Abstract
The influence of carbon metabolism on oxidative phosphorylation is poorly understood in mycobacteria. M. tuberculosis expresses two respiratory terminal oxidases, the cytochrome bc1:aa3 and the cytochrome bd oxidase, which are jointly required for oxidative phosphorylation and mycobacterial viability. The essentiality of the cytochrome bc1:aa3 for optimum growth is illustrated by its vulnerability to chemical inhibition by the clinical drug candidate Q203 and several other chemical series. The cytochrome bd oxidase is not strictly essential for growth but is required to maintain bioenergetics when the function of the cytochrome bc1:aa3 is compromised. In this study, we observed that the potency of drugs targeting the cytochrome bc1:aa3 is influenced by carbon metabolism. The efficacy of Q203 and related derivatives was alleviated by glycerol supplementation. The negative effect of glycerol supplementation on Q203 potency correlated with an upregulation of the cytochrome bd oxidase-encoding cydABDC operon. Upon deletion of cydAB, the detrimental effect of glycerol on the potency of Q203 was abrogated. The same phenomenon was also observed in recent clinical isolates, but to a lesser extent compared to the laboratory-adapted strain H37Rv. This study reinforces the importance of optimizing in vitro culture conditions for drug evaluation in mycobacteria, a factor which appeared to be particularly essential for drugs targeting the cytochrome bc1:aa3 terminal oxidase.
Highlights
Mycobacterium tuberculosis is a heterotrophic bacterium capable of deriving energy from a wide array of carbon sources when grown in artificial culture broth media[1,2,3,4,5]
We show that the potency of drugs targeting the cytochrome bc1:aa[3] are modulated by carbon catabolism and the composition of the culture broth medium
Glycerol supplementation interferes with the potency of drugs targeting the Cyt-bc1:aa[3] in mycobacteria
Summary
Received: 12 December 2018 Accepted: 23 May 2019 Published: xx xx xxxx the cytochrome bc1:aa[3] in Mycobacterium tuberculosis. We observed that the potency of drugs targeting the cytochrome bc1:aa[3] is influenced by carbon metabolism. In addition of the FOF1 ATP synthase, type II NADH dehydrogenases[23,24], the menaquinone biosynthetic pathway[25,26], and the cytochrome bc1:aa[3] terminal oxidase[27,28,29] are chemically-validated drug targets in M. tuberculosis. Glycerol supplementation in the widely used 7H9 broth medium had a detrimental effect on the potency of the imidazopyridine carboxamide Q203 and ND-1088530, another in vivo active imidazopyridine carboxamide under study This phenomenon was explained by a significant up-regulation of the Cyt-bd terminal oxidase that diminishes the potency of cytochrome bc1:aa[3] inhibitors by providing an alternate respiratory route
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
