phosphorylation in cellular life, the electron transport chain proteins, their cofactors, and ATP synthase components serve as a target for antibacterial, antifungal, and antiparasitic drugs. Whether by (1) inhibition of electron flow through transport chain complexes, (2) collapsing of the motive force, (3) competitive inhibition, or (4) blocking proton flow through the catalytic subunits of ATP synthase, small molecules can selectively inhibit bacterial, fungal, and parasitic life while not showing high toxicity in mammalian systems. Because of robust antimicrobial resistance against the traditional mechanisms of microbial control (cell wall integrity, protein synthesis, nucleotide and nucleic acid synthesis, etc.), the study of alternative targets, such as the respiratory chain, is prudent and timely. This review summarizes the current research on small molecule and peptide inhibition of the aerobic respiratory chain complexes, electron flow, and ion translocation in a series of human and plant pathogens.