Terminal Respiratory Oxidases: A Targetables Vulnerability of Mycobacterial Bioenergetics?

Abstract

Recently, ATP synthase inhibitor Bedaquiline was approved for the treatment of multi-drug resistant tuberculosis emphasizing the importance of oxidative phosphorylation for the survival of mycobacteria. ATP synthesis is primarily dependent on the generation of proton motive force through the electron transport chain in mycobacteria. The mycobacterial electron transport chain utilizes two terminal oxidases for the reduction of oxygen, namely the bc1-aa3 supercomplex and the cytochrome bd oxidase. The bc1-aa3 supercomplex is an energy-efficient terminal oxidase that pumps out four vectoral protons, besides consuming four scalar protons during the transfer of electrons from menaquinone to molecular oxygen. In the past few years, several inhibitors of bc1-aa3 supercomplex have been developed, out of which, Q203 belonging to the class of imidazopyridine, has moved to clinical trials. Recently, the crystal structure of the mycobacterial cytochrome bc1-aa3 supercomplex was solved, providing details of the route of transfer of electrons from menaquinone to molecular oxygen. Besides providing insights into the molecular functioning, crystal structure is aiding in the targeted drug development. On the other hand, the second respiratory terminal oxidase of the mycobacterial respiratory chain, cytochrome bd oxidase, does not pump out the vectoral protons and is energetically less efficient. However, it can detoxify the reactive oxygen species and facilitate mycobacterial survival during a multitude of stresses. Quinolone derivatives (CK-2-63) and quinone derivative (Aurachin D) inhibit cytochrome bd oxidase. Notably, ablation of both the two terminal oxidases simultaneously through genetic methods or pharmacological inhibition leads to the rapid death of the mycobacterial cells. Thus, terminal oxidases have emerged as important drug targets. In this review, we have described the current understanding of the functioning of these two oxidases, their physiological relevance to mycobacteria, and their inhibitors. Besides these, we also describe the alternative terminal complexes that are used by mycobacteria to maintain energized membrane during hypoxia and anaerobic conditions.

Cytochrome bd promotes Escherichia coli biofilm antibiotic tolerance by regulating accumulation of noxious chemicals

“…While our results stand in contrast to the antibiotic resistance phenotype generated by respiratory deficiency in small colony variants described in Staphylococcus aureus and other species 51 , they are consistent with studies in Mycobacterium tuberculosis in which targeting of the electron transport chain is a promising avenue for the development of novel classes of antibiotics 52 , 53 . In recent years two electron transport chain inhibitors—bedaquiline, an ATPase inhibitor, and pretomanid, a nitric oxide donor and respiratory poison—have been approved by the Food and Drug Administration (FDA) for the treatment of multidrug resistant M. tuberculosis 52 , 54 . Additionally, promising results from a phase 2 clinical trial were recently reported for telacebec (Q203), an inhibitor of the terminal cytochrome oxidase supercomplex bc 1 -aa 3 55 .…”

“…Additionally, promising results from a phase 2 clinical trial were recently reported for telacebec (Q203), an inhibitor of the terminal cytochrome oxidase supercomplex bc 1 -aa 3 55 . In addition to the known clinical utility of these agents, preclinical studies have identified numerous small molecule inhibitors of all electron transport chain components (NADH dehydrogenases, succinate dehydrogenases, quinol oxidases, ATPase), some of which are known to eradicate even highly drug resistant isolates 52 , 53 . Although the potential for disrupting energetics as a therapeutic approach has not been thoroughly evaluated outside mycobacterial species, in combination with our findings these studies raise the possibility of inhibiting cytochrome bd to treat or prevent urinary tract infections.…”

“…Although the potential for disrupting energetics as a therapeutic approach has not been thoroughly evaluated outside mycobacterial species, in combination with our findings these studies raise the possibility of inhibiting cytochrome bd to treat or prevent urinary tract infections. Notably, previous work has identified several natural small molecule quinol analogs that serve as potent inhibitors of E. coli quinol oxidases, including several molecules that preferentially inhibit bd- type oxidases 52 , 56 . Importantly, the bd -type oxidases are unique to bacteria, suggesting inhibitors of cytochrome bd could be used clinically to inhibit biofilm formation and potentiate the effects of antibiotics.…”

Structure of Escherichia coli cytochrome bd-II type oxidase with bound aurachin D

“…Aurachins inhibit electron transfer from ubiquinol-8 to heme b 558 by blocking the quinol binding site that is located close to the membrane surface (Fig. 3a, b ) 34 – 37 . Although aurachin C and D bind with high affinity to bd oxidases, a reliable IC 50 value for bd -II has not yet been determined 38 .…”

Recent Advances in Structural Studies of Cytochrome bd and Its Potential Application as a Drug Target

“…The M. tuberculosis electron transport chain has recently gained interest as a target space for next-generation antibacterials [ 91 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 ]. M. tuberculosis possesses a branched aerobic respiratory chain.…”